Cutaneous toxicities of mitogen-activated protein kinase inhibitors in children and young adults with neurofibromatosis-1.

PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. However, cutaneous adverse events (CAEs) are common and may hinder patients' abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. METHODS: We reviewed institutional medical records of patients under 30 years with a diagnosis of "NF1," "NF2," or "other neurofibromatoses" on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. RESULTS: Our cohort consisted of 40 patients with NF1 (median age, 14 years). Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi. There was no significant association between CAE presence and tumor response (p = 0.39). CONCLUSIONS: Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

Enhancing Provider Mental Health Screening in Primary Care: A Quality Improvement Project.

Background: Depression and anxiety occur in 7.8% and 19.1% of the US population, respectively. About half of those patients are diagnosed in primary care. Objective: The purpose of this quality improvement project was to improve the screening and diagnosing of anxiety and/or depression among adult patients at a primary care clinic by implementing an evidence-based mental health screening interview technique. Methods: The team implemented a mental health screening interview technique that incorporates background, affect, trouble, handling, and empathy and motivational interviewing techniques in addition to self-report surveys. Pre- and post-intervention surveys were conducted to assess providers' perceptions of the new interview technique. ICD-10 code data were gathered to assess the effectiveness of the new mental health screening interview technique. Results: The number of documented diagnoses of single-episode major depressive disorder decreased by 18%, recurrent major depressive disorder increased by 34%, and anxiety disorders increased by 3%. There were more favorable provider perceptions of the new screening interview technique versus the traditional screening method. Conclusions: The results show an improvement in provider comfort and providers preferred the new mental health screening when using an evidence-based mental health screening interview technique. Implications for nursing: The results show the potential benefits of using a structured mental health interview with self-report screening tools when diagnosing anxiety and depression in primary care.

Enhancing Provider Mental Health Screening in Primary Care: A Quality Improvement Project.

Background: Depression and anxiety occur in 7.8% and 19.1% of the US population, respectively. About half of those patients are diagnosed in primary care. Objective: The purpose of this quality improvement project was to improve the screening and diagnosing of anxiety and/or depression among adult patients at a primary care clinic by implementing an evidence-based mental health screening interview technique. Methods: The team implemented a mental health screening interview technique that incorporates background, affect, trouble, handling, and empathy and motivational interviewing techniques in addition to self-report surveys. Pre- and post-intervention surveys were conducted to assess providers' perceptions of the new interview technique. ICD-10 code data were gathered to assess the effectiveness of the new mental health screening interview technique. Results: The number of documented diagnoses of single-episode major depressive disorder decreased by 18%, recurrent major depressive disorder increased by 34%, and anxiety disorders increased by 3%. There were more favorable provider perceptions of the new screening interview technique versus the traditional screening method. Conclusions: The results show an improvement in provider comfort and providers preferred the new mental health screening when using an evidence-based mental health screening interview technique. Implications for nursing: The results show the potential benefits of using a structured mental health interview with self-report screening tools when diagnosing anxiety and depression in primary care.

Immune checkpoint inhibitor-induced cutaneous toxicities: a review of histopathologic and clinical features.

Immune checkpoint inhibitors (ICIs) represent an emerging treatment option for a variety of cancer types. Through inhibition of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and/or cytotoxic lymphocyte-associated antigen-4 (CTLA-4), ICIs activate the host's immune system causing a heightened anti-tumor response. However, off-target effects of ICIs can result in numerous different immune-related cutaneous adverse events (irCAEs). Beyond impacting quality of life, irCAEs can lead to dose limitations or discontinuation of anti-cancer therapies. Correct diagnosis is necessary for expedient and appropriate management. Skin biopsies are often performed to increase diagnostic accuracy and guide clinical management. An extensive literature review was performed using the PubMed database to identify the reported clinical and histopathologic features of irCAEs. This comprehensive review primarily details the histopathologic features of various irCAEs reported to date. Clinical presentation and immunopathogenesis are also discussed in relation to histopathology.

Immune checkpoint inhibitor-induced vitiligo in cancer patients: characterization and management.

This study highlights the range of non-melanoma cancers where ICI-induced vitiligo can be present and challenges the exclusivity of this phenomenon to melanoma. We believe our manuscript will encourage awareness in our colleagues and stimulate interest in further studies to elucidate the mechanisms of ICI-induced vitiligo in both melanoma and non-melanoma cancers, and to understand whether this phenomenon holds the same positive prognostic value in both cancer groups. This is a retrospective cohort study from a single-institution's electronic medical record for cancer patients treated with ICIs who subsequently developed vitiligo. We identified 151 patients with ICI-induced vitiligo, 19 (12.6%) non-melanoma and 132 (77.4%) melanoma patients. Time to onset of vitiligo was nearly doubled in the non-melanoma cohort, however, this is confounded by possible delayed diagnosis or under reporting of this asymptomatic condition in patients who do not regularly receive skin exams. The majority of patients had a stable course of vitiligo with 91.4% receiving no treatment in this largely Caucasian cohort. Two patients with non-melanoma cancers and Fitzpatrick type IV or above skin received treatment with narrowband ultraviolet B light therapy and topical steroids with near-complete response. This study highlights the occurrence of ICI-induced vitiligo in a variety of non-melanoma cancers, where skin of color patients will be more prevalent and the need for treatment will potentially be more urgent. Further study is needed to elucidate the mechanism of ICI-induced vitiligo and determine if non-melanoma cancers have the same association between vitiligo and increased tumor response.

