8q Gain Has No Additional Predictive Value in SF3B1MUT Uveal Melanoma but Is Predictive for a Worse Prognosis in Patients with BAP1MUT Uveal Melanoma.

Purpose: Gain of chromosome 8q has been associated with poor prognosis in uveal melanoma (UM), and an increase in the absolute number of 8q-copies correlated with an even shorter survival. Splicing factor 3b subunit 1 (SF3B1)-mutated (SF3B1MUT) tumors display structural chromosomal anomalies and frequently show a partial gain of chromosome 8qter. A recent subset of SF3B1MUT UM with early-onset metastases has been identified, prompting the investigation of the relationship between survival, 8q gain, and SF3B1MUT UM. Design: Retrospective cohort study. Subjects: Patients diagnosed with UM who underwent enucleation or received a biopsy at the Erasmus MC Cancer Institute or the Rotterdam Eye Hospital, The Netherlands were included. Methods: Fifty-nine patients with SF3B1MUT tumors and 211 patients with BRCA1 associated protein 1 (BAP1)-mutated (BAP1MUT) tumors were included in this study. Copy number status and gene expression were assessed using either a single nucleotide polymorphism array, fluorescence in situ hybridization, and karyotyping, or a combination of these techniques. Disease-free survival was determined and a cut-off of 60 months was used to define early-onset metastatic disease. Main Outcome Measures: Disease-free survival. Results: Forty-eight patients with SF3B1MUT UM (81%) had chromosome 8q gain (3 copies, 78%; 4 copies, 22%). Kaplan-Meier analysis of SF3B1MUT UM did not indicate a difference in survival in patients with or without gain of 8q (P = 0.99). Furthermore, the number of 8q copies was not associated with survival when comparing early (P = 0.97) versus late (P = 0.23) metastases group. In contrast, the presence of 8q gain (86%) was correlated with a decreased survival in BAP1MUT UM (P = 0.013). Conclusions: We did not find a correlation between 8q gain and early-onset metastasis in SF3B1MUT tumors. Gain of 8q has no additional predictive value in SF3B1MUT tumors. In contrast, 8q gain is predictive of a worse prognosis in patients with BAP1MUT tumors. Thus, gain of chromosome 8q has additional predictive value for BAP1MUT tumors, but not for SF3B1MUT tumors. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Disparities of Cutaneous Malignancies in the US Military.

Occupational sun exposure is a well-known risk factor for the development of melanoma and nonmelanoma skin cancer (NMSC), especially among US military personnel who may have inadequate access to sun protection, are located in geographic regions with increased sun exposure, and work with potential carcinogens. Herein, we describe a case of a military service member who developed skin cancer at an early age potentially due to occupational sun exposure. We also provide a review of the literature to examine the risk factors and incidence of melanoma and NMSC in US military personnel and veterans, as well as provide recommendations for skin cancer prevention, screening, and intervention in the military population.

FOXD1 Is a Transcription Factor Important for Uveal Melanocyte Development and Associated with High-Risk Uveal Melanoma.

Uveal melanoma (UM) is a deadly ocular malignancy, originating from uveal melanocytes. Although much is known regarding prognostication in UM, the exact mechanism of metastasis is mostly unknown. Metastatic tumor cells are known to express a more stem-like RNA profile which is seen often in cell-specific embryonic development to induce tumor progression. Here, we identified novel transcription regulators by reanalyzing publicly available single cell RNA sequencing experiments. We identified five transcription regulators of interest: ELL2, KDM5B, REXO4, RBFOX2 and FOXD1. Our most significant finding is FOXD1, as this gene is nearly exclusively expressed in high-risk UM and its expression is associated with a poor prognosis. Even within the BAP1-mutated UM, the expression of FOXD1 is correlated with poor survival. FOXD1 is a novel factor which could potentially be involved in the metastatic capacity of high-risk UM. Elucidating the function of FOXD1 in UM could provide insight into the malignant transformation of uveal melanocytes, especially in high-risk UM.

Identification of Early-Onset Metastasis in SF3B1 Mutated Uveal Melanoma.

