Isaac Brownell

The Abscopal Effect Associated With a Systemic Anti-melanoma Immune Response

The clearance of nonirradiated tumors after localized radiation therapy is known as the abscopal effect. Activation of an antitumor immune response has been proposed as a mechanism for the abscopal effect. Here we report a patient with metastatic melanoma who received palliative radiation to his primary tumor with subsequent clearance of all his nonirradiated in-transit metastases. Anti-MAGEA3 antibodies were found upon serological testing, demonstrating an association between the abscopal effect and a systemic antitumor immune response. A brain recurrence was then treated with a combination of stereotactic radiosurgery and immunotherapy with ipilimumab. The patient experienced a complete remission that included resolution of nodal metastases, with a concomitant increase in MAGEA3 titers and a new response to the cancer antigen PASD1. This case supports the immune hypothesis for the abscopal effect, and illustrates the potential of combining radiotherapy and immunotherapy in the treatment of melanoma.

Hedgehog signaling regulates the generation of ameloblast progenitors in the continuously growing mouse incisor

In many organ systems such as the skin, gastrointestinal tract and hematopoietic system, homeostasis is dependent on the continuous generation of differentiated progeny from stem cells. The rodent incisor, unlike human teeth, grows throughout the life of the animal and provides a prime example of an organ that rapidly deteriorates if newly differentiated cells cease to form from adult stem cells. Hedgehog (Hh) signaling has been proposed to regulate self-renewal, survival, proliferation and/or differentiation of stem cells in several systems, but to date there is little evidence supporting a role for Hh signaling in adult stem cells. We used in vivo genetic lineage tracing to identify Hh-responsive stem cells in the mouse incisor and we show that sonic hedgehog (SHH), which is produced by the differentiating progeny of the stem cells, signals to several regions of the incisor. Using a hedgehog pathway inhibitor (HPI), we demonstrate that Hh signaling is not required for stem cell survival but is essential for the generation of ameloblasts, one of the major differentiated cell types in the tooth, from the stem cells. These results therefore reveal the existence of a positive-feedback loop in which differentiating progeny produce the signal that in turn allows them to be generated from stem cells.

Role of canonical Wnt signaling/β-catenin via Dermo1 in cranial dermal cell development

Cranial dermis develops from cephalic mesoderm and neural crest cells, but what signal(s) specifies the dermal lineage is unclear. Using genetic tools to fate map and manipulate a cranial mesenchymal progenitor population in the supraorbital region, we show that the dermal progenitor cells beneath the surface ectoderm process canonical Wnt signaling at the time of specification. We show that Wnt signaling/β-catenin is absolutely required and sufficient for Dermo1 expression and dermal cell identity in the cranium. The absence of the Wnt signaling cue leads to formation of cartilage in craniofacial and ventral trunk regions at the expense of dermal and bone lineages. Dermo1 can be a direct transcription target and may mediate the functional role of Wnt signaling in dermal precursors. This study reveals a lineage-specific role of canonical Wnt signaling/β-catenin in promoting dermal cell fate in distinct precursor populations.

Increased Malignancy Risk in the Cutaneous T-Cell Lymphoma Patient Population

BACKGROUNDnCutaneous T-cell lymphoma (CTCL) has been associated with increased risk for second malignancies. However, the degree of risk and types of second cancers detected have been inconsistent in previous studies.nnnPATIENTS AND METHODSnTo further characterize the risk for malignancy associated with CTCL, patients treated for CTCL at M. D. Anderson Cancer Center in Houston, Texas, between November 1979 and November 1999 were assessed for the occurrence of additional cancers by analysis of institutional tumor registry data.nnnRESULTSnOf 672 patients with CTCL, 112 had > or = 1 additional cancer, 37 occurring after the diagnosis of CTCL. This represents a significant elevation in cancer prevalence and incidence, with a 1.79-fold risk (95% CI, 1.22-2.39) for developing cancer after CTCL. An excess of Hodgkin and non-Hodgkin lymphoma, acute myeloid leukemia, and vulvar cancers was seen.nnnCONCLUSIONnThese data provide evidence for an increased overall incidence of second malignancy in CTCL, particularly with respect to other lymphoproliferative malignancies. Appropriate monitoring for the early detection of second cancers might be warranted in patients with CTCL.

Levamisole toxicity mimicking autoimmune disease

BACKGROUNDnLevamisole is present as a contaminant or additive in most cocaine sold in the United States. Cases of agranulocytosis attributed to levamisole-tainted cocaine have been widely described. Axa0vasculopathic reaction to levamisole has also been reported; however, diagnostic features such as antineutrophil cytoplasmic antibody (ANCA) and additional autoimmune marker positivity are not well recognized. As such, many patients are given a misdiagnosis, prompting aggressive and often unnecessary treatment.nnnOBJECTIVEnWe hope to educate practitioners about the clinical and laboratory features of levamisole-induced vasculopathy to ensure accurate diagnosis and management.nnnMETHODSnThis was a case series.nnnRESULTSnSix patients were admitted with purpuric lesions and vasculitic changes on biopsy specimen; 5 of them were given the diagnosis of and treated for autoimmune conditions before their true diagnosis was revealed. All patients had ANCA positivity, and 4 had additional abnormalities in autoimmune markers. All patients reported recent cocaine abuse, and were ultimately given the diagnosis of levamisole-induced vasculopathy.nnnLIMITATIONSnThis observational study is limited by sample size.nnnCONCLUSIONSnPatients presenting with purpuric lesions with ANCA positivity should be assessed for cocaine exposure. It is important to recognize that levamisole may not only induce ANCA positivity butxa0alsoxa0other autoimmune marker abnormalities. Patients can often be treated with less aggressive therapeutic strategies than what is used for primary ANCA-associated vasculitides.

