Evaluating the diagnostic performance of a large language model-powered chatbot for providing immunohistochemistry recommendations in dermatopathology.

BACKGROUND: Large language model (LLM)-powered chatbots such as ChatGPT have numerous applications. However, their effectiveness in dermatopathology has not been formally evaluated. Dermatopathological cases often require immunohistochemical workup. Here, we evaluate the performance of a chatbot in providing diagnostically useful information on immunohistochemistry relating to dermatological diseases. METHODS: We queried a commonly used chatbot for the immunophenotypes of 51 cutaneous diseases, including a diverse variety of epidermal, adnexal, hematolymphoid, and soft tissue entities. We requested it to provide references for each diagnosis. All tests were repeated, compiled, quantified, and then compared with established literature standards. RESULTS: Clustering analysis demonstrated that recommendations correlated with tumor type, suggesting chatbots can supply appropriate panels. However, a significant portion of recommendations were factually incorrect (13.9%). Citations were rarely clinically useful (24.5%). Many were confabulated (27.2%). Prompt responses for cutaneous adnexal lesions tended to be less accurate while literature references were less useful. Reference retrieval performance was associated with the number of PubMed entries per entity. CONCLUSIONS: This foundational study suggests that LLM-powered chatbots may be useful for generating immunohistochemical panels for dermatologic diagnoses. However, specific performance capabilities and biases must be considered. In addition, extreme caution is advised regarding the tendencies to fabricate material. Future models intentionally fine-tuned to augment diagnostic medicine may prove to be valuable.

Frequency and features of malignant tumors clinically mimicking cutaneous cysts: A retrospective chart review.

BACKGROUND: Many cutaneous lesions are clinically suspected as "cyst"; however, following histopathological examination, are found to be more significant lesions. Here, we examine the frequency and features of malignancies with cutaneous cysts in the clinical differential. METHODS: A retrospective study of surgical pathology specimens at the James A. Haley Veterans' Hospital from January 2018 to December 2022 was conducted. Cutaneous specimens containing the clinical diagnosis of "cyst" were included. The clinicopathological features were summarized. RESULTS: Premalignant or malignant neoplasms accounted for 4.5% of all specimens submitted with cysts in the clinical differential. Most cyst-mimicking cancers were basal cell carcinoma (BCC) or squamous cell carcinoma (SCC); however, cancers with poorer prognoses, such as Merkel cell carcinoma and melanoma, also clinically masqueraded as cysts. The BCCs were predominately nodular, and the SCCs were largely well-differentiated and invasive. Many exhibited clinical signs and symptoms compatible with benign cysts, such as central punctum, pain, and rapid growth. Identified risk factors included history of prior non-melanoma skin cancer diagnosis, previous excision, and immunosuppression. CONCLUSIONS: Many lesions clinically concerning cutaneous cysts were found to be malignancies following histopathological review. Accordingly, following biopsy all cyst-like lesions should be examined microscopically, especially in certain clinical contexts in which the incidence of skin cancer is increased.

A rare case of hidradenocarcinoma with anaplastic and invasive features arising from a nodulocystic hidradenoma.

A 91-year-old man presented with a cutaneous left abdominal mass. The mass was longstanding (over 5 years) and slow-growing. Examination revealed a violaceous, multinodular, and exophytic non-tender mass surrounded by patchy erythema. Excisional biopsy was performed and revealed a nodular and cystic dermal proliferation of predominately basaloid cells with focal duct formation, surrounded by prominent hyalinized stroma. The superficial portion of the mass was identified as a nodulocystic hidradenoma. Along the deep aspect and in association with the benign hidradenoma, sheets of markedly atypical epithelioid cells invaded the surrounding tissue, consistent with malignant transformation. Perineural and lymphovascular invasion were seen among areas with anaplastic features. This case supports that some hidradenocarcinoma originates from benign counterparts, and as such, ample sampling is required to definitively exclude a more sinister diagnosis. Diagnostic, prognostic, histopathological, and molecular characteristics, and current knowledge limitations are briefly discussed.

Utilization of Our Toolkit: A Systematic Review and Meta-analysis of Surgical Therapies in Vitiligo Treatment.

