Pediatric Dermatology for People of Color.

When evaluating pediatric patients of color, it is essential to consider the unique diagnostic and treatment factors that apply to this population. Certain dermatologic conditions are more common in these patients, including postinflammatory hyperpigmentation, pityriasis alba, progressive macular hypomelanosis, tinea capitis, traction alopecia, keloids, hypertrophic scars, pseudofolliculitis barbae, acne keloidalis nuchae, and hidradenitis suppurativa. Furthermore, conditions such as vitiligo are more noticeable in people of color. This can lead to a significantly diminished quality of life, so these conditions should be quickly recognized and treated. Notably, inflammation can be difficult to recognize on the skin of people of color, which can lead to the underestimation of severity as well as inappropriate treatment. Treatment recommendations can also differ based on lifestyle or cultural norms, such as the use of tinted sunscreens and the consideration of hair care practices. Pediatricians should be aware of these conditions and treatment considerations to best treat pediatric patients of color. [Pediatr Ann. 2024;53(4):e146-e151.].

Neurological adverse effects associated with anti-PD1 antibodies alone or in combination with ipilimumab: a multicenter case series.

Anti-programmed cell death protein 1 (PD1) antibodies, pembrolizumab and nivolumab, alone or in combination with ipilimumab, have become standard treatment for melanoma and multiple other malignancies. Neurological adverse effects are rare and have not been well characterized to date. Patients who developed neurological adverse effects while being treated with PD1, alone or in combination with ipilimumab, were retrospectively identified from 10 cancer centers. Fifty-eight patients were included, and the median time from treatment initiation to development of neurological adverse effects was 7 weeks (range, 1-86.5 weeks). Thirty-seven (64%) toxicities affected the peripheral nervous system. Fifty (86%) patients were treated with corticosteroids, with 22 (37%) patients requiring further immunomodulation including intravenous immunoglobulin (16), plasmapheresis (7), mycophenolate mofetil (4), cyclophosphamide (1), and rituximab (1). Twenty-seven (46%) had a complete resolution of their neurological symptoms, and two (4%) patients died secondary to complications from their neurological adverse effects. The response rate of the cancer to immunotherapy was 78%, and the median progression free survival was not reached. Neurological adverse effects can occur with PD1 treatment, do not appear to impact treatment response, but may be irreversible or worsen in some patients. Management may require immunomodulation beyond corticosteroids.

Benefit and toxicity of programmed death-1 blockade vary by ethnicity in patients with advanced melanoma: an international multicentre observational study.

BACKGROUND: Programmed cell death receptor-1 (PD-1) monotherapy is a standard treatment for advanced cutaneous melanoma, but its efficacy and toxicity are defined in white populations and remain poorly characterized in other ethnic groups, such as East Asian, Hispanic and African. OBJECTIVES: To determine the efficacy and toxicity of PD-1 monotherapy in different ethnic groups. METHODS: Clinical data for patients with unresectable or advanced melanoma treated with anti-PD-1 monotherapy between 2009 and 2019 were collected retrospectively from five independent institutions in the USA, Australia and China. Tumour response, survival and immune-related adverse events (irAEs) were compared by ethnicity (white vs. East Asian/Hispanic/African) across different melanoma subtypes: nonacral cutaneous (NAC)/unknown primary (UP) and acral/mucosal/uveal. RESULTS: In total, 1135 patients were included. White patients had significantly higher objective response rate (ORR) [54%, 95% confidence interval (CI) 50-57% vs. 20%, 95% CI 13-28%; adjusted P < 0·001] and longer progression-free survival (14·2 months, 95% CI 10·7-20·3 vs. 5·4 months, 95% CI 4·5-7·0; adjusted P < 0·001) than East Asian, Hispanic and African patients in the NAC and UP subtypes. White ethnicity remained independently associated with a higher ORR (odds ratio 4·10, 95% CI 2·48-6·81; adjusted P < 0·001) and longer PFS (hazard ratio 0·58, 95% CI 0·46-0·74; adjusted P < 0·001) in multivariate analyses after adjustment for age, sex, primary anatomical location, metastasis stage, baseline lactate dehydrogenase level, mutational status and prior systemic treatment. White and East Asian/Hispanic/African patients shared similar ORR and progression-free survival in acral/mucosal/uveal melanomas. Similar melanoma-subtype-specific ethnic discrepancies were observed in complete response rate and overall survival. White patients had higher rates of gastrointestinal irAEs but lower rates of endocrine, liver and other rare types of irAEs. These differences in irAEs by ethnicity were not attributable to varying melanoma subtypes. CONCLUSIONS: Ethnic discrepancy in clinical benefit is specific to melanoma subtype, and East Asian, Hispanic and African patients with NAC and UP melanomas have poorer clinical benefits than previously recognized. The ethnic discrepancy in toxicity observed across different melanoma subtypes warrants an ethnicity-based irAE surveillance strategy. More research is needed to elucidate the molecular and immunological determinants of these differences. What is already known about this topic? There is a great difference in response to immunotherapy between different subtypes of melanoma (cutaneous, mucosal, acral and uveal) in patients with advanced disease. What does this study add? Our data show for the first time that there are differences between different ethnic groups in terms of both response and toxicity to immunotherapy beyond the well-appreciated discrepancies due to melanoma subtype.

