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Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2020)

Disabling Pansclerotic Morphea (DPM) is a rare fibrotic skin disorder that is characterized by rapid sclerosis in all skin layers, fascia, muscle, and bone. This disease primarily affects children under 14 years of age and has an unknown etiology. Diagnosis of DPM is largely dependent on recognition of clinical features and current treatment options are nonspecific. To determine the current state of knowledge of DPM, we conducted a literature review to identify all published cases of disease. This is the first study to summarize all DPM patients reported in the literature and the collective information will function as a valuable resource for both clinicians and scientists who are seeking more information about this disease. Our findings revealed that patients typically present with prominent skin findings accompanied by various extracutaneous complications which contribute to morbidity and mortality. Additionally, patient responses to current treatment options are inconsistent. Given the rarity of the disease and limited understanding of its pathophysiology, we attempted to define the etiology underlying DPM through use of primary human cell lines, and evaluation of wound healing by an in vitro scratch assay. Results from our optimization experiments show that scratching at a 45° angle decreases interexperiment variability. Finally, we have proposed experiments that will examine the inherent disease features on elements of fibroblast biology including inflammatory gene transcription and cell morphology. We believe results from these experiments will help unveil the molecular basis of DPM and aid in the identification of a more specific therapy for these patients.

    Cover page: Use of primary skin fibroblasts to understand the etiology of Disabling Pansclerotic Morphea
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2020)

    Objective

    Treatment delays and suboptimal adherence to posttreatment surveillance may adversely affect head and neck cancer (HNC) outcomes. Such challenges can be exacerbated in safety-net settings that struggle with limited resources and serve a disproportionate number of patients vulnerable to gaps in care. This study aims to characterize treatment delays and adherence with posttreatment surveillance in HNC care at an urban tertiary care public hospital in San Francisco.

    Study design

    Retrospective chart review.

    Setting

    Urban tertiary care public hospital in San Francisco.

    Subjects and methods

    We identified all cases of HNC diagnosed from 2008 to 2010 through the electronic medical record. We abstracted data, including patient characteristics, disease characteristics, pathology and radiology findings, treatment details, posttreatment follow-up, and clinical outcomes.

    Results

    We included 64 patients. Median time from diagnosis to treatment initiation (DTI) was 57 days for all patients, 54 days for patients undergoing surgery only, 49 days for patients undergoing surgery followed by adjuvant radiation ± chemotherapy, 65 days for patients undergoing definitive radiation ± chemotherapy, and 29 days for patients undergoing neoadjuvant chemotherapy followed by radiation or chemoradiation. Overall, 69% of patients completed recommended treatment. Forty-two of 61 (69%) patients demonstrated adherence to posttreatment visits in year 1; this fell to 14 out of 30 patients (47%) by year 5.

    Conclusion

    DTI was persistently prolonged in this study compared with prior studies in other public hospital settings. Adherence to posttreatment surveillance was suboptimal and continued to decline as the surveillance period progressed.
      Cover page: Gaps in Treatment and Surveillance: Head and Neck Cancer Care in a Safety‐Net Hospital
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2023)

      Background

      Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma. The cause is unknown, and mortality is high.

      Methods

      We evaluated four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM. Genomic sequencing independently identified three heterozygous variants in a specific region of the gene that encodes signal transducer and activator of transcription 4 (STAT4). Primary skin fibroblast and cell-line assays were used to define the functional nature of the genetic defect. We also assayed gene expression using single-cell RNA sequencing of peripheral-blood mononuclear cells to identify inflammatory pathways that may be affected in DPM and that may respond to therapy.

      Results

      Genome sequencing revealed three novel heterozygous missense gain-of-function variants in STAT4. In vitro, primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion. Inhibition of Janus kinase (JAK)-STAT signaling with ruxolitinib led to improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that were appropriately modified through JAK inhibition.

      Conclusions

      Gain-of-function variants in STAT4 caused DPM in the families that we studied. The JAK inhibitor ruxolitinib attenuated the dermatologic and inflammatory phenotype in vitro and in the affected family members. (Funded by the American Academy of Allergy, Asthma, and Immunology Foundation and others.).
        Cover page: Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome
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