Predictive biomarkers for response to trametinib in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a leading cause of cancer deaths. Current companion diagnostics use driver mutation sequencing to select patients for molecularly targeted agents (MTA), even though most patients lack actionable mutations. These diagnostics utilize static biomarkers, ignoring real-time tumor cell biology. OBJECTIVE: Trametinib is FDA-approved in combination with dabrafenib for BRAF V600E-positive NSCLC, however, it has plausible utility beyond these patients. We sought to identify novel biomarkers for maximizing trametinib application. METHODS: Trametinib responses were evaluated in 12 EGFR/BRAF wild-type (WT) NSCLC cell lines with diverse RAS mutational status. We identified three response categories by colony assay. Trametinib-induced molecular dynamics were studied using immunoassays and apoptosis/necrosis assays, to identify predictive response biomarkers. RESULTS: p27 accumulation and cyclin D1 downregulation suggested universal cell cycle arrest with trametinib. However, 4 cell lines showed PARP cleavage and 8 showed increased phospho-4E-BP1, suggesting varied cellular outcomes from apoptosis, necrosis, senescence to autophagy. Cleaved PARP, phospho-4E-BP1 and phospho-AKT expression can predict these outcomes. CONCLUSIONS: Trametinib monotherapy outcome may depend upon cellular context more than oncogenic mutation status. In BRAF WT NSCLC, trametinib may be best suited for combination therapy and dynamic biomarkers could select combinations and predict responses.

What lies beneath: Cutaneous involvement of mantle cell lymphoma underlying an insect-bite-like reaction.

Mantle cell lymphoma (MCL) is an uncommon subtype of mature B-cell non-Hodgkin lymphoma characterized by specific morphologic, immunophenotypic, and genetic characteristics, namely the t(11;14)(q13;q32) chromosomal translocation with resultant cyclin D1 overexpression. MCL has a generally aggressive course and is often widely disseminated at the time of diagnosis. Skin involvement is exceedingly rare and is seldom the first manifestation of MCL. We present a case of MCL in an 84-year-old man with cutaneous involvement as the first manifestation, discovered incidentally after biopsy of a persistent nodule believed to be an insect bite. This case not only serves to raise awareness of the possibility of MCL presenting in the skin but also to point out that MCL can have lesions with both an insect-bite-like reaction and a deeper dermal MCL infiltrate.

Blastic Plasmacytoid Dendritic Cell Neoplasm: A Case Series and Review.

ABSTRACT: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy that frequently has cutaneous manifestations. The diagnosis can be a challenge because of its heterogenous clinical presentation, ranging from a brown or violaceous solitary nodule or patch to mixed, disseminated lesions. Furthermore, BPDCN tumor cells express immunohistochemical markers in common with acute myeloid leukemia, which can lead to misdiagnosis. Timely diagnosis requires awareness of its cutaneous manifestations and unique histopathology and immunophenotype. We present a case series of patients diagnosed with BPDCN and review the cutaneous and histopathologic characteristics of this uncommon entity.

An unusual case of cutaneous Waldenström macroglobulinemia with the MYD88 L265P mutation.

Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma with bone marrow involvement and a monoclonal IgM gammopathy. Infiltration of the skin by neoplastic cells is very rare, and it can be difficult to distinguish from marginal zone lymphoma. The MYD88 L265P mutation is strongly associated with Waldenström macroglobulinemia, and it may be helpful in differentiating the two disorders, although the presence of this mutation is not specific, and other factors must be considered when making the final diagnosis. We present a diagnostically challenging case of cutaneous Waldenström macroglobulinemia in which the MYD88 L265P mutation was identified in the skin but not in the bone marrow, due to a low tumor burden.

A case of S-100-negative CD1a-positive indeterminate cell histiocytosis.

Histiocytoses are a group of rare disorders characterized by a proliferation of monocytes/macrophages and dendritic cells. We present a case of a 3-year-old girl with a diffuse papular eruption without systemic symptoms demonstrating a proliferation of strongly CD1a+ histiocytes, but negative for S-100 and langerin on histopathology. Systemic work-up including bone marrow biopsy was unremarkable, and the patient received a diagnosis of CD1a+ S- 100-indeterminate cell histiocytosis.

Multiple flat-topped scaly violaceous papules.

Epidermodysplasia verruciformis (EV) is an autosomal recessive genodermatosis characterized by susceptibility to beta-genus human papillomavirus (HPV) infection. Owing to TMC6/EVER1 and TMC8/EVER2 mutations that lead to abnormal transmembrane channels in the endoplasmic reticulum involved in immunological pathways, keratinocytes cannot combat infection from non-pathogenic HPV strains. Mutations involving RHOH, MST-1, CORO1A, and IL-7 have also been associated with EV in patients without TMC6 or TMC8 mutations. We highlight a 27-year-old man with multiple violaceous flat-topped papules with scale and irregular borders distributed on his chest, extremities, abdomen, and back. The striking physical examination and the subsequent biopsy findings of enlarged nests of cells in the granular and spinous layers with blue-gray cytoplasm and keratohyaline granules confirmed the diagnosis. We conclude with a brief discussion on the differential diagnosis, which includes confluent and reticulated papillomatosis, Darier disease, and disseminated superficial actinic porokeratosis.

Melanoma patient notification and treatment timelines.