Approximately 25% of all uveal melanoma (UM) contain driver mutations in the gene encoding the spliceosome factor SF3B1, and whilst patients with such SF3B1 mutations generally have an intermediate risk on developing metastatic disease, a third of these patients develop early metastasis within 5 years after diagnosis. We therefore investigated whether clinical and/or genetic variables could be indicative of short progression-free survival (PFS < 60 months) or long PFS (PFS ≥ 60 months) for SF3B1-mutated (SF3B1mut) UM patients. We collected 146 SF3B1mut UM from our Rotterdam Ocular Melanoma Studygroup (ROMS) database and external published datasets. After stratification of all SF3B1mut UM using short PFS vs. long PFS, only largest tumor diameter (LTD) was significantly larger (mean: 17.7 mm (±2.8 SD) in the short PFS SF3B1mut group vs. the long PFS group (mean: 14.7 (±3.7 SD, p = 0.001). Combined ROMS and The Cancer Genome Atlas (TCGA) transcriptomic data were evaluated, and we identified SF3B1mut-specific canonical transcripts (e.g., a low expression of ABHD6 indicative for early-onset metastatic disease) or distinct expression of SF3B1mut UM aberrant transcripts, indicative of early- or late-onset or no metastatic SF3B1mut UM.

Spliceosome Mutations in Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy of the eye. It has a high metastatic potential and mainly spreads to the liver. Genetics play a vital role in tumor classification and prognostication of UM metastatic disease. One of the driver genes mutated in metastasized UM is subunit 1 of splicing factor 3b (SF3B1), a component of the spliceosome complex. Recurrent mutations in components of the spliceosome complex are observed in UM and other malignancies, suggesting an important role in tumorigenesis. SF3B1 is the most common mutated spliceosome gene and in UM it is associated with late-onset metastasis. This review summarizes the genetic and epigenetic insights of spliceosome mutations in UM. They form a distinct subgroup of UM and have similarities with other spliceosome mutated malignancies.

Can Robin Sequence Be Predicted From Prenatal Ultrasonography?

PURPOSE: Prenatal diagnosis of Robin sequence (RS) could promote safe delivery and improve perinatal care. The purpose of this study was to evaluate the correlation between prenatal ultrasonography (US) and magnetic resonance imaging (MRI) studies for assessing micrognathia to determine if US alone can be used to reliably screen for RS. MATERIALS AND METHODS: This was a retrospective case-control study of fetuses evaluated in the Advanced Fetal Care Center at Boston Children's Hospital from 2002 to 2017. To be included, 1) prenatal MRI and US must have been performed during the same visit, 2) the infant must have been live-born, and 3) the diagnosis must have been confirmed postnatally. Patients with images of inadequate quality for analysis were excluded. Patients were divided into 4 groups based on postnatal diagnosis: 1) RS (micrognathia, glossoptosis, and airway obstruction) (RS group), 2) micrognathia without RS (micrognathia group), 3) cleft lip and palate (CLP) without micrognathia (CLP group), and 4) gestational age-matched controls with normal craniofacial morphology (control group). The inferior facial angle (IFA) was measured using both imaging modalities and compared. Receiver operating characteristic curves were applied to identify a threshold for the diagnosis of RS from US. The sensitivity, specificity, positive predictive value, negative predictive value, and odds ratio were calculated. RESULTS: A total of 94 patients were included (mean gestational age at imaging, 24.9 ± 5.2 weeks), with 25 in the RS group (26.6%), 29 in the micrognathia group (30.9%), 23 in the CLP group (24.5%), and 17 in the control group (18.1%). The IFA was significantly smaller in the RS group than in all other groups on both US and MRI (P < .001). A moderate correlation was found between IFA measurements on US and MRI (intraclass correlation coefficient, 0.729). An IFA threshold on US of 45.5° maximized sensitivity (84%) and specificity (81%) for the diagnosis of RS. CONCLUSIONS: We suggest incorporating the IFA into routine prenatal US and referring patients for confirmatory MRI when the US IFA is lower than 45.5°.

Impact of Obstructive Sleep Apnea on Optic Nerve Function in Patients With Craniosynostosis and Recurrent Intracranial Hypertension.

