Publications by authors named "Michael Girardi"

Cutaneous T cell lymphoma (CTCL) is a form of non-Hodgkin lymphoma that can involve the skin, along with lymph nodes and blood. The two most common subtypes of CTCL are mycosis fungoides and Sézary syndrome, Since the initial description of mycosis fungoides by Dr. Jean-Louis Alibert in 1806, there have been significant advances in our understanding of the pathogenesis of CTCL, its diverse clinical and histologic variants, and the evolving treatment landscape.

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  • - Benzoyl peroxide (BPO), commonly used in acne treatments, can degrade into benzene, a harmful carcinogen, especially when stored or used at high temperatures.
  • - A study detected varying levels of benzene (0.16 to 35.30 ppm) in 111 over-the-counter BPO products when kept at room temperature, while a prescription version showed none at low temperatures but significant benzene at high temperatures.
  • - Experiments revealed that using BPO on skin models can lead to detectable benzene levels in the air, especially under UV light, highlighting health risks from benzene exposure regardless of the initial concentration in the products.
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  • T-cell lymphomas are complex cancers with generally poor outcomes, and the study focuses on the effectiveness of the EPOCH chemotherapy regimen among patients with aggressive cases, including both peripheral and cutaneous types.
  • Out of 38 patients treated, the overall response rate (ORR) was 77%, with over half achieving complete remission, showing similar effectiveness across different racial backgrounds but varying success based on CD30 status.
  • The EPOCH regimen demonstrated good safety and tolerance, making it a promising option for both newly diagnosed and relapsed/refractory T-cell lymphoma patients.
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Carcinogen-induced mutations are thought near-random, with rare cancer-driver mutations underlying clonal expansion. Using high-fidelity Duplex Sequencing to reach a mutation frequency sensitivity of 4×10 per nt, we report that sun exposure creates pervasive mutations at sites with ∼100-fold UV-sensitivity in RNA-processing gene promoters - cyclobutane pyrimidine dimer (CPD) hyperhotspots - and these mutations have a mini-driver clonal expansion phenotype. Numerically, human skin harbored 10-fold more genuine mutations than previously reported, with neonatal skin containing 90,000 per cell; UV signature mutations increased 8,000-fold in sun-exposed skin, averaging 3×10 per nt.

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  • The text discusses the classification of Cutaneous T-cell Lymphomas (CTCL), highlighting the prevalence of CD4+ T-helper cell variants and a spectrum of CD8+ variants with various clinical and histological features.
  • CD8 and cytotoxic molecules can be identified through immunohistochemical staining, but their presence alone is not enough for diagnosis or determining prognosis.
  • The review covers specific CTCL subtypes that express CD8 positivity, including mycosis fungoides, lymphomatoid papulosis, and aggressive forms, underscoring the importance of combining clinical, histologic, and immunohistochemical data for accurate diagnosis and treatment.
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Immunomodulatory agents have significant potential to enhance cancer treatment but have demonstrated limited efficacy beyond the preclinical setting owing to poor pharmacokinetics and toxicity associated with systemic administration. Conversely, when locally delivered, immunomodulatory agents require repeated administration to optimize immune stimulation. To overcome these challenges, we encapsulated the toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) within hyperbranched polyglycerol-coated biodegradable nanoparticles (NPs) engineered for gradual drug release from the NP core, resulting in a more persistent stimulation of antitumor immune responses while minimizing systemic side effects.

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The therapeutic efficacy of camptothecin (CPT), a potent antitumor alkaloid, is hindered by its hydrophobic nature and instability, limiting its clinical use in treating cutaneous squamous cell carcinoma (SCC). This study introduces a novel nano drug delivery system (NDDS) utilizing functionalized mesoporous silica nanoparticles (FMSNs) for efficient CPT delivery. The FMSNs were loaded with CPT and subsequently coated with chitosan (CS) for enhanced stability and bioadhesion.