BACKGROUND: Although vitiligo is often treated medically, there is increasing evidence for surgical therapies. Overlap with in-office surgical therapies that are already employed for other dermatologic conditions suggest that there is a significant opportunity to expand dermatologists' therapeutic repertoire for vitiligo. OBJECTIVE: To systematically review the efficacy of nonphototherapy surgical treatments for vitiligo in comparative or placebo-controlled trials. METHODS: A systematic review for surgical treatments for vitiligo was conducted. Primary outcomes were treatment success (>75% repigmentation) and failure (<25% repigmentation) for which meta-analyses were performed. Adverse effects were noted. The Cochrane risk of bias tool was used to assess study quality. RESULTS: Surgical treatments reviewed included platelet-rich plasma, microneedling, ablative therapies, and surgical modalities. Seventy-three studies with 2,911 patients were included. The repigmentation benefits and adverse events are summarized. Meta-analyses suggest benefits for ablative laser therapies or microneedling in combination with narrowband ultraviolet B (NB-UVB) and for suction blister epidermal grafting over punch grafting. CONCLUSION: The addition of microneedling or ablative laser therapy to NB-UVB phototherapy may improve repigmentation with minimal adverse effects. Surgical therapies, such as suction blister grafting and punch grafting, may offer the highest likelihood of repigmentation but have a risk of adverse effects including scarring and hyperpigmentation.

Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice.

GPCR 37 (GPR37) is a GPCR expressed in the CNS; its physiological and pathophysiological functions are largely unknown. We tested the role of GPR37 in the ischemic brain of GPR37 knockout (KO) mice, exploring the idea that GPR37 might be protective against ischemic damage. In an ischemic stroke model, GPR37 KO mice exhibited increased infarction and cell death compared with wild-type (WT) mice, measured by 2,3,5-triphenyl-2H-tetrazolium chloride and TUNEL staining 24 h after stroke. Moreover, more severe functional deficits were detected in GPR37 KO mice in the adhesive-removal and corner tests. In the peri-infarct region of GPR37 KO mice, there was significantly more apoptotic and autophagic cell death accompanied by caspase-3 activation and attenuated mechanistic target of rapamycin signaling. GPR37 deletion attenuated astrocyte activation and astrogliosis compared with WT stroke controls 24-72 h after stroke. Immunohistochemical staining showed more ionized calcium-binding adapter molecule 1-positive cells in the ischemic cortex of GPR37 KO mice, and RT-PCR identified an enrichment of M1-type microglia or macrophage markers in the GPR37 KO ischemic cortex. Western blotting demonstrated higher levels of inflammatory factors IL-1ß, IL-6, monocyte chemoattractant protein, and macrophage inflammatory protein-1α in GPR37-KO mice after ischemia. Thus, GPR37 plays a multifaceted role after stroke, suggesting a novel target for stroke therapy.-McCrary, M. R., Jiang, M. Q., Giddens, M. M., Zhang, J. Y., Owino, S., Wei, Z. Z., Zhong, W., Gu, X., Xin, H., Hall, R. A., Wei, L., Yu, S. P. Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice.

Glycosaminoglycan scaffolding and neural progenitor cell transplantation promotes regenerative immunomodulation in the mouse ischemic brain.

Ischemic stroke is a leading cause of morbidity and mortality, with limited treatments that can facilitate brain regeneration. Neural progenitor cells (NPCs) hold promise for replacing tissue lost to stroke, and biomaterial approaches may improve their efficacy to overcome hurdles in clinical translation. The immune response and its role in stroke pathogenesis and regeneration may interplay with critical mechanisms of stem cell and biomaterial therapies. Cellular therapy can modulate the immune response to reduce toxic neuroinflammation early after ischemia. However, few studies have attempted to harness the regenerative effects of neuroinflammation to augment recovery. Our previous studies demonstrated that intracerebrally transplanted NPCs encapsulated in a chondroitin sulfate-A hydrogel (CS-A + NPCs) can improve vascular regeneration after stroke. In this paper, we found that CS-A + NPCs affect the microglia/macrophage response to promote a regenerative phenotype following stroke in mice. Following transplantation, PPARγ-expressing microglia/macrophages, and MCP-1 and IL-10 protein levels are enhanced. Secreted immunomodulatory factor expression of other factors was altered compared to NPC transplantation alone. Post-stroke depression-like behavior was reduced following cellular and material transplantation. Furthermore, we showed in cultures that microglia/macrophages encapsulated in CS-A had increased expression of angiogenic and arteriogenic mediators. Neutralization with anti-IL-10 antibody negated these effects in vitro. Cumulatively, this work provides a framework for understanding the mechanisms by which immunomodulatory biomaterials can enhance the regenerative effects of cellular therapy for ischemic stroke and other brain injuries.

GPR37 modulates progenitor cell dynamics in a mouse model of ischemic stroke.

