No abstract

Malignant peripheral nerve sheath tumors (MPNST) develop in ~10% of neurofibromatosis type-1 patients and are a major contributing factor to neurofibromatosis-1 patient mortality and morbidity. MPNSTs are multidrug resistant, and thus long-term patient survival rates are poor after standard doxorubicin or multiagent chemotherapies. We show that the hyaluronan receptor CD44 forms complexes with multidrug transporters, BCRP (ABCG2) and P-glycoprotein (ABCB1), in the plasma membrane of human MPNST cells. Small hyaluronan oligosaccharides antagonize hyaluronan-CD44–mediated processes and inhibit hyaluronan production. Treatment of MPNST cells with the hyaluronan oligomers causes disassembly of CD44-transporter complexes and induces internalization of CD44, BCRP, and P-glycoprotein. Consequently, the oligomers suppress drug transporter activity and increase sensitivity to doxorubicin treatment in culture. In vivo, systemic administration of hyaluronan oligomers inhibits growth of MPNST xenografts. Moreover, the oligomers and doxorubicin act synergistically in vivo, in that combined suboptimal doses induce tumor regression to a greater extent than the additive effects of each agent alone. These findings indicate that constitutive hyaluronan-CD44 interactions contribute to drug transporter localization and function at the plasma membrane, and that attenuating hyaluronan-CD44 interactions sensitizes MPNSTs to doxorubicin in vitro and in vivo. These results also show the potential efficacy of hyaluronan oligomers, which are nontoxic and nonimmunogenic, as an adjuvant for chemotherapy in MPNST patients.

Sebaceous carcinoma is a rare and potentially aggressive cutaneous malignancy. Commonly reported in the periocular area and the head and neck region, sebaceous carcinoma can arise from any sebaceous gland in the skin. The clinical presentation may be nonspecific, and a biopsy is important to establish a diagnosis and to differentiate from mimickers including benign sebaceous neoplasms, other adnexal tumors, and basal cell carcinoma. A diagnosis of Muir Torre syndrome should be considered in patients presenting with a sebaceous neoplasm. Early treatment is important given the potential of sebaceous carcinoma to spread to the regional lymph nodes and beyond. Sentinel lymph node biopsy and imaging to complete tumor staging may be indicated for larger or more aggressive tumors. Surgery, including Mohs micrographic surgery, remains the primary treatment modality for sebaceous carcinoma. Mohs micrographic surgery has the advantage of complete margin evaluation and low recurrence rates. Advanced cases may be treated with orbital exenteration, radiation therapy, chemotherapy, or combination therapy.

There is increasing evidence that the intestinal microbiome plays an important role in modulating systemic inflammation and disease. Oral probiotics can modulate the intestinal microbiome and have demonstrated to be efficacious in treating topical skin conditions, such as atopic dermatitis, acne and rosacea. By proxy, exogenous application to the skin of probiotics should also promote a positive bacterial balance to mitigate or potentially eliminate pathologic conditions. The goal of this article was to provide a systematic review of studies that have investigated the role of topical probiotics in mitigating skin conditions. Additionally, skin conditions where dysbiosis has been identified but topical probiotics have not been investigated are discussed. We hope this review both analyses the evidence for the role that topical probiotics could play in topical skin conditions and highlights additional areas in need of research and exploration.