A Rare Case of Renal Angiomyolipoma and Polycystic Kidney Disease in a Patient with Tuberous Sclerosis.

Renal angiomyolipoma (AML) is a rare benign tumor that follows an autosomal dominant inheritance pattern. Its association with polycystic kidney disease is uncommon, with only a handful of cases documented in the literature. The growth of lesions to a significant size may lead to life-threatening complications. We report a case of a 32-year-old female who presented with a palpable mass and bilateral flank pain. Following clinical assessment and CT examination, the patient underwent a left radical nephrectomy. The resected mass measured 9.3 x 8.2 x 7.5 cm, and the subsequent histopathological examination confirmed the diagnosis as renal AML.

Central nervous system active medication use in Medicare enrollees receiving home health care: association with chronic pain and anxiety level.

ABSTRACT: No comparative effectiveness data exist on nonopioid analgesics and nonbenzodiazepine anxiolytics to treat pain with anxiety. We examined the relationship between drug class and central nervous system (CNS) active drug polypharmacy on pain and anxiety levels in Medicare enrollees receiving home health (HH) care. This retrospective cohort study included enrollees with diagnoses and 2+ assessments of pain and anxiety between HH admission and discharge. Three sets of linear regression difference-in-reduction analyses assessed the association of pain or anxiety reduction with number of drugs; drug type; and drug combinations in those with daily pain and daily anxiety. Logistic regression analysis assessed the effect of medication number and class on less-than-daily pain or anxiety at HH discharge. A sensitivity analysis using multinomial regression was conducted with a three-level improvement to further determine clinical significance. Of 85,403 HH patients, 43% received opioids, 27% benzodiazepines, 26% gabapentinoids, 32% selective serotonin reuptake inhibitors, and 8% serotonin and norepinephrine reuptake inhibitors (SNRI). Furthermore, 75% had depression, 40% had substance use disorder diagnoses, and 6.9% had PTSD diagnoses. At HH admission, 83%, 35%, and 30% of patients reported daily pain, daily anxiety, and both, respectively. Central nervous system polypharmacy was associated with worse pain control and had no significant effect on anxiety. For patients with daily pain plus anxiety, pain was best reduced with one medication or any drug combination without opioid/benzodiazepine; anxiety was best reduced with combinations other than opiate/benzodiazepine. Gabapentinoids or SNRI achieved clinically meaningful pain control. Selective serotonin reuptake inhibitors provided clinically meaningful anxiety relief.

Adapting with the Pandemic: Modified Mohs Micrographic Surgery Using Rim and Deep Margin Technique.

The COVID-19 pandemic has changed many facets of medical care and has resulted in a rise in delayed treatments across all specialties, including cosmetic dermatology. Delayed care for squamous cell carcinomas (SCC) and basal cell carcinoma (BCC) is not only a burden for medical providers, but also confers a risk to patients, as delayed surgeries are associated with increased metastatic risk and tumor size. Mohs micrographic surgery (MMS) delayed by more than one year leads to increased risk of complications, including bleeding and impaired wound healing, especially in the elderly population. To decrease bleeding risks, we have developed a modified MMS technique known as the "rim and deep margin" technique. Here, we present additional cases using this technique to minimize bleeding and operative time for patients with an increased risk of morbidity. This technique has been used successfully in the past for large tumors and can now be used for patients who have faced delay of care, as evidenced by its success during the COVID-19 pandemic.

Extramammary Paget disease. Part I. epidemiology, pathogenesis, clinical features, and diagnosis.

Extramammary Paget disease (EMPD) is a rare skin cancer of apocrine-rich skin that mimics common inflammatory and infectious dermatoses, leading to delays in diagnosis and increased patient morbidity. Better clinical recognition of this entity, multidisciplinary patient assessment, and deeper understanding of the underlying pathophysiology are essential to improve patient care and disease outcomes. It is important to distinguish primary intraepithelial/micro-invasive EMPD from invasive EMPD or cases with adenocarcinoma arising within EMPD. This 2-part continuing medical education series provides a complete picture of EMPD. Part 1 of this continuing medical education series reviews the epidemiology, oncogenesis, clinical and histopathologic presentation, workup, and prognosis of this rare cancer.

Artificial Intelligence in Dermatology: A Systematic Review of Its Applications in Melanoma and Keratinocyte Carcinoma Diagnosis.

