Network-Based Transcriptome Analysis Reveals FAM3C as a Novel Potential Biomarker for Glioblastoma.

Glioblastoma (GBM) is the most common form of malignant primary brain tumor with a high mortality rate. The aim of the present study was to investigate the clinical significance of Family with Sequence Similarity 3, Member C, FAM3C, in GBM using bioinformatic-integrated analysis. First, we performed the transcriptomic integration analysis to assess the expression profile of FAM3C in GBM using several data sets (RNA-sequencing and scRNA-sequencing), which were obtained from TCGA and GEO databases. By using the STRING platform, we investigated FAM3C-coregulated genes to construct the protein-protein interaction network. Next, Metascape, Enrichr, and CIBERSORT databases were used. We found FAM3C high expression in GBM with poor survival rates. Further, we observed, via FAM3C coexpression network analysis, that FAM3C plays key roles in several hallmarks of cancer. Surprisingly, we also highlighted five FAM3C­coregulated genes overexpressed in GBM. Specifically, we demonstrated the association between the high expression of FAM3C and the abundance of the different immune cells, which may markedly worsen GBM prognosis. For the first time, our findings suggest that FAM3C not only can be a new emerging biomarker with promising therapeutic values to GBM patients but also gave a new insight into a potential resource for future GBM studies.

Altering biomolecular condensates as a potential mechanism that mediates cannabidiol effect on glioblastoma.

Glioblastoma (GBM) is an extremely aggressive primary brain tumor with poor prognosis, short survival time post-diagnosis and high recurrence. Currently, no cure for GBM exists. The identification of an effective therapeutic modality for GBM remains a high priority amongst medical professionals and researches. In recent studies, inhalant cannabidiol (CBD) has demonstrated promise in effectively inhibiting GBM tumor growth. However, exactly how CBD treatment affects the physiology of these tumor cells remains unclear. Stress granules (SG) (a sub-class of biomolecular condensates (BMC)) are dynamic, membrane-less intracellular microstructures which contain proteins and nucleic acids. The formation and signaling of SGs and BMCs plays a significant role in regulating malignancies. This study investigates whether inhaled CBD may play an intervening role towards SGs in GBM tumor cells. Integrated bioinformatics approaches were preformed to gain further insights. This includes use of Immunohistochemistry and flow cytometry to measure SGs, as well as expression and phosphorylation of eukaryotic initiation factor-2α (eIF2α). The findings of this study reveal that CBD receptors (and co-regulated genes) have the potential to play an important biological role in the formation of BMCs within GBM. In this experiment, CBD treatment significantly increased the volume of TIAR-1. This increase directly correlated with elevation in both eIF2α expression and p-eIF2α in CBD treated tissues in comparison to the placebo group (p < 0.05). These results suggest that inhalant CBD significantly up-regulated SGs in GBM, and thus support a theory of targeting BMCs as a potential therapeutic substrate for treating GBM.

Reprofiling synthetic glucocorticoid-induced leucine zipper fusion peptide as a novel and effective hair growth promoter.

Hair is a biofilament with unique multi-dimensional values. In human, in addition to physiologic impacts, hair loss and hair related disorders can affect characteristic features, emotions, and social behaviors. Despite significant advancement, there is a dire need to explore alternative novel therapies with higher efficacy, less side effects and lower cost to promote hair growth to treat hair deficiency. Glucocorticoid-induced leucine zipper (GILZ) is a protein rapidly induced by glucocorticoids. Studies from our group and many others have suggested that a synthetic form of GILZ, TAT-GILZ, a fusion peptide of trans-activator of transcription and GILZ, can function as a potent regulator of inflammatory responses, re-establishing and maintaining the homeostasis. In this study, we investigate whether TAT-GILZ could promote and contribute to hair growth. For our pre-clinical model, we used 9-12 week-old male BALB/c and nude (athymic, nu/J) mice. We applied TAT-GILZ and/or TAT (vehicle) intradermally to depilated/hairless mice. Direct observation, histological examination, and Immunofluorescence imaging were used to assess the effects and compare different treatments. In addition, we tested two current treatment for hair loss/growth, finasteride and minoxidil, for optimal evaluation of TAT-GILZ in a comparative fashion. Our results showed, for the first time, that synthetic TAT-GILZ peptide accelerated hair growth on depilated dorsal skin of BALB/c and induced hair on the skin of athymic mice where hair growth was not expected. In addition, TAT-GILZ was able to enhance hair follicle stem cells and re-established the homeostasis by increasing counter inflammatory signals including higher regulatory T cells and glucocorticoid receptors. In conclusion, our novel findings suggest that reprofiling synthetic TAT-GILZ peptide could promote hair growth by increasing hair follicle stem cells and re-establishing homeostasis.

Inhalant cannabidiol impedes tumor growth through decreased tumor stemness and impaired angiogenic switch in NCI-H1437-induced human lung cancer model.

Lung cancer remains the most chronic form of cancer and the leading cause of cancer mortality in the world. Despite significant improvements in the treatment of lung cancer, the current therapeutic interventions are only partially effective, necessitating the continued search for better, novel alternative treatments. Angiogenesis and cancer stem cells play a central role in the initiation and propagation of cancers. Tumor angiogenesis is triggered by an angiogenic switch when pro-angiogenic factors exceed anti-angiogenic components. Although many anti-angiogenic agents are used in cancer treatment, there are therapeutic limitations with significant side effects. In recent years, cannabinoids have been investigated extensively for their potential anti-neoplastic effects. Our previous findings showed that cannabidiol (CBD) could impede tumor growth in mouse models of melanoma and glioblastoma. Importantly, CBD has been suggested to possess anti-angiogenic activity. In this study, we tested, for the first time, inhalant CBD in the treatment of heterotopic lung cancer and