Stage-Specific Generation of Human Pluripotent Stem Cell Derived Lung Models to Measure CFTR Function.

Human embryonic stem cells (ES) and induced pluripotent stem cells (iPSC) are powerful tools that have the potential to generate in vitro human lung epithelial cells. However, challenges in efficiency and reproducibility remain in utilizing the cells for therapy discovery platforms. Here, we optimize our previously published protocols to efficiently generate three developmental stages of the lung model (fetal lung epithelial progenitors, fLEP; immature airway epithelial spheroid, AES; air-liquid interface culture, ALI), and demonstrate its potential for cystic fibrosis (CF) drug discovery platforms. The stepwise approach directs differentiation from hPSC to definitive endoderm, anterior ventral foregut endoderm, and fetal lung progenitor cells. The article also describes the generation of immature airway epithelial spheroids in Matrigel with epithelial cells sorted by a magnetic-activated cell sorting system, and the generation of adult-like airway epithelia through air-liquid interface conditions. We demonstrate that this optimized procedure generates remarkably higher cystic fibrosis transmembrane conductance regulator (CFTR) expression and function than our previous method, and thus is uniquely suitable for CF research applications. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: hESC/hiPSC differentiation to fetal lung progenitors Basic Protocol 2: Formation of airway epithelial spheroids Alternate Protocol 1: Cryopreservation of airway epithelial spheroids Basic Protocol 3: Differentiation and maturation in air-liquid interface culture Alternate Protocol 2: Differentiation and maturation of epithelial progenitors from airway epithelial spheroids in ALI culture.

Cutaneous adverse events caused by immune checkpoint inhibitors.

IMPORTANCE: Immune checkpoint inhibitors (ICIs) have emerged as active therapies for a variety of cancers. Cutaneous toxicities are common immune-related adverse events and patients will often be referred to dermatologists for evaluation. OBSERVATIONS: Cutaneous adverse events to ICIs can have a variety of clinical presentations. Among the more common are eczematous, morbilliform, and lichenoid dermatoses, as well as vitiligo and pruritus. Less common adverse events include psoriasiform dermatoses, bullous disorders, and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Because of the immunologic mechanism of ICIs, there are also a variety of rheumatologic adverse reactions with cutaneous manifestations, such as scleroderma, dermatomyositis, cutaneous lupus erythematosus, and various vasculitides. These cutaneous reactions often respond to topical or systemic steroids, although specific toxicities may have alternative treatments available. CONCLUSIONS AND RELEVANCE: As they become more widely prescribed, dermatologists will see an increasing number of patients with cutaneous adverse events caused by ICI therapies. Accurately diagnosing and treating these toxicities is paramount to achieving the most favorable outcomes for patients.

Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated with Poorer Survival in Patients with Advanced Melanoma Treated with Anti-PD-1 Monotherapy.

PURPOSE: Programmed cell death receptor-1 (PD-1) inhibitors are frontline therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti-PD-1 monotherapy remains unclear. EXPERIMENTAL DESIGN: In this multicenter retrospective analysis, patients treated with anti-PD-1 monotherapy between 2009 and 2019 and detailed GCC use, data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti-PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed. RESULTS: Of the entire cohort of 947 patients, 509 (54%) developed irAEs. In the MGH cohort [irAE(+) n = 90], early-onset irAE (within 8 weeks of anti-PD-1 initiation) with high-dose GCC use (≥60-mg prednisone equivalent once a day) was independently associated with poorer post-irAE PFS/OS (progression-free survival/overall survival) [post-irAE PFS: HR, 5.37; 95% confidence interval (CI), 2.10-13.70; P < 0.001; post-irAE OS: HR, 5.95; 95% CI, 2.20-16.09; P < 0.001] compared with irAEs without early high-dose GCC use. These findings were validated in the combined validation cohort [irAE(+) n = 419, post-irAE PFS: HR, 1.69; 95% CI, 1.04-2.76; P = 0.04; post-irAE OS: HR, 1.97; 95% CI, 1.15-3.39; P = 0.01]. Similar findings were also observed in the 26-week landmark analysis for post-irAE-PFS but not for post-irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results. CONCLUSIONS: Early high-dose GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti-PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.