Melanoma is an extremely aggressive cancer for which the American Academy of Dermatology currently does not have formal recommendations outlining a timeline from biopsy to definitive treatment. Our dermatology department investigated our treatment timeline for melanoma. Using the database from our electronic medical record, Epic, we evaluated patients over a one-year period; in total we identified 109 melanomas. We evaluated patient demographics, tumor characteristics, and timelines regarding diagnosis and treatments. There was a statistically significant difference in patient notification of diagnosis and treatment times between stage 1 and stages 2-4 combined (based on the American Joint Committee on Cancer staging system). We found that 84% of melanomas were treated within 4 weeks of diagnosis and 96% within 6 weeks. The lower the stage, the earlier the melanoma was definitively treated; higher stage melanomas had a longer delay to definitive treatment. Herein, we have presented our single institutional experience of the melanoma timeline from diagnosis to definitive treatment and have identified factors that impact timely definitive treatment.

NADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease.

Ataxia telangiectasia (A-T), a rare autosomal recessive disorder characterized by progressive cerebellar degeneration and a greatly increased incidence of cancer among other symptoms, is caused by a defective or missing ataxia telangiectasia mutated (ATM) gene. The ATM protein has roles in DNA repair and in the regulation of reactive oxygen species (ROS). Here, we provide, to our knowledge, the first evidence that NADPH oxidase 4 (NOX4) is involved in manifesting A-T disease. We showed that NOX4 expression levels are higher in A-T cells, and that ATM inhibition leads to increased NOX4 expression in normal cells. A-T cells exhibit elevated levels of oxidative DNA damage, DNA double-strand breaks and replicative senescence, all of which are partially abrogated by down-regulation of NOX4 with siRNA. Sections of degenerating cerebelli from A-T patients revealed elevated NOX4 levels. ATM-null mice exhibit A-T disease but they die from cancer before the neurological symptoms are manifested. Injecting Atm-null mice with fulvene-5, a specific inhibitor of NOX4 and NADPH oxidase 2 (NOX2), decreased their elevated cancer incidence to that of the controls. We conclude that, in A-T disease in humans and mice, NOX4 may be critical mediator and targeting it will open up new avenues for therapeutic intervention in neurodegeneration.

Perforating gout of the ear.

Gout is the most common cause of inflammatory arthritis in men over 40 [1]. The prevalence of gout in the US is approximately 3.9%. Tophus is a characteristic sign of gout and results when monosodium urate deposits at the joint, skin, or cartilage. Tophi develop in 12-35% of patients who are diagnosed with gout [2]. We report a case of a 70-year-old man who was diagnosed with squamous cell carcinoma of the helix via shave biopsy. During Mohs micrographic surgery, a vigorous foreign-body reaction was noted. Review of the initial biopsy slides identified crystals with pseudoepitheliomatous hyperplasia (PEH) rendering a diagnosis of gout. This case emphasizes the importance of recognizing causes of PEH and the predilection for tophi to form on the ear.

Infantile epidermolytic ichthyosis with prominent maternal palmoplantar keratoderma.

Epidermolytic Ichthyosis (EI) is a rare autosomal dominant genodermatosis. Although an inherited disorder, 50% of cases represent novel mutations. This disorder presents as a bullous disease in newborns progressing to a lifelong ichthyotic skin disorder.  Other manifestations include palmoplantar keratoderma (PPK).  EI results from mutations in the keratin 1 and keratin 10 genes. Phenotypic variability is seen in affected individuals based on the genotypic mutation.  We present a mother and her newborn son with EI and prominent PPK in the mother, which also developed in the child at a few months of age.  Genotype analysis was performed on the newborn child who was found to harbor a mutation in the keratin 1 gene. This family demonstrates the phenotypic expression of PPK associated with keratin 1 gene mutations and illustrates the importance of genotype-phenotypecorrelation in this disorder.

Linear acral pseudolymphomatous angiokeratoma of children with associated nail dystrophy.

Acral pseudolymphomatous angiokeratoma of children (APACHE) is a rare entity that typically occurs on the extremities of young females. Although linear arrangement of cutaneous lesions has been rarely reported, accompanying nail dystrophy has not been linked with this condition to our knowledge. We describe a case of linearly-oriented infiltrative papules and nodules on the index finger of a young female with associated onychodystrophy. Histology demonstrated a heavy lymphocytic infiltrate with plasma cells and proliferation of blood vessels consistent with APACHE. Our case is unique given the linear array of cutaneous lesions and associated nail dystrophy.

IgG/IgA pemphigus.

IgG/IgA pemphigus has recently been described in the literature as an overlap of pemphigus vulgaris or pemphigus foliaceus with IgA pemphigus. There has also been some postulation that this IgG/IgA pemphigus may be associated with internal malignancy as well. Our case demonstrates the unique clinical, histopathological, and direct immunofluorescence findings of IgG/IgA pemphigus and further highlights the possibility of association of this disease with internal malignancy.

Successful treatment of facial papules with electrodessication in a patient with Birt-Hogg-Dubé syndrome.

We report a case of a 51-year-old Hispanic female who presented with a several year history of multiple flesh colored papules of cosmetic concern on the nose and medial cheeks. Biopsies revealed fibrofolliculoma and trichodiscoma. The patient was referred for genetic testing and was found to be positive for the FLCN gene defect, confirming a diagnosis of Birt-Hogg-Dubé syndrome. Further work-up with screening renal ultrasound and CT scan of the thorax and abdomen was unrevealing. For treatment of these skin lesions, dermasanding was attempted initially with only minimal benefit. She subsequently had multiple lesions treated with electrodessication at a low setting and was very pleased with the results. Curettage was not performed and importantly, there has yet to be a recurrence of lesions treated with only hyfrecation.