BACKGROUND: Limited access to dermatologic care may pose an obstacle to the early detection and intervention of cutaneous malignancies. The role of artificial intelligence (AI) in skin cancer diagnosis may alleviate potential care gaps. OBJECTIVE: The aim of this systematic review was to offer an in-depth exploration of published AI algorithms trained on dermoscopic and macroscopic clinical images for the diagnosis of melanoma, basal cell carcinoma, and cutaneous squamous cell carcinoma (cSCC). METHODS: Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, a systematic review was conducted on peer-reviewed articles published between January 1, 2000, and January 26, 2023. RESULTS AND DISCUSSION: Among the 232 studies in this review, the overall accuracy, sensitivity, and specificity of AI for tumor detection averaged 90%, 87%, and 91%, respectively. Model performance improved with time. Despite seemingly impressive performance, the paucity of external validation and limited representation of cSCC and skin of color in the data sets limits the generalizability of the current models. In addition, dermatologists coauthored only 12.9% of all studies included in the review. Moving forward, it is imperative to prioritize robustness in data reporting, inclusivity in data collection, and interdisciplinary collaboration to ensure the development of equitable and effective AI tools.

Jet-injection assisted photodynamic therapy for superficial and nodular basal cell carcinoma: A pilot study.

BACKGROUND: Photodynamic therapy (PDT) with topical δ-Aminolevulinic acid (ALA) has efficacy in treating basal cell carcinoma (BCC) but is limited by incomplete penetration of ALA into the deeper dermis. This prospective open-label pilot trial investigated the safety and efficacy of photosensitizer jet injection for PDT (JI-PDT) for BCC treatment. It was performed with 15 patients (n = 15) with histologically confirmed, untreated, low-risk nodular BCCs at a single institution. METHODS: For the intervention, JI-PDT patients (n = 11) received two sessions of jet-injected ALA with PDT separated by four to 6 weeks. To further understand treatment technique, another group of patients (n = 4) received jet-injected ALA followed by tumor excision and fluorescence microscopy (JI-E). Treatment tolerability was assessed by local skin responses (LSR) score at five distinct time intervals. Fluorescence microscopy assessed protoporphyrin IX penetration depth and biodistribution within the tumor. At the primary endpoint, tumor clearance was evaluated via visual inspection, dermoscopy and reflectance confocal microscopy. Postinjection and postillumination pain levels, and patient satisfaction, were scored on a 0-10 scale. RESULTS: Fifteen participants with mean age of 58.3, who were 15/15 White, non-Hispanic enrolled. The median composite LSR score immediately after JI-PDT was 5 (interquartile range [IQR] = 3) which decreased to 0.5 (IQR = 1) at primary endpoint (p < 0.01). Immunofluorescence of excised BCC tumors with jet-injected ALA showed photosensitizer penetration into papillary and reticular dermis. Of the 13 JI-PDT tumors, 11 had tumor clearance confirmed, 1 recurred, and 1 was lost to follow-up. 1/11 patients experienced a serious adverse event of cellulitis. 70% of patients had local scarring at 3 months. Patients reported an average pain level of 5.6 (standard deviation [SD] = 2.3) during jet injection and 3.7 (SD = 1.8) during light illumination. CONCLUSIONS: Jet injection of ALA for PDT treatment of nodular low-risk BCC is tolerable and feasible and may represent a novel modality to improve PDT.

Extramammary Paget disease. Part II. Evidence-based approach to management.

Extramammary Paget disease is a rare cutaneous malignancy that most commonly affects the genitals, perianal area, and axilla of elderly patients. Delays in care often lead to high levels of disease burden for patients. Thus, evidence-based recommendations are paramount in mitigating morbidity and mortality for this unique patient population. This 2-part continuing medical education series provides a complete picture of extramammary Paget disease. Part 2 of this continuing medical education series focuses on the complex management of extramammary Paget disease including surgical and noninvasive therapies, as well as novel approaches for advanced disease.

A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury.

Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal damage and impairment of spatial memory in HIVgp120tg mice. Altogether, our findings suggest a novel critical role for cysteinyl-leukotrienes in HIV-associated brain injury.

Oral Metformin Inhibits Choroidal Neovascularization by Modulating the Gut-Retina Axis.