Impact of body composition on outcomes from anti-PD1 +/- anti-CTLA-4 treatment in melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed treatment for melanoma, but identifying reliable biomarkers of response and effective modifiable lifestyle factors has been challenging. Obesity has been correlated with improved responses to ICI, although the association of body composition measures (muscle, fat, etc) with outcomes remains unknown. METHODS: We performed body composition analysis using Slice-o-matic software on pretreatment CT scans to quantify skeletal muscle index (SMI=skeletal muscle area/height2), skeletal muscle density (SMD), skeletal muscle gauge (SMG=SMI × SMD), and total adipose tissue index (TATI=subcutaneous adipose tissue area + visceral adipose tissue area/height2) of each patient at the third lumbar vertebrae. We then correlated these measures to response, progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Among 287 patients treated with ICI, body mass index was not associated with clinical benefit or toxicity. In univariable analyses, patients with sarcopenic obesity had inferior PFS (HR 1.4, p=0.04). On multivariable analyses, high TATI was associated with inferior PFS (HR 1.7, p=0.04), which was particularly strong in women (HR 2.1, p=0.03). Patients with intermediate TATI and high SMG had the best outcomes, whereas those with low SMG/high TATI had inferior PFS and OS (p=0.02 for both PFS and OS). CONCLUSIONS: Body composition analysis identified several features that correlated with improved clinical outcomes, although the associations were modest. As with other studies, we identified sex-specific associations that warrant further study.

Health care utilization and steroid-refractory toxicities from immune checkpoint inhibitors.

BACKGROUND: Anti-programmed death protein 1 (anti-PD-1) agents have transformed the treatment of advanced melanoma and other cancers, but the rates of steroid-refractory toxicities and health care utilization are not well described. This study assessed these endpoints in patients with melanoma treated with anti-PD-1 with or without ipilimumab. METHODS: This study retrospectively evaluated 344 patients with metastatic melanoma treated with anti-PD-1 or a combination of ipilimumab and nivolumab at Vanderbilt University Medical Center from 2009 to 2018. The incidence, types, grades, management, and outcomes of immune-related adverse events (irAEs) and hospitalizations for irAEs and disease progression were assessed. RESULTS: Patients on combination therapy were more likely to develop irAEs than those on monotherapy (72% vs 37%; P < .001) and were more likely to require systemic steroids (61% vs 20%; P < .001), steroid dose re-escalation (23% vs 6%; P < .001), and second-line immunosuppressive use (17% vs 2%; P < .001) and to suffer high-dose steroid-refractory toxicities (23% vs 3%; P < .001). Combination-treated patients were more likely to have any hospitalization (32% vs 7%; P < .001) or multiple hospitalizations for irAEs (11% vs 3%; P = .001) and had a longer average time of hospitalization (mean, 1.92 vs 0.62 days; P = .002). Among 176 hospitalizations related to disease progression in patients who died during evaluable follow-up, 69% occurred within the 90 days before death. Early hospitalizations for disease-related reasons portended a very poor prognosis (median time from admission to death, 58 days). CONCLUSIONS: Patients treated with a combination of ipilimumab and nivolumab had higher rates of hospitalization and steroid-refractory toxicities than those treated with anti-PD-1 monotherapy. Disease-associated hospitalizations were similar between the 2 groups, portended a poor prognosis, and mostly occurred in the last months of life.

Integrating Specialty-Specific Clinical Anatomy Education into the Post-Clerkship Curriculum.

Anatomy is a foundational science mainstay of undergraduate medical school education, particularly in the pre-clerkship curriculum. During the post-clerkship curriculum, students closer to graduate medical education may benefit from a focused concentration on human anatomy related to their specific clinical interests. Here, we describe a course for post-clerkship students that uniquely incorporates a multimodal approach of dissection, didactics, and clinical correlation to radiologic imaging, with the opportunity to personalize student learning on a specialty-specific anatomic region. The course increased students' confidence of anatomical knowledge and its clinical relevance. Other institutions may benefit from establishing a similar multimodal integrated post-clerkship anatomy curriculum.

Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study.

BACKGROUND: Immune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized. METHODS: We performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC025 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. RESULTS: Among the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14.5-18.9]; IC025 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2-11.8]; IC025 3.15), peripheral neuropathy (1.16% vs. 0.67%, IC025 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5-3.9]; IC025 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~ 20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6-12%), later onset (median 61-80 days), and were non-overlapping. CONCLUSIONS: ICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations.

Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy.

