Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity.

Cutaneous T-cell lymphomas (CTCLs) are a clinically heterogeneous collection of lymphomas of the skin-homing T cell. To identify molecular drivers of disease phenotypes, we assembled representative samples of CTCLs from patients with diverse disease subtypes and stages. Via DNA/RNA-sequencing, immunophenotyping, and ex vivo functional assays, we identified the landscape of putative driver genes, elucidated genetic relationships between CTCLs across disease stages, and inferred molecular subtypes in patients with stage-matched leukemic disease. Collectively, our analysis identified 86 putative driver genes, including 19 genes not previously implicated in this disease. Two mutations have never been described in any cancer. Functionally, multiple mutations augment T-cell receptor-dependent proliferation, highlighting the importance of this pathway in lymphomagenesis. To identify putative genetic causes of disease heterogeneity, we examined the distribution of driver genes across clinical cohorts. There are broad similarities across disease stages. Many driver genes are shared by mycosis fungoides (MF) and Sezary syndrome (SS). However, there are significantly more structural variants in leukemic disease, leading to highly recurrent deletions of putative tumor suppressors that are uncommon in early-stage skin-centered MF. For example, TP53 is deleted in 7% and 87% of MF and SS, respectively. In both human and mouse samples, PD1 mutations drive aggressive behavior. PD1 wild-type lymphomas show features of T-cell exhaustion. PD1 deletions are sufficient to reverse the exhaustion phenotype, promote a FOXM1-driven transcriptional signature, and predict significantly worse survival. Collectively, our findings clarify CTCL genetics and provide novel insights into pathways that drive diverse disease phenotypes.

Low Utility of Screening Hematologic Testing for Image-Guided Biopsies in Patients Without Bleeding Risks.

OBJECTIVE. This study evaluates the prevalence of an abnormal international normalized ratio (INR) and platelet count before image-guided percutaneous needle biopsies over a 10-year period, comparing data from patients with and those without known conditions predisposing to coagulopathy. MATERIALS AND METHODS. A review of electronic medical records identified patients who were scheduled for a biopsy in a single institution's radiology department for the period of 2007-2016. The following information was recorded: demographic data, patient history of conditions that predispose to bleeding (e.g., liver disease, anticoagulant therapy, history of coagulopathy), and INR and platelet values within 30 days before biopsy. Data were stratified by biopsies that were performed versus those that were cancelled. RESULTS. Over 10 years, 3864 percutaneous biopsies were performed, and 6371 were cancelled. Approximately half of the biopsies (48.2%) were performed in patients without a predisposing condition; of those patients, 0.8% and 0.1% had an INR greater than 1.5 and greater than 1.8, respectively, and 0.4% had a platelet count of 50,000/µL or less (≤ 50 × 109/L). In patients with no known predisposing condition, 0.6% and 0.0% of biopsies cancelled were in patients who had an INR greater than 1.5 and greater than 1.8, respectively, and 0.1% of biopsies cancelled were in patients who had a platelet count of 50,000/µL or less. Ordering prebiopsy testing of patients with no predisposing conditions for the 1864 percutaneous biopsies performed over the 10-year study period resulted in more than $850,000 in laboratory-related health care costs. Our results suggest that the cost of identifying one abnormal INR is nearly $700,000. CONCLUSION. For patients without any known bleeding risks who are scheduled to undergo image-guided percutaneous biopsies, identifying an abnormal INR or abnormal platelet count is rare. Eliminating this testing in patients without predisposing conditions has the potential to create savings in costs and time for both physicians and patients.

Primary cutaneous marginal zone lymphoma treated with doxycycline in a pediatric patient.

We present the third reported case of a primary cutaneous marginal zone lymphoma (PCMZL) treated with doxycycline in a pediatric patient with negative serology for Borrelia burgdorferi. A 14-year-old boy presented with multiple asymptomatic erythematous papules and nodules on his extremities and trunk which biopsy confirmed to be PCMZL. He was started on doxycycline and experienced a near-complete response. Given the favorable side effect profile of doxycycline and the indolent nature of PCMZL, we believe doxycycline is a possible therapy for PCMZL pediatric patients who have widely disseminated cutaneous disease.

Racial and Ethnic Diversity in Janus Kinase Inhibitor Alopecia Areata Clinical Trials: A Systematic Review.