PURPOSE: Assessment of combined impact of intracranial hypertension (ICH) and obstructive sleep apnea (OSA) on optic nerve function in children with craniosynostosis (CS). DESIGN: Retrospective cross-sectional study. METHODS: Patients treated at Boston Children's Hospital for CS who had an ophthalmic examination that included pattern reversal (pr)VEP (2013-2014) and history of ICH based on direct measurement, papilledema, or classic features on neuroimaging and during cranial vault expansion were included. History of OSA was determined by polysomnography and associated conditions, including apnea and (adeno)tonsillectomy. Subjects were divided into 4 groups: group 1, resolved ICH absent history of OSA; group 2, resolved ICH with history of OSA; group 3, recurrent ICH absent history of OSA; and group 4, recurrent ICH with history of OSA. Predictor variables included latency of P100 component of pattern-reversal visual evoked potential, best-corrected visual acuity, optic nerve appearance, visual fields, and global retinal nerve fiber layer. Primary outcome was association of prolonged P100 latency with resolved vs recurrent ICH and OSA. RESULTS: Twenty-eight children met inclusion criteria (mean age 11.6 ± 6.9 years): group 1 (n = 3), group 2 (n = 6), group 3 (n = 8), and group 4 (n = 11). P100 latencies were not prolonged in groups 1 and 2. Three of 8 in group 3 and 9 of 11 in group 4 had prolonged P100 latency. Group 4 was significantly worse than group 3 (P = .005). CONCLUSIONS: History of OSA, in addition to recurrent ICH, is associated with greatest risk of optic neuropathy with CS. Ophthalmologists should encourage early management of OSA as well as ICH to optimize ophthalmic outcomes.

Delayed lower cranial neuropathies following primary radiotherapy for oropharyngeal squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: Delayed lower cranial neuropathy is a rare complication following primary radiotherapy for head and neck cancer, and has been most associated with nasopharyngeal carcinoma with minimal data regarding this outcome in the treatment of the oropharynx. No reports, to the authors' knowledge, have described this complication following intensity modulated radiation therapy (IMRT) for oropharyngeal primaries. Once encountered, this adverse outcome can have serious impacts on speech and swallowing. We present here our institution's experience with delayed cranial neuropathies following primary radiation therapy for oropharyngeal squamous cell carcinoma, as well as document the only reported case following IMRT.

Leclercia adecarboxylata cellulitis in a child with acute lymphoblastic leukemia.

Leclercia adecarboxylata is a rare, gram-negative rod that has been infrequently reported in the literature. The organism has been documented to cause solitary infections in immunocompromised hosts and polymicrobial wound infections in the immunocompetent. We present a case of an 8-year-old boy with significant past medical history of acute lymphoblastic leukemia who developed cellulitis due to local infection by L. adecarboxylata. This case is presented to raise awareness of this rare organism's ability to cause common cutaneous disease, especially in the immunocompromised.

The risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: There is a need to better understand the safety of tumor necrosis factor (TNF) inhibitors in patients with psoriatic disease in whom TNF inhibitors are frequently used as monotherapy. OBJECTIVE: We sought to examine the risks of infection and malignancy with the use of TNF antagonists in adult patients with psoriatic disease. METHODS: We conducted a systematic search for trials of TNF antagonists for adults with plaque psoriasis and psoriatic arthritis. We included randomized, placebo-controlled trials of etanercept, infliximab, adalimumab, golimumab, and certolizumab for the treatment of plaque psoriasis and psoriatic arthritis. Twenty of 820 identified studies with a total of 6810 patients were included. Results were calculated using fixed effects models and reported as pooled odds ratios. RESULTS: Odds ratios for overall infection and serious infection over a mean of 17.8 weeks were 1.18 (95% confidence interval [CI] 1.05-1.33) and 0.70 (95% CI 0.40-1.21), respectively. When adjusting for patient-years, the incidence rate ratio for overall infection was 1.01 (95% CI 0.92-1.11). The odds ratio for malignancy was 1.48 (95% CI 0.71-3.09) and 1.26 (95% CI 0.39-4.15) when nonmelanoma skin cancer was excluded. LIMITATIONS: Short duration of follow-up and rarity of malignancies and serious infections are limitations. CONCLUSIONS: There is a small increased risk of overall infection with the short-term use of TNF antagonists for psoriasis that may be attributable to differences in follow-up time between treatment and placebo groups. There was no evidence of an increased risk of serious infection and a statistically significant increased risk in cancer was not observed with short-term use of TNF inhibitors.

Relapsing Legionella pneumophila cellulitis: a case report and review of the literature.