BACKGROUND: Immune checkpoint inhibitors such as pembrolizumab and nivolumab have emerged as active treatment options for patients with many cancers, including metastatic melanoma, but can also cause symptomatic or life-threatening immune-related adverse events, including encephalitis. Epididymitis and orchitis are rare complications of these therapies. CASE PRESENTATION: We describe herein a patient with metastatic melanoma who developed epididymo-orchitis followed by encephalitis while receiving pembrolizumab. The patient developed testicular pain and fever after his third dose of pembrolizumab; ultrasound evaluation demonstrated bilateral epididymo-orchitis. He then developed headaches, fever, and altered mental status over the next week and was admitted to the hospital. Lumbar puncture revealed inflammatory changes consistent with meningoencephalitis; he did not improve with broad-spectrum antibiotics, and an extensive workup for infectious etiologies, including cerebrospinal fluid testing using a clinical metagenomic next-generation sequencing assay, was negative. He received high-dose steroids for suspected autoimmune encephalitis, and both his orchitis and meningoencephalitis improved rapidly after one dose. He fully recovered after a 5-week taper of oral steroids. DISCUSSION: Here, we report a case of epididymo-orchitis complicating immune checkpoint inhibitor therapy. This patient subsequently developed severe encephalitis but rapidly improved with steroids. Clinicians should be aware of rare complications of these agents. KEY POINTS: Epididymo-orchitis is a rare and potentially life-threatening complication of anti-programmed death protein 1 (anti-PD-1) therapy.For patients on anti-PD-1 therapy who develop either epididymo-orchitis or epididymitis without clear infectious cause, immune-related adverse events should be considered in the differential diagnosis.If severe, epididymo-orchitis related to anti-PD-1 therapy may be treated with high-dose corticosteroids.

Incidence of acute kidney injury among pediatric hematology/oncology patients receiving vancomycin in combination with piperacillin/tazobactam or cefepime.

There is mounting evidence that combination of antibiotic therapy with vancomycin and piperacillin/tazobactam (pip/tazo) is associated with acute kidney injury (AKI). To determine whether vancomycin plus pip/tazo is associated with higher rates of AKI compared to vancomycin plus cefepime among pediatric hematology/oncology (heme/onc) patients, we examined 121 heme/onc patients receiving at least two consecutive days of therapy with vancomycin and either pip/tazo or cefepime. Rate of AKI was higher in the pip/tazo than the cefepime group (4/27 [14.8%] vs 2/94 [2.1%], P = 0.022).

Expanding the scope of replicable unnatural DNA: stepwise optimization of a predominantly hydrophobic base pair.

As part of an ongoing effort to expand the genetic alphabet for in vitro and eventually in vivo applications, we have synthesized a wide variety of predominantly hydrophobic unnatural base pairs exemplified by d5SICS-dMMO2 and d5SICS-dNaM. When incorporated into DNA, the latter is replicated and transcribed with greater efficiency and fidelity than the former; however, previous optimization efforts identified the para and methoxy-distal meta positions of dMMO2 as particularly promising for further optimization. Here, we report the stepwise optimization of dMMO2 via the synthesis and evaluation of 18 novel para-derivatized analogs of dMMO2, followed by further derivatization and evaluation of the most promising analogs with meta substituents. Subject to size constraints, we find that para substituents can optimize replication via both steric and electronic effects and that meta methoxy groups are unfavorable, while fluoro substituents can be beneficial or deleterious depending on the para substituent. In addition, we find that improvements in the efficiency of unnatural triphosphate insertion translate most directly into higher fidelity replication. Importantly, we identify multiple, unique base pair derivatives that when incorporated into DNA are well replicated. The most promising, d5SICS-dFEMO, is replicated under some conditions with greater efficiency and fidelity than d5SICS-dNaM. These results clearly demonstrate the generality of hydrophobic forces for the control of base pairing within DNA, provide a wealth of new SAR data, and importantly identify multiple new candidates for eventual in vivo evaluation.

Efficient and sequence-independent replication of DNA containing a third base pair establishes a functional six-letter genetic alphabet.

The natural four-letter genetic alphabet, comprised of just two base pairs (dA-dT and dG-dC), is conserved throughout all life, and its expansion by the development of a third, unnatural base pair has emerged as a central goal of chemical and synthetic biology. We recently developed a class of candidate unnatural base pairs, exemplified by the pair formed between d5SICS and dNaM. Here, we examine the PCR amplification of DNA containing one or more d5SICS-dNaM pairs in a wide variety of sequence contexts. Under standard conditions, we show that this DNA may be amplified with high efficiency and greater than 99.9% fidelity. To more rigorously explore potential sequence effects, we used deep sequencing to characterize a library of templates containing the unnatural base pair as a function of amplification. We found that the unnatural base pair is efficiently replicated with high fidelity in virtually all sequence contexts. The results show that, for PCR and PCR-based applications, d5SICS-dNaM is functionally equivalent to a natural base pair, and when combined with dA-dT and dG-dC, it provides a fully functional six-letter genetic alphabet.