Purpose: Emerging data indicate that metformin may prevent the development of age-related macular degeneration (AMD). Whereas the underlying mechanisms of metformin's anti-aging properties remain undetermined, one proposed avenue is the gut microbiome. Using the laser-induced choroidal neovascularization (CNV) model, we investigate the effects of oral metformin on CNV, retinal pigment epithelium (RPE)/choroid transcriptome, and gut microbiota. Methods: Specific pathogen free (SPF) male mice were treated via daily oral gavage of metformin 300 mg/kg or vehicle. Male mice were selected to minimize sex-specific differences to laser induction and response to metformin. Laser-induced CNV size and macrophage/microglial infiltration were assessed by isolectin and Iba1 immunostaining. High-throughput RNA-seq of the RPE/choroid was performed using Illumina. Fecal pellets were analyzed for gut microbiota composition/pathways with 16S rRNA sequencing/shotgun metagenomics, as well as microbial-derived metabolites, including small-chain fatty acids and bile acids. Investigation was repeated in metformin-treated germ-free (GF) mice and antibiotic-treated/GF mice receiving fecal microbiota transplantation (FMT) from metformin-treated SPF mice. Results: Metformin treatment reduced CNV size (P < 0.01) and decreased Iba1+ macrophage/microglial infiltration (P < 0.005). One hundred forty-five differentially expressed genes were identified in the metformin-treated group (P < 0.05) with a downregulation in pro-angiogenic genes Tie1, Pgf, and Gata2. Furthermore, metformin altered the gut microbiome in favor of Bifidobacterium and Akkermansia, with a significant increase in fecal levels of butyrate, succinate, and cholic acid. Metformin did not suppress CNV in GF mice but colonization of microbiome-depleted mice with metformin-derived FMT suppressed CNV. Conclusions: These data suggest that oral metformin suppresses CNV, the hallmark lesion of advanced neovascular AMD, via gut microbiome modulation.

Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases.

The DNAJB1-PRKACA oncogenic gene fusion results in an active kinase enzyme, J-PKAcα, that has been identified as an attractive antitumor target for fibrolamellar hepatocellular carcinoma (FLHCC). A high-throughput assay was used to identify inhibitors of J-PKAcα catalytic activity by screening the NCI Program for Natural Product Discovery (NPNPD) prefractionated natural product library. Purification of the active agent from a single fraction of an Aplidium sp. marine tunicate led to the discovery of two unprecedented alkaloids, aplithianines A (1) and B (2). Aplithianine A (1) showed potent inhibition against J-PKAcα with an IC50 of ∼1 µM in the primary screening assay. In kinome screening, 1 inhibited wild-type PKA with an IC50 of 84 nM. Further mechanistic studies including cocrystallization and X-ray diffraction experiments revealed that 1 inhibited PKAcα catalytic activity by competitively binding to the ATP pocket. Human kinome profiling of 1 against a panel of 370 kinases revealed potent inhibition of select serine/threonine kinases in the CLK and PKG families with IC50 values in the range ∼11-90 nM. An efficient, four-step total synthesis of 1 has been accomplished, enabling further evaluation of aplithianines as biologically relevant kinase inhibitors.

Postoperative micronutrient changes in bariatric surgery patients compliant with nutritional supplementation.

BACKGROUND: Bariatric surgery is commonly used in patients with body mass indexes over 35 kg/m and obesity-related comorbidities. Despite the significant clinical benefits of bariatric surgery, nutritional deficiencies post-surgery remain a challenge for both patient and healthcare provider [Toninello et al. in Nutrients 13:1565, 2021, Gasmi et al. in Eur J Nutr 61:55-67, 2022]. Nutritional supplementation is a way of reducing the likelihood of postoperative deficiencies; however, prior studies have shown varying degrees of mostly poor to moderate patient adherence [Spetz et al. in Obes Res Clin Pract 16:407-412, 2022, Mahawar et al. in Obes Surg 29:1551-1556, 2019, Santonicola et al. in J Am Nutr Assoc 41:11-19, 2022, Sherf Dagan et al. in Obes Surg 27:2258-2271, 2017]. Our present study aims to provide insights into the micronutrient biochemical profile in patients previously found to be compliant with supplementation following roux-en-y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG). METHODS: An 11-point outpatient survey was administered to consecutive patients ≥ 18 years who had undergone either RYGB or VSG to determine adherence with nutritional supplementation. Medical records were retrospectively reviewed to determine preoperative and postoperative lab values, including vitamins A, B1, B12, and D, thyroid stimulating hormone (TSH), iron binding capacity, transferrin, ferritin, folate, iron, albumin, hemoglobin A1C, zinc, glomerular filtration rate (GFR, and liver function values. Values were classified as "abnormal" or "normal." Preoperative and postoperative values were compared for differences. Postoperative values were also compared between RYGB and VSG. RESULTS: There were no significant differences between preoperative and postoperative values for any nutritional marker aside from vitamin B12. A total of 51/60 patients (85.0%) had normal preoperative B12 measurements, compared with 40/65 (61.5%) patients postoperatively (P = 0.03). Notably, of 25 "abnormal" postoperative measurements, 20 (80%) were elevated values. There were no differences in postoperative deficiencies between RYGB and VSG. CONCLUSIONS: Patients in our sample did not have worsened micronutrient deficiencies following bariatric surgery, and there were no differences in micronutrient deficiencies between surgical technique.