The generation of neural stem and progenitor cells following injury is critical for the function of the central nervous system, but the molecular mechanisms modulating this response remain largely unknown. We have previously identified the G protein-coupled receptor 37 (GPR37) as a modulator of ischemic damage in a mouse model of stroke. Here we demonstrate that GPR37 functions as a critical negative regulator of progenitor cell dynamics and gliosis following ischemic injury. In the central nervous system, GPR37 is enriched in mature oligodendrocytes, but following injury we have found that its expression is dramatically increased within a population of Sox2-positive progenitor cells. Moreover, the genetic deletion of GPR37 did not alter the number of mature oligodendrocytes following injury but did markedly increase the number of both progenitor cells and injury-induced Olig2-expressing glia. Alterations in the glial environment were further evidenced by the decreased activation of oligodendrocyte precursor cells. These data reveal that GPR37 regulates the response of progenitor cells to ischemic injury and provides new perspectives into the potential for manipulating endogenous progenitor cells following stroke.

Cortical Transplantation of Brain-Mimetic Glycosaminoglycan Scaffolds and Neural Progenitor Cells Promotes Vascular Regeneration and Functional Recovery after Ischemic Stroke in Mice.

Stroke causes significant mortality and morbidity. Currently, there are no treatments which can regenerate brain tissue lost to infarction. Neural progenitor cells (NPCs) are at the forefront of preclinical studies for regenerative stroke therapies. NPCs can differentiate into and replace neurons and promote endogenous recovery mechanisms such as angiogenesis via trophic factor production and release. The stroke core is hypothetically the ideal location for replacement of neural tissue since it is in situ and develops into a potential space where injections may be targeted with minimal compression of healthy peri-infarct tissue. However, the compromised perfusion and tissue degradation following ischemia create an inhospitable environment resistant to cellular therapy. Overcoming these limitations is critical to advancing cellular therapy. In this work, the therapeutic potential of mouse-induced pluripotent stem cell derived NPCs is tested encapsulated in a basic fibroblast growth factor (bFGF) binding chondroitin sulfate-A (CS-A) hydrogel transplanted into the infarct core in a mouse sensorimotor cortex mini-stroke model. It is shown that CS-A encapsulation significantly improves vascular remodeling, cortical blood flow, and sensorimotor behavioral outcomes after stroke. It is found these improvements are negated by blocking bFGF, suggesting that the sustained trophic signaling endowed by the CS-A hydrogel combined with NPC transplantation can promote tissue repair.

Molecular Targets and Natural Compounds in Drug Development for the Treatment of Inflammatory Pain.

This chapter explores therapeutic targets and the anti-inflammatory nature of some naturally- occurring compounds and the current or potential use of these compounds in the treatment of chronic inflammatory pain states. We will review the mechanisms of chronic inflammatory pain, the molecular targets of selected natural compounds in inhibiting inflammatory pain, and the traditional and current approaches to treating pain using these compounds. Previous research on experimental as well as clinical pain will be summarized from in vitro to animal and human models. Potential areas for further research will also be discussed.

Priming of the Cells: Hypoxic Preconditioning for Stem Cell Therapy.

OBJECTIVE: Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues. DATA SOURCES: This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: "stem cells," "hypoxic preconditioning," "ischemic preconditioning," and "cell transplantation." STUDY SELECTION: Original articles and critical reviews on the topics were selected. RESULTS: Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified. CONCLUSIONS: In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications.

5-Aminolevulinic Acid Guided Sampling of Glioblastoma Microenvironments Identifies Pro-Survival Signaling at Infiltrative Margins.

Glioblastoma (GBM) contains diverse microenvironments with uneven distributions of oncogenic alterations and signaling networks. The diffusely infiltrative properties of GBM result in residual tumor at neurosurgical resection margins, representing the source of relapse in nearly all cases and suggesting that therapeutic efforts should be focused there. To identify signaling networks and potential druggable targets across tumor microenvironments (TMEs), we utilized 5-ALA fluorescence-guided neurosurgical resection and sampling, followed by proteomic analysis of specific TMEs. Reverse phase protein array (RPPA) was performed on 205 proteins isolated from the tumor margin, tumor bulk, and perinecrotic regions of 13 previously untreated, clinically-annotated and genetically-defined high grade gliomas. Differential protein and pathway signatures were established and then validated using western blotting, immunohistochemistry, and comparable TCGA RPPA datasets. We identified 37 proteins differentially expressed across high-grade glioma TMEs. We demonstrate that tumor margins were characterized by pro-survival and anti-apoptotic proteins, whereas perinecrotic regions were enriched for pro-coagulant and DNA damage response proteins. In both our patient cohort and TCGA cases, the data suggest that TMEs possess distinct protein expression profiles that are biologically and therapeutically relevant.