Litigation Arising From Minimally Invasive Cosmetic Procedures: A Review of the Literature.

BACKGROUND: Minimally invasive cosmetic procedures are on the rise. To meet this rising demand, increasing numbers of physicians and nonphysicians are performing these procedures. Understanding malpractice trends and reasons for litigation in cosmetic medicine is important to establish safeguards for patient care and minimize liability. OBJECTIVE: Perform a comprehensive review of the literature on litigation associated with minimally invasive cosmetic procedures and discuss strategies to avoid facing a lawsuit. MATERIALS AND METHODS: The authors searched PubMed databases using a variety of keywords to identify studies of lawsuits arising from minimally invasive cosmetic procedures through December 2020. RESULTS: A total of 12 studies of litigation meeting inclusion criteria were identified: botulinum toxin (1), soft tissue fillers (3), lasers (5), body contouring/liposuction (1), chemical peels/dermabrasion (1), and sclerotherapy (1). Principle factors associated with litigation included negligence, lack of informed consent, vicarious liability for action of delegates, lack of communication, poor cosmetic result, failure to inform of risks, inappropriate treatment or dose, and failure to recognize or treat injury. CONCLUSION: Understanding malpractice trends and reasons for litigation in minimally invasive cosmetic procedures can strengthen the patient-provider relationship, establish safeguards for patient care, and may minimize future risk of a lawsuit.

Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome.

Malignant melanoma is considered the most lethal skin cancer if it is not detected and treated during its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (ie, unilateral lineage, multigenerational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. These patients have a high risk of developing multiple primary melanomas and internal organ malignancies, especially pancreatic cancer; therefore, a multidisciplinary approach is necessary in many cases. The value of dermoscopic examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first-degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. This must be performed with care, however, and only by qualified individuals trained in cancer risk analysis.

Hereditary melanoma: Update on syndromes and management: Emerging melanoma cancer complexes and genetic counseling.

Recent advances in cancer genomics have enabled the discovery of many cancer-predisposing genes that are being used to classify new familial melanoma/cancer syndromes. In addition to CDKN2A and CDK4, germline variants in TERT, MITF, and BAP1 have been added to the list of genes harboring melanoma-predisposing mutations. These newer entities may have escaped earlier description in part because of more advanced technologies now being used and in part because of their mixed cancer phenotype as opposed to a melanoma-focused syndrome. Dermatologists should be aware of (and be able to recognize) the clinical signs in high-risk patients in different contexts. Personal and family histories of cancer should always be sought in patients with multiple nevi or a positive history for melanoma, and should be updated annually. Various features that are unique to specific disorders, such as the appearance of melanocytic BAP1-mutated atypical intradermal tumors in cases of BAP1 melanoma syndrome, should also be recognized early. These patients should be offered regular screenings with the use of dermoscopy and total body photography, as needed. More importantly, referral to other specialists may be needed if a risk for internal malignancy is suspected. It is important to have in mind that these patients tend to develop multiple melanomas, along with various internal organ malignancies, often at younger ages; a multidisciplinary approach to their cancer screening and treatment is ideal.

High MITF Expression Is Associated with Super-Enhancers and Suppressed by CDK7 Inhibition in Melanoma.

Cutaneous melanoma is an aggressive tumor that accounts for most skin cancer deaths. Among the physiological barriers against therapeutic success is a strong survival program driven by genes such as MITF that specify melanocyte identity, a phenomenon known in melanoma biology as lineage dependency. MITF overexpression is occasionally explained by gene amplification, but here we show that super-enhancers are also important determinants of MITF overexpression in some melanoma cell lines and tumors. Although compounds that directly inhibit MITF are unavailable, a covalent CDK7 inhibitor, THZ1, has recently been shown to potently suppress the growth of various cancers through the depletion of master transcription-regulating oncogenes and the disruption of their attendant super-enhancers. We also show that melanoma cells are highly sensitive to CDK7 inhibition both in vitro and in vivo and that THZ1 can dismantle the super-enhancer apparatus at MITF and SOX10 in some cell lines, thereby extinguishing their intracellular levels. Our results show a dimension to MITF regulation in melanoma cells and point to CDK7 inhibition as a potential strategy to deprive oncogenic transcription and suppress tumor growth in melanoma.

Cutaneous melanoma in women.

