Transcriptional Profiling Supports the Notochordal Origin of Chordoma and Its Dependence on a TGFB1-TBXT Network.

Chordoma is a rare malignant tumor demonstrating notochordal differentiation. It is dependent on brachyury (TBXT), a hallmark notochordal gene and transcription factor, and shares histologic features and the same anatomic location as the notochord. This study involved a molecular comparison of chordoma and notochord to identify dysregulated cellular pathways. The lack of a molecular reference from appropriate control tissue limits our understanding of chordoma and its relationship to notochord. Therefore, an unbiased comparison of chordoma, human notochord, and an atlas of normal and cancerous tissue was conducted using gene expression profiling to clarify the chordoma/notochord relationship and potentially identify novel drug targets. The study found striking consistency in gene expression profiles between chordoma and notochord, supporting the hypothesis that chordoma develops from notochordal remnants. A 12-gene diagnostic chordoma signature was identified and the TBXT/transforming growth factor beta (TGF-ß)/SOX6/SOX9 pathway was hyperactivated in the tumor, suggesting that pathways associated with chondrogenesis were a central driver of chordoma development. Experimental validation in chordoma cells confirmed these findings and emphasized the dependence of chordoma proliferation and survival on TGF-ß. The computational and experimental evidence provided the first molecular connection between notochord and chordoma and identified core members of a chordoma regulatory pathway involving TBXT. This pathway provides new therapeutic targets for this unique malignant neoplasm and highlights TGF-ß as a prime druggable candidate.

Mohs micrographic surgery in the surgical treatment paradigm of melanoma in situ and invasive melanoma: A clinical review of treatment efficacy and ongoing controversies.

Mohs Micrographic Surgery (MMS) for treatment of melanoma offers several advantages over wide local excision (WLE), including complete histologic margin evaluation, same-day resection and closure, and sparing of healthy tissue in critical anatomic sites. Recently, a large volume of clinical data demonstrating efficacy in MMS treatment of melanoma was published, leading to emerging patient safety considerations of incurred treatment costs, risk of tumor upstaging, and failure of care coordination for sentinel lymph node biopsy (SLNB). MMS offers a safe, effective, and value-based treatment for both melanoma in situ (MIS) and invasive melanoma (IM), particularly with immunohistochemistry use on frozen sections. Compared to wide local excision, MMS treatment demonstrates similar or improved outcomes for local tumor recurrence, melanoma-specific survival, and overall survival at long-term follow-up. Tumor upstaging risk is low, and if present, alteration to clinical management is minimal. Discussion of SLNB for eligible head and neck IM cases should be done prior to MMS. Though challenging, successful multidisciplinary coordination of SLNB with MMS has been demonstrated. Herein, we provide a detailed clinical review of evidence for MMS treatment of cutaneous melanoma and offer recommendations to address current controversies surrounding the evolving paradigm of surgical management for both MIS and invasive melanoma (IM).

Nodular lymphangitis related to methicillin-resistant staphylococcus aureus infection.

Nodular lymphangitis, also known as lymphocutaneous syndrome or sporotrichoid lymphangitis, presents with inflammatory nodules along the lymphatic vessels, typically involving the upper or lower extremities. Although the most common cause of nodular lymphangitis is infection due to Sporothrix schenckii, Nocardia brasiliensis, Mycobacterium marinum, or Leishmania braziliensis, it is important for clinicians to be aware of methicillin-resistant Staphylococcus aureus as a rare cause of nodular lymphangitis and perform gram stain, bacterial culture, and antibiotic sensitivity profiles when appropriate. History of recent travel or exposures, incubation time, presence of systemic symptoms, and presence of ulceration, suppuration, or drainage can serve as diagnostic clues, but microbiological tissue cultures and histopathologic studies confirm the diagnosis. Herein, we present a case of nodular lymphangitis caused by methicillin-resistant Staphylococcus aureus (MRSA); tissue culture and antibiotic sensitivities were used to guide treatment.

Cumulative Erythemal Ultraviolet Radiation and Risk of Cancer in 3 Large US Prospective Cohorts.

Ultraviolet radiation (UVR) exposure is the major risk factor for melanoma. However, epidemiologic studies on UVR and noncutaneous cancers have reported inconsistent results, with some suggesting an inverse relationship potentially mediated by vitamin D. To address this, we examined 3 US prospective cohorts, the Health Professionals Follow-up Study (HPFS) (1986) and Nurses' Health Study (NHS) I and II (1976 and 1989), for associations between cumulative erythemal UVR and incident cancer risk, excluding nonmelanoma skin cancer. We used a validated spatiotemporal model to calculate erythemal UVR. Participants (47,714 men; 212,449 women) were stratified into quintiles by cumulative average erythemal UVR, using the first quintile as referent, for Cox proportional hazards regression analysis. In the multivariable-adjusted meta-analysis of all cohorts, compared with the lowest quintile, risk of any cancer was slightly increased across all other quintiles (highest quintile hazard ratio (HR) = 1.04, 95% confidence interval (CI): 1.01, 1.07; P for heterogeneity = 0.41). All UVR quintiles were associated with similarly increased risk of any cancer excluding melanoma. As expected, erythemal UVR was positively associated with risk of melanoma (highest quintile HR = 1.17, 95% CI: 1.04, 1.31; P for heterogeneity = 0.83). These findings suggest that elevated UVR is associated with increased risk of both melanoma and noncutaneous cancers.

Increased relative proportions of advanced melanoma among veterans: A comparative analysis with the Surveillance, Epidemiology, and End Results registry.

BACKGROUND: The Surveillance, Epidemiology, and End Results (SEER) program reflects a third of the population of the United States. However, SEER may not be generalizable to the veteran population. Because veterans comprise a high-risk population, this discrepancy may limit our understanding of the epidemiology of melanoma in such high-risk populations. OBJECTIVES: To assess differences in demographics, tumor characteristics, and melanoma-specific survival (MSS) in veterans compared to the general population. METHODS: Data were collected from the Veterans Affairs Cancer Registry (VACR) and SEER (18 registries) from 2009 to 2017. RESULTS: We identified 15,334 veterans and 166,265 SEER patients with melanoma. Veterans were more likely to present with regional or distant disease (17.5% vs 13.0% in SEER). In VACR relative to SEER, the 5-year MSS was lower across all ages, except those diagnosed at ≥80 years. From 2009 to 2017, MSS by stage was lower across all stages in VACR. However, for stage IV melanomas diagnosed in 2015 to 2017 compared to 2011-2014, 2-year MSS increased from 37.8% to 51.5% in VACR versus 36.4% to 44.8% in SEER. LIMITATIONS: Unique veteran demographics and missing data inherent to VACR. CONCLUSION: Compared to SEER, veterans with melanoma were diagnosed at later stages; however, both exhibited recent improvement in stage IV MSS.