Imaging Tools for Noninvasive Hair Assessment.

Trichology tools historically have been limited in their ability to provide noninvasive detailed assessments of the hair and scalp. Recent advances in diagnostic and treatment monitoring technologies have begun to fill this gap. Global photography previously relied on a film camera and stereotactic imaging equipment but has been simplified by the advent of cameras that use software analysis and provide adjustable outlines to match facial features for the capture of standardized views. Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) both enable in vivo visualization of subcutaneous structures and provide new insight into the dynamic subclinical changes of alopecia. Recent efforts focus on training convolutional neural networks to quantify various hair parameters on OCT scans. When scalp biopsy is necessary, trichoscopy, RCM, and OCT can guide in selecting biopsy sites. Because of the growing clinical applications of these technologies, clinicians should be aware of the advantages and limitations of noninvasive hair-imaging tools.

Efficacy of Intralesional Vitamin D3 for Treatment of Verruca Vulgaris: A Randomized Control Study.

Cutaneous warts are benign epithelial lesions caused by human papillomavirus and are common entities, affecting nearly 10 percent of the United States population. While most warts spontaneously resolve, the immunocompromised are susceptible to recalcitrant warts which often require medical treatment. Most current therapies use either physical or chemical destruction for wart removal, but these treatments are associated with adverse effects. Intralesional vitamin D3 has the potential to demonstrate a stronger treatment response due to its ability to stimulate the immune system at the injection site via cell-mediated immunity. We sought to test the efficacy of intralesional vitamin D3 for wart treatment in a sample size of 70 patients over a three-month period. Efficacy was determined as "excellent" if there was greater than a 90-percent reduction in both size and number of lesions, "good" if there was a 60 to 89-percent reduction, and "fair" if there was less than a 60-percent reduction. Treatment efficacy was excellent in 20 (28.6%) patients, good in 29 (41.4%) patients, fair in 18 (25.7%) patients, and poor in three (4.3%) patients. Patients in the younger age group had a higher treatment efficacy compared to other treatment groups. Thus, intralesional vitamin D3 has promising qualities as a treatment for cutaneous warts and should be considered at the clinician's disposal. Vitamin D is an innovative approach for treating warts without the various side effects posed by other commonly used agents. The unique features of this treatment modality including its simplicity, safety, and efficiency make it a promising option for a very common cutaneous condition.

Annular and acral/facial dyskeratotic paraneoplastic disorders.

Annular and acral/facial dyskeratotic paraneoplastic disorders are inflammatory dermatoses that occur in association with distant cancers but are not precursors, extensions, or metastases of them. There are four classical entities under this rubric: two gyrate entities, erythema annulare centrifugum and erythema gyratum repens, and two acral/facial dyskeratotic entities, acrokeratosis paraneoplastic (Bazex syndrome) and tripe palms. Each of these entities may also occur in association with another etiopathogenesis and may present either as a classical entity or as a barely recognizable disease. We discuss these entities, their associated causes, and their differential diagnoses in turn.

Patient perspectives on post-bariatric surgery nutritional supplementation.

BACKGROUND: Bariatric procedures increase patient risk of long-term metabolic complications primarily due to nutrient deficiencies. The mainstay of prevention includes routine vitamin and mineral supplementation; however, patient-reported barriers to daily compliance are poorly understood. METHODS: Post-bariatric surgery patients electively participated in an 11-point outpatient survey at a single academic institution. Surgical procedures included either laparoscopic sleeve gastrectomy (SG) or gastric bypass (GB). At the time of survey, patients ranged from 1-month to 15 years from surgery. Survey items consisted of dichotomous (yes/no), multiple choice, and open-ended free response questions. Descriptive statistics were evaluated. RESULTS: Two hundred and fourteen responses were collected, 116 (54%) underwent SG and 98 (46%) underwent GB. Of these, 49% of samples were during short-term postoperative follow-up visits (0-3 months), 34% intermediate follow-up (4-12 months), and 17% long-term follow-up (> 1 year). A total of 98% of patients reported that insurance did not cover their supplement cost. Most patients reported current vitamin use (95%), with 87% reporting daily compliance. Daily compliance was observed in 94%, 79%, and 73% of SG patients at short-, intermediate-, and long-term follow-up visits, respectively. While GB patients reported daily compliance in 84%, 100%, and 92% of short, intermediate, and long-term responses. Of those who were unable to take vitamins daily, non-compliance was attributed most to forgetting (54%), and less often to side effects (11%), or taste (11%). Patient-reported strategies for remembering to take vitamins included tying into daily routine (55%), use of a pill box (7%), and alarm reminders (7%). CONCLUSIONS: Daily compliance with post-bariatric surgery vitamin supplementation does not appear to vary based on postoperative time-period or surgical procedure. While a minority of patients struggle with daily compliance, factors associated with non-compliance include patient forgetting, side effects, and taste. Widespread utilization of patient-reported daily reminder strategies may lead to improved overall compliance and reduce incidence of nutritional deficiencies.