BACKGROUND: Gender disparity in melanoma outcome is consistently observed, suggesting that gender is as an important prognostic factor. However, the source of this gender disparity in melanoma remains unclear. OBJECTIVE: This article reviews advances in our understanding of gender differences in melanoma and how such differences may contribute to outcomes. METHODS: A broad literature search was conducted using the PubMed database, with search terms such as 'gender differences in melanoma' and 'sex differences in melanoma.' Additional articles were identified from cited references. RESULTS: Herein, we address the gender-linked physiologic differences in skin and melanoma. We discuss the influence of estrogen on a woman's risk for melanoma and melanoma outcomes with regard to pregnancy, oral contraceptives, hormone replacement therapy, and UV tanning. CONCLUSIONS: The published findings on gender disparities in melanoma have yielded many advances in our understanding of this disease. Biological, environmental, and behavioral factors may explain the observed gender difference in melanoma incidence and outcome. Further research will enable us to learn more about melanoma pathogenesis, with the goal of offering better treatments and preventative advice to our patients.

New Insights into the Molecular Distinction of Dysplastic Nevi and Common Melanocytic Nevi-Highlighting the Keratinocyte-Melanocyte Relationship.

Mitsui et al. approach the problem of differentiating dysplastic nevi from common melanocytic nevi through a molecular lens. Whereas most of the literature on this topic shines the spotlight toward melanocytes, the focus of this paper is shifted to the tumor microenvironment. Using microarrays, reverse transcriptase-PCR, and immunohistochemistry, their results emphasize the role of keratinocyte dysplasia within dysplastic nevi.

A novel multi-CDK inhibitor P1446A-05 restricts melanoma growth and produces synergistic effects in combination with MAPK pathway inhibitors.

Nearly 100% of melanomas have a defect in the p16(INK4A):cyclin D-CDK4/6:RB pathway, leading to abnormal cell cycle control and unregulated cellular proliferation. Here, we report that P1446A-05, a novel multi-CDK inhibitor has significant inhibitory activity against cutaneous and uveal melanoma. Mechanistic studies revealed that P1446A-05 inhibits phosphorylation targets of CDK members, and induces cell cycle arrest and apoptosis irrespective of melanoma genotype or phenotype. Additionally, we show preclinical evidence that P1446A-05 can synergize with other small molecule inhibitors previously studied in melanoma. Collectively, these data demonstrate that targeting cell cycle and transcriptional CDKs with a small molecule multi-CDK inhibitor is a viable approach for developing novel anti-melanoma therapeutics.

Oncogene-directed small molecule inhibitors for the treatment of cutaneous melanoma.

Achievements in cancer genetics and molecular biology have revolutionized the treatment options available for advanced melanoma. Patients with certain molecularly defined melanomas have been the most fortunate beneficiaries of recently US FDA-approved therapies that target aberrant MAPK pathway signaling, yet response rates and duration of response remain suboptimal. Furthermore, many patients harbor melanomas for which no approved targeted therapies currently exist. Since the approval of vemurafenib, a selective BRAF V600E inhibitor, in 2011, there has been a surge of preclinical and clinical studies aimed at developing novel targeted therapies for a wide range of molecularly defined melanomas. In this review, we will examine the present status and future potential of molecularly targeted therapies directed at the most significant oncogenic signaling pathways in melanoma.

Genetics of melanocytic nevi.

Melanocytic nevi are a benign clonal proliferation of cells expressing the melanocytic phenotype, with heterogeneous clinical and molecular characteristics. In this review, we discuss the genetics of nevi by salient nevi subtypes: congenital melanocytic nevi, acquired melanocytic nevi, blue nevi, and Spitz nevi. While the molecular etiology of nevi has been less thoroughly studied than melanoma, it is clear that nevi and melanoma share common driver mutations. Acquired melanocytic nevi harbor oncogenic mutations in BRAF, which is the predominant oncogene associated with melanoma. Congenital melanocytic nevi and blue nevi frequently harbor NRAS mutations and GNAQ mutations, respectively, while Spitz and atypical Spitz tumors often exhibit HRAS and kinase rearrangements. These initial 'driver' mutations are thought to trigger the establishment of benign nevi. After this initial phase of the cell proliferation, a senescence program is executed, causing termination of nevi growth. Only upon the emergence of additional tumorigenic alterations, which may provide an escape from oncogene-induced senescence, can malignant progression occur. Here, we review the current literature on the pathobiology and genetics of nevi in the hope that additional studies of nevi promise to inform our understanding of the transition from benign neoplasm to malignancy.

Cutaneous Melanoma in Women.