Legionella spp. rarely cause soft tissue infections, with only a few cases reported and usually in the setting of immunocompromise. We report a case of L. pneumophila cellulitis, without pneumonia, in a 65-year-old immunocompromised woman. The patient had a history of interstitial lung disease and idiopathic thrombocytopenic purpura, for which she was receiving high-dose corticosteroids, and had recently experienced an episode of L. pneumophila cellulitis of the lower extremity, which responded to an extended course of levofloxacin. She was initially transferred to this institution for definitive workup of presumed B cell lymphoma and, during her hospital course, suffered a relapse of L. pneumophila-associated cellulitis that responded promptly to azithromycin. More unusual organisms such as Legionella spp. should be considered in the etiology of cellulitis, particularly in the setting of immunocompromise, in cases that are refractory to conventional antibiotics routinely administered for skin and soft tissue infections.

Melanoma associated with long-term voriconazole therapy: a new manifestation of chronic photosensitivity.

BACKGROUND: Voriconazole is a triazole antifungal agent approved by the US Food and Drug Administration for serious fungal infections, including with Aspergillus, Fusarium, Pseudallescheria, and Scedosporium species. In initial clinical trials, approximately 2% of patients developed cutaneous reactions, including photosensitivity, cheilitis, and xerosis. Subsequent reports have implicated voriconazole as a cause of severe photosensitivity and accelerated photoaging, pseudoporphyria cutanea tarda, and aggressive squamous cell carcinoma. OBSERVATION: We report 5 melanoma in situ lesions in the setting of extreme photosensitivity associated with long-term voriconazole therapy. CONCLUSIONS: We recommend surveillance for skin cancer formation in all patients who require long-term voriconazole treatment, particularly those who manifest signs or symptoms of photosensitivity or chronic photodamage. Further study of the mechanism underlying voriconazole photosensitivity and oncogenesis is warranted.

Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole.

BACKGROUND: Voriconazole is a broad-spectrum antifungal agent associated with photosensitivity and accelerated photoaging. A possible link with aggressive squamous cell carcinoma (SCC) has also been reported. OBJECTIVE: We sought to determine the incidence and frequency of cutaneous SCC among patients undergoing long-term treatment with voriconazole who also manifest features of chronic phototoxicity. METHODS: We conducted a retrospective review of patients who developed one or more squamous cell neoplasms during long-term treatment with voriconazole at 3 academic dermatology centers. RESULTS: A total of 51 cutaneous SCC were identified in 8 patients (median age 34.5 years, range 9-54) treated with chronic voriconazole (median duration 46.5 months, range 13-60). Underlying diagnoses included graft-versus-host disease, HIV, and Wegener granulomatosis. Signs of chronic phototoxicity and accelerated photoaging included erythema, actinic keratoses, and lentigo formation. LIMITATIONS: The retrospective nature of the study cannot determine the true population risk of SCC associated with voriconazole therapy. A prospective cohort study is needed. CONCLUSION: A high index of suspicion for photosensitivity and SCC may be warranted with chronic voriconazole use when used in the setting of concurrent immunosuppression.

Evaluation of digital dermoscopy in a pigmented lesion clinic: clinician versus computer assessment of malignancy risk.

Digital dermoscopy systems employ computer-based algorithms to quantitate features of pigmented skin lesions (PSLs) and provide an assessment of malignancy risk. We evaluated interobserver concordance of PSL malignancy risk between a pigmented lesion specialist and an artificial neural network (ANN)-based automated digital dermoscopy system. While digital dermoscopy provides a reliable means of image capture, storage, and comparison of PSLs over time, the ANN algorithm requires further training and validation before the malignancy risk assessment feature can be widely used in clinical practice.

Pyoderma gangrenosum occurring near an arteriovenous dialysis shunt.

Pyoderma gangrenosum (PG) is an uncommon cutaneous disease of unknown etiology. In 50 percent of affected patients, PG is associated with systemic disease including inflammatory bowel disease, arthritis, and hematologic malignancies.(1) Diagnosis of PG is based on clinical presentation, histopathology and on the exclusion of other diseases that can produce clinically similar lesions, e.g. infection, vasculitis, malignancy, collagen vascular diseases, diabetes, and trauma. Four variants of PG have been described: ulcerative, pustular, bullous, and vegetative.(2) We report a woman with renal failure who developed PG in the absence of any obvious triggering trauma in a distinctive unilateral crop just distal to an arteriovenous dialysis shunt.