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  • Response rates for systemic therapies in cutaneous T-cell lymphoma (CTCL) are low, around 30%, indicating a need for better treatment options; this study focuses on extracorporeal photopheresis (ECP) as a potential solution.
  • A chart review of 52 adults with CTCL treated with ECP from 2017 to 2019 showed that nearly 37% of patients experienced significant improvement, with a median time to response of 6.5 months.
  • The study findings suggest that despite the older age and more advanced disease stages of the patients, ECP remains an effective treatment option for those with CTCL, comparable to results from past clinical trials.
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Current treatments for T cell malignancies encounter issues of disease relapse and off-target toxicity. Using T cell receptor (TCR)Vβ2 as a model, here we demonstrate the rapid generation of an off-the-shelf allogeneic chimeric antigen receptor (CAR)-T platform targeting the clone-specific TCR Vβ chain for malignant T cell killing while limiting normal cell destruction. Healthy donor T cells undergo CRISPR-induced TRAC, B2M and CIITA knockout to eliminate T cell-dependent graft-versus-host and host-versus-graft reactivity.

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The genomic basis of cutaneous T-cell lymphoma has been characterized by gene copy number alterations and genomic sequencing, but there are few clinical tests that are being widely used to inform the diagnosis and prognosis of leukemic cutaneous T-cell lymphoma that may arise as a progression from mycosis fungoides or de novo as Sézary syndrome. An 11-gene FISH panel of , , , , , , , and deletions and , (), and amplifications was previously found to encapsulate >95% of gene copy number variations in leukemic cutaneous T-cell lymphoma. Through a retrospective analysis of patients with leukemic cutaneous T-cell lymphoma seen at the Yale Cancer Center from 2014 to 2020, we gathered the relevant genes as they became available and correlated them to factors with prognostic relevance as a proof of concept to show the potential utility in further developing a limited gene panel for prognosis.

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The use of nanoparticles (NPs) as a therapeutic delivery system has expanded markedly over the past decade, particularly regarding applications targeting the skin. The delivery of NP-based therapeutics to the skin requires special consideration owing to its role as both a physical and immunologic barrier, and specific technologies must not only take into consideration the target but also the pathway of delivery. The unique challenge this poses has been met with the development of a wide panel of NP-based technologies meant to precisely address these considerations.

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Background Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL). Although it often has an indolent course, it can progress to more aggressive CTCL forms. There is sparse data in current literature describing specific clinical factors associated with in-hospital mortality in mycosis fungoides patients.

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The incidence of cutaneous T-cell lymphoma (CTCL) increases with age, and blood involvement portends a worse prognosis. To advance our understanding of the development of CTCL and identify potential therapeutic targets, we performed integrative analyses of paired single-cell RNA and T-cell receptor (TCR) sequencing of peripheral blood CD4+ T cells from patients with CTCL to reveal disease-unifying features. The malignant CD4+ T cells of CTCL showed highly diverse transcriptomic profiles across patients, with most displaying a mature Th2 differentiation and T-cell exhaustion phenotype.

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Importance: Given that mycosis fungoides-cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT).

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First-line treatments for mild to moderate psoriasis are typically topical formulations containing corticosteroids, however, the therapeutic efficacy of these formulations is compromised by limited penetration and skin retention. Even more challenging, off-target corticosteroids are known to adversely affect healthy skin, including induction of epidermal and dermal atrophy. Here, we report a nanoparticle-based topical formulation that cures psoriasis in a single dose, but leaves healthy skin intact.

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Cutaneous T-cell lymphoma (CTCL) is a life-debilitating malignancy of lymphocytes homing to the skin. Although CTCL is thought to arise from a combination of genetic, epigenetic, and environmental factors, specific triggers are unclear. The skin is colonized by a unique microbiota and is heavily influenced by its interactions.

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Importance: Acral lentiginous melanoma (ALM) is a rare subtype of malignant melanoma typically occurring on the palmar and plantar surfaces. Although it has distinctive genetic, prognostic, and behavioral characteristics relative to cutaneous melanomas overall, owing to its rarity, treatment is largely guided by data extrapolated from more common subtypes. Although sentinel lymph node (SLN) status has been shown to be a significant prognostic factor for ALM, the independent effect of ALM-subtype disease on the likelihood of SLN positivity and the stage-specific positivity rates for ALM are not well characterized.

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The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs.

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