Systematic review of programmed cell death-1 inhibitor therapy for advanced-stage cutaneous squamous cell carcinoma in solid-organ transplant recipients.

BACKGROUND: Programmed cell death-1 (PD-1) inhibitors represent an effective treatment option for advanced cutaneous squamous cell carcinoma (cSCC). However, solid organ transplant (SOT) recipients with cSCC have traditionally been excluded from clinical trials. OBJECTIVE: To assess the safety and efficacy of PD-1 inhibitors for stage III-IV cSCC in SOT recipients. MATERIALS & METHODS: A systematic review was performed using the PubMed, EMBASE, and Scopus databases. RESULTS: We identified 21 articles describing 33 SOT recipients (26 kidney, four liver, two lung, and one heart) with stage III-IV cSCC treated with PD-1 inhibitors. Eleven patients (33.3%) experienced allograft rejection. Of the 25 cases with iRECIST scores, twelve patients (48.0%) had a complete response (CR), eight (32.0%) showed a partial response (PR), three (12.0%) progressive disease, and two (8.0%) stable disease (SD). Including patients without available iRECIST scores, 21 patients (63.6%) showed tumor response. Eleven patients died, with six (54.5%) due to tumor progression and one (9.1%) due to allograft rejection after foregoing dialysis. CONCLUSION: PD-1 inhibitors demonstrate efficacy for advanced cSCC and confer a risk of allograft rejection in SOT recipients, requiring careful assessment of risks and benefits. If anti-PD-1 therapy is pursued, use of mTOR inhibitors, prophylactic steroids, and donor-derived cell-free DNA monitoring may mitigate the risk of rejection.

Surgical Intervention for Paronychia Induced by Targeted Anticancer Therapies.

BACKGROUND: Paronychia is a common toxicity associated with targeted anticancer therapies. Antibiotics and steroids are the standard treatments for severe paronychia, yet they are often inadequate, prolonging the patient's suffering and resulting in changes to effective cancer therapy. OBJECTIVE: This article describes the clinical course of drug-induced paronychia and attempts to identify circumstances under which nail surgery may be beneficial. MATERIALS AND METHODS: This is a retrospective case series from a single institution's electronic medical record for patients on paronychia-inducing anticancer therapies with nail disease visit diagnosis codes. RESULTS: The authors identified 36 nail procedures performed on 12 patients, all of whom were managed with conservative steroid and antibiotic therapy with varying degrees of improvement; however, no further improvement was seen after 90 days. Partial matricectomy, nail avulsion, debridement/clipping, and incision and drainage were performed with resolution rates of 100% (11/11), 38.5% (5/13), 12.5% (1/8), and 0% (0/4), respectively. The average time to surgical intervention was 196 days, and the average time to resolution was 268 days. CONCLUSION: This series highlights the prolonged course of severe drug-induced paronychia and the importance of surgical intervention to reduce pain and impact on cancer treatment. Partial matricectomy should be considered for paronychia unresponsive to conservative therapy by 3 months.

Transgenic Xenopus laevis Line for In Vivo Labeling of Nephrons within the Kidney.

Xenopus laevis embryos are an established model for studying kidney development. The nephron structure and genetic pathways that regulate nephrogenesis are conserved between Xenopus and humans, allowing for the study of human disease-causing genes. Xenopus embryos are also amenable to large-scale screening, but studies of kidney disease-related genes have been impeded because assessment of kidney development has largely been limited to examining fixed embryos. To overcome this problem, we have generated a transgenic line that labels the kidney. We characterize this cdh17:eGFP line, showing green fluorescent protein (GFP) expression in the pronephric and mesonephric kidneys and colocalization with known kidney markers. We also demonstrate the feasibility of live imaging of embryonic kidney development and the use of cdh17:eGFP as a kidney marker for secretion assays. Additionally, we develop a new methodology to isolate and identify kidney cells for primary culture. We also use morpholino knockdown of essential kidney development genes to establish that GFP expression enables observation of phenotypes, previously only described in fixed embryos. Taken together, this transgenic line will enable primary kidney cell culture and live imaging of pronephric and mesonephric kidney development. It will also provide a simple means for high-throughput screening of putative human kidney disease-causing genes.

Tissue-Specific Gene Inactivation in Xenopus laevis: Knockout of lhx1 in the Kidney with CRISPR/Cas9.

Studying genes involved in organogenesis is often difficult because many of these genes are also essential for early development. The allotetraploid frog, Xenopus laevis, is commonly used to study developmental processes, but because of the presence of two homeologs for many genes, it has been difficult to use as a genetic model. Few studies have successfully used CRISPR in amphibians, and currently there is no tissue-targeted knockout strategy described in Xenopus The goal of this study is to determine whether CRISPR/Cas9-mediated gene knockout can be targeted to the Xenopus kidney without perturbing essential early gene function. We demonstrate that targeting CRISPR gene editing to the kidney and the eye of F0 embryos is feasible. Our study shows that knockout of both homeologs of lhx1 results in the disruption of kidney development and function but does not lead to early developmental defects. Therefore, targeting of CRISPR to the kidney may not be necessary to bypass the early developmental defects reported upon disruption of Lhx1 protein expression or function by morpholinos, antisense RNA, or dominant negative constructs. We also establish a control for CRISPR in Xenopus by editing a gene (slc45a2) that when knocked out results in albinism without altering kidney development. This study establishes the feasibility of tissue-specific gene knockout in Xenopus, providing a cost-effective and efficient method for assessing the roles of genes implicated in developmental abnormalities that is amenable to high-throughput gene or drug screening techniques.