The incidence of cutaneous melanoma (CM) continues to increase in the Caucasian population in the United States. In 2014, women only accounted for 42% of the 76,100 new melanoma cases and only 33% of the 9,710 deaths associated with CM in the US.1 These trends are consistently observed in populations around the world. Indeed, gender disparity in melanoma outcome is so consistently observed that gender has been suggested as an important prognostic factor in melanoma, despite not being formerly incorporated in staging algorithms.2 The source of this gender disparity in melanoma remains unclear but likely represents both biological and behavioral etiologies. Herein, we review the current knowledge of how melanoma differs between men and women.

Unilateral Pedicle Screw Fixation is Associated with Reduced Cost and Similar Outcomes in Selected Patients Undergoing Minimally Invasive Transforaminal Lumbar Interbody Fusion for L4-5 Degenerative Spondylolisthesis.

STUDY DESIGN: Retrospective study of 24 patients who underwent either a bilateral or unilateral TLIF procedure for the treatment of degenerative spondylolisthesis. OBJECTIVE: To analyze differences in cost and outcome between patients undergoing minimally invasive transforaminal lumbar interbody fusion (mi-TLIF) with unilateral or bilateral pedicle screw fixation for L4-5 degenerative spondylolisthesis. SUMMARY OF BACKGROUND DATA: Lumbar fusion surgeries, including the TLIF procedure, have been shown to be an effective treatment for leg and low back pain caused by degenerative spondylolisthesis. Some studies have shown TLIF surgeries to be cost-effective, but there is still a paucity of data and no consensus. Unilateral TLIFs can provide the same benefits as bilateral TLIFs, but come with additional benefits of a less invasive surgery. METHODS: We retrospectively analyzed a consecutive series of patients with L4-5 degenerative stenosis and spondylolisthesis who either received a unilateral or bilateral mi-TLIF, paying particular attention to hospital cost and clinical outcome. Of the 33 patients eligible for analysis, we were able to obtain appropriate clinical and radiographic follow-up data on 24 patients (72.7%), 14 patients who underwent unilateral fixation, and 10 patients who underwent bilateral fixation. RESULTS: The cohorts were similar with regard to age, comorbidities, and demographics. Most patients reported good or excellent results, and there were no significant differences between the cohorts with regard to clinical outcome. There was one interbody graft extrusion in the unilateral cohort that required explantation, but no other hardware failures. Hospital cost was significantly lower in the unilateral cohort, and hardware savings accounted for only part of the difference. CONCLUSION: Unilateral pedicle screw fixation is an acceptable surgical strategy in patients with stable L4-5 degenerative spondylolisthesis undergoing mi-TLIF. In our series, unilateral fixation led to significant hospital cost savings without compromising clinical or radiographic outcomes.

Generation of adaptive regulatory T cells by alloantigen is required for some but not all transplant tolerance protocols.

BACKGROUND: Because CD4CD25Foxp3 regulatory T cells (Tregs) are essential for the maintenance of self-tolerance, significant interest surrounds the developmental cues for thymic-derived natural Tregs (nTregs) and periphery-generated adaptive Tregs (aTregs). In the transplant setting, the allograft may play a role in the generation of alloantigen-specific Tregs, but this role remains undefined. We examined whether the immune response to a transplant allograft results in the peripheral generation of aTregs. METHODS: To identify generation of aTregs, purified graft-reactive CD4CD25 T cells were adoptively transferred to mice-bearing skin allograft. To demonstrate that aTregs are necessary for tolerance, DBA/2 skin was transplanted onto C57BL/6-RAG-1-deficient recipients adoptively transferred with purified sorted CD4CD25 T cells; half of the recipients undergo tolerance induction treatment. RESULTS: By tracking adoptively transferred cells, we show that purified graft-reactive CD4CD25 T lymphocytes up-regulate Foxp3 in mice receiving skin allografts in the absence of any treatment. Interestingly, cotransfer of antigen-specific nTregs suppresses the up-regulation of Foxp3 by inhibiting the proliferation of allograft-responsive T cells. In vitro data are consistent with our in vivo data-Foxp3 cells are generated on antigen activation, and this generation is suppressed on coculture with antigen-specific nTregs. Finally, blocking aTreg generation in grafted, rapamycin-treated mice disrupts alloantigen-specific tolerance induction. In contrast, blocking aTreg generation in grafted mice treated with nondepleting anti-CD4 plus anti-CD40L antibodies does not disrupt graft tolerance. CONCLUSIONS: We conclude that graft alloantigen stimulates the de novo generation of aTregs, and this generation may represent a necessary step in some but not all protocols of tolerance induction.