Topical Application of 0.5% Timolol Maleate Hydrogel for the Treatment of Superficial Infantile Hemangiomas.

BACKGROUND: Oral propranolol is considered the first line therapy in the treatment of infantile hemangiomas (IHs). However, there are considerable side effects due to its ability to penetrate the blood brain barrier. Alternatively, topical timolol, a non-selective beta blocker, has resulted in fewer side effects and is 4–10 times more potent in comparison to oral propranolol. This study evaluates the efficacy of 0.5% timolol maleate hydrogel for the treatment of IH. METHODS: This study was conducted via a quasi-experimental design from October 30, 2020 – April 29, 2021, at the Department of Dermatology Benazir Bhutto Hospital, Rawalpindi. 145 infants between 1–12 months in age diagnosed with superficial cutaneous hemangiomas were included in the study with a male to female ratio of 2.4:1. A thin layer of timolol maleate 0.5% hydrogel was applied to the entire surface of the patient’s IH three times daily. Digital photographs and measurements of the hemangiomas were taken at one-month intervals for a maximum of 6 months. RESULTS: The age range in this study was from 1–12 months with a mean age of 6.10 ± 2.52 months. The majority of the patients 89 (61.4%) were between 1–6 months of age. Of the 145 patients, 89 (61.4%) showed an excellent response, 44 (30.3%) showed a good response, and 12 (8.3%) showed no response to the topical 0.5% timolol maleate hydrogel treatment. CONCLUSION: The use of topical 0.5% timolol maleate hydrogel is a promising therapeutic option for the treatment of superficial IHs. Anwar F, Mahmood E, Sharif S, et al. Topical application of 0.5% timolol maleate hydrogel for the treatment of superficial infantile hemangiomas. J Drugs Dermatol. 2023;22(6):594-598. doi:10.36849/JDD.7054.

Integrating Echocardiography Parameters With Explainable Artificial Intelligence for Data-Driven Clustering of Primary Mitral Regurgitation Phenotypes.

BACKGROUND: Primary mitral regurgitation (MR) is a heterogeneous clinical disease requiring integration of echocardiographic parameters using guideline-driven recommendations to identify severe disease. OBJECTIVES: The purpose of this preliminary study was to explore novel data-driven approaches to delineate phenotypes of MR severity that benefit from surgery. METHODS: The authors used unsupervised and supervised machine learning and explainable artificial intelligence (AI) to integrate 24 echocardiographic parameters in 400 primary MR subjects from France (n = 243; development cohort) and Canada (n = 157; validation cohort) followed up during a median time of 3.2 years (IQR: 1.3-5.3 years) and 6.8 (IQR: 4.0-8.5 years), respectively. The authors compared the phenogroups' incremental prognostic value over conventional MR profiles and for the primary endpoint of all-cause mortality incorporating time-to-mitral valve repair/replacement surgery as a covariate for survival analysis (time-dependent exposure). RESULTS: High-severity (HS) phenogroups from the French cohort (HS: n = 117; low-severity [LS]: n = 126) and the Canadian cohort (HS: n = 87; LS: n = 70) showed improved event-free survival in surgical HS subjects over nonsurgical subjects (P = 0.047 and P = 0.020, respectively). A similar benefit of surgery was not seen in the LS phenogroup in both cohorts (P = 0.70 and P = 0.50, respectively). Phenogrouping showed incremental prognostic value in conventionally severe or moderate-severe MR subjects (Harrell C statistic improvement; P = 0.480; and categorical net reclassification improvement; P = 0.002). Explainable AI specified how each echocardiographic parameter contributed to phenogroup distribution. CONCLUSIONS: Novel data-driven phenogrouping and explainable AI aided in improved integration of echocardiographic data to identify patients with primary MR and improved event-free survival after mitral valve repair/replacement surgery.