Background: Alopecia areata (AA) is a chronic autoimmune disease that causes non-scarring alopecia. A few studies have shown increased odds of AA in Black individuals compared to White individuals and increased odds of AA in Latinos compared to non-Latinos. Another study showed that Asians have lower odds of AA compared to Whites. Baricitinib, a Janus kinase inhibitor (JAKi), became the first Federal Drug Administration (FDA)-approved medication for adult patients with severe AA in June 2022. Objectives: The aim of this review was to analyze published JAKi AA randomized controlled trials to characterize and assess the racial and ethnic representation of participants. Animal studies, studies unrelated to AA, and studies not investigating JAKis were excluded. Methods: PubMed and clinicaltrials.gov were searched for systematic reviews of clinical trials between 1990 and 2022. Results: Six clinical trials were included with a total of 1,690 subjects. Four trials were industry-sponsored, while two were university-sponsored. The three largest races represented included White (59.9%), Asian (28.0%), and African American/Black (8.1%). Three out of the 10 patients identified as Hispanic. None of the trials included sub-analyses of clinical efficacy based on race and/or ethnicity. Conclusions: Our results show that populations with lower odds of AA (Whites and Asians) are overrepresented in JAKi AA clinical trials compared to Black and Hispanic/Latino patients.

Cellular origins and genetic landscape of cutaneous gamma delta T cell lymphomas.

Primary cutaneous γδ T cell lymphomas (PCGDTLs) represent a heterogeneous group of uncommon but aggressive cancers. Herein, we perform genome-wide DNA, RNA, and T cell receptor (TCR) sequencing on 29 cutaneous γδ lymphomas. We find that PCGDTLs are not uniformly derived from Vδ2 cells. Instead, the cell-of-origin depends on the tissue compartment from which the lymphomas are derived. Lymphomas arising from the outer layer of skin are derived from Vδ1 cells, the predominant γδ cell in the epidermis and dermis. In contrast, panniculitic lymphomas arise from Vδ2 cells, the predominant γδ T cell in the fat. We also show that TCR chain usage is non-random, suggesting common antigens for Vδ1 and Vδ2 lymphomas respectively. In addition, Vδ1 and Vδ2 PCGDTLs harbor similar genomic landscapes with potentially targetable oncogenic mutations in the JAK/STAT, MAPK, MYC, and chromatin modification pathways. Collectively, these findings suggest a paradigm for classifying, staging, and treating these diseases.

Incorporating Social Determinants of Health Into Medical Decision-making-Implications for Dermatology.

This Viewpoint discusses incorporating social determinants of health into medical decision-making and its implications for dermatology.

Amyloid precursor protein mutation disrupts reproductive experience-enhanced normal cognitive development in a mouse model of Alzheimer's disease.

Women experience dramatic changes in hormones, mood and cognition through different periods of their reproductive lives, particularly during pregnancy and giving birth. While limited human studies of early pregnancy and motherhood showed alteration of cognitive functions in later life, researches on rodents showed a persistent improvement of learning and memory performance in females with history of giving birth compared to virgin controls. Alzheimer's disease (AD), the most common dementia in elderly, is more prevalent in women than in men. One of the risk factors is related to the sharp reduction of estrogen in aged women. It is unknown whether the history of fertility activity plays any roles in altering risk of AD in females, such as altering cognitive function. Would reproductive experience alter the risk of AD in females? If so, what might be the mechanisms of the change? In this study, we examined the effects of reproductive experience on cognitive function in an AD transgenic mouse model (APP23) and age-matched wild-type non-transgenic control mice (WT). Our data showed an age-dependent effect of reproductive experience on learning and memory activity between breeders (had one or more litters) and non-breeders (virgins). More importantly, our data, for the first time, demonstrated a genotype-dependent effect of parity on cognitive function between APP23 and WT mice. At the age of 12 months, WT breeders outperform non-breeders in spatial working and reference memory while APP23 breeders performed worse in spatial learning and memory than age-matched APP23 non-breeders. These genotype- and age-dependent effects of reproductive activity on cognitions are significantly associated with changes of neuropathology of AD in the APP23 mice, expression of proteins related to synaptic plasticity and cognitive functions in the brain.

Early reproductive experiences in females make differences in cognitive function later in life.

Women experience dramatic changes in hormones, mood, and cognition through different periods of their reproductive lives, particularly during pregnancy and giving birth. While limited human studies of early pregnancy and motherhood showed alteration of cognitive function in later life, research conducted on rodents showed a persistent improvement of learning and memory performance in females with history of giving birth (primiparous or multiparous) compared to virgin controls (nulliparous). In this mini review, we will focus on the effect of early motherhood on cognitive function later in life, which would provide insight on how reproductive experiences influence women's health during aging.