Mosaic partial deletion of the PTEN gene in a patient with Cowden syndrome

Cowden syndrome is an autosomal dominant condition caused by pathogenic mutations in the phosphatase and tensin homolog (PTEN) gene. Only a small proportion of identified pathogenic mutations have been reported to be large deletions and rearrangements. We report on a female patient with a previous history of breast ductal carcinoma in situ who presented to our institution for management of gastrointestinal hamartomatous polyposis. Although several neoplastic predisposition syndromes were considered, genetic evaluation determined that the patient met clinical diagnostic criteria for Cowden syndrome. Array-based comparative genomic hybridization was performed and revealed a mosaic partial deletion of the PTEN gene. Follow-up clinical history including bilateral thyroid nodules, dermatological findings, and a new primary “triple-negative” adenocarcinoma of the contralateral breast are discussed. We highlight the need for recognition and awareness of mosaicism as it may provide an explanation for variable phenotypic presentations and may alter the genetic counseling risk assessment of affected individuals and family members.

Cyclophosphamide-associated acneiform drug eruption in a patient with multiple myeloma

benign prostatic hyperplasia (BPH) with elevated PSA levels (5.7-7.3 ng/mL; age-adjusted normal range 0-6.5 ng/mL) and confirmatory prostatic biopsy. His PSA normalized after treatment with dutasteride and finasteride. A stool guaiac and urinalysis were normal. The physical examination revealed a large weeping eczematous plaque on the right scrotum extending to the groin andperineum (Fig 1). A biopsy specimen revealed intraepithelial Paget cells, which were CK-7 positive and S-100 negative. Treatment options were discussed and he was started on a course of imiquimod 5%, used twice a day, 3 times a week for 4months, accompanied by an inflammatory reaction, but he failed to respond to this therapy. A surgical consult advised against surgery; the patient is scheduled to receive radiation therapy. In conclusion, although there are at least three reports of successful treatment of scrotal EMPD with imiquimod 5%, our two cases failed to respond. Shelbi C. Jim On, BA, and Allan K. Izumi, MD Medical student and the Division of Dermatology, Department of Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, Hawaii

Recurrent erythematous plaques on sun-exposed sites in an African American boy with chronic granulomatous disease

Key teaching points •We report a case of a 6-year-old African American boy with X-linked CGD who developed DLE–like skin lesions after starting voriconazole. •Voriconazole is commonly used to treat fungal infections in patients with CGD. •Lupus erythematosus–like skin lesions have been reported in carriers of X-linked CGD and, less commonly, in patients with CGD. •Voriconazole is a significant cause of drug-induced photosensitivity, and may play a role inxa0unmasking an underlying predisposition to lupuslike skin lesions. •Photoprotective measures and routine examinations to monitor for skin toxicity, including skinxa0cancer, are prudent during voriconazole treatment.

Longitudinal lift biopsy technique with flat fixation for the diagnosis of mycosis fungoides.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. It is often slow to develop and evolve, and therefore, obtaining a conclusive biopsy of early stage MF is a challenge. Histopathologic features of MF are necessary to make a diagnosis and include a superficial lymphoid infiltrate with epidermotropic lymphocytes, atypical lymphoid cells, and haloed intraepidermal lymphocytes. Consequently, a biopsy technique that yields a large sample of the epidermis and superficial dermis increases the probability of identifying definitive histopathology. At present, standard sampling modalities for suspected MF lesions include performing multiple punch or shave biopsies of affected areas. The notion of executing a thin, 1 cm shave biopsy was popularized by Fung et al. in an effort to enhance diagnostic precision and avoid the need for multiple biopsies. We suggest a modified shave biopsy technique for sampling skin lesions that are suspicious for MF.

19-P008 SHH is a master regulator of stem cell-driven continuous growth of the mouse incisor

in vertebrates and to determine the molecular and cellular basis for such currents. Methods: We use zebrafish caudal fin as an adult regeneration model. Specific ion flux measurements are done using a non-invasive Ion-Specific Scanning Microprobe coupled with transcriptional profiling and genetic functional analysis. Results: Our data points to an important role for protons (H[+]) during the regeneration process. H[+] effluxes are triggered during wound healing and maintained throughout regeneration. Microarray analysis revealed the proton pump V-ATPase as a putative mediator of such H[+] fluxes and we observed that it is expressed in the blastema. We are now exploring this proton-based mechanism with genetic and pharmacological approaches coupled with advanced pH imaging. Other ions are also under study. Conclusions: Overall, our results reveal that important ion-driven mechanisms underlie adult tissue regeneration and its comprehension may open way for new therapeutic strategies and drug screenings, both in regenerative and developmental medicine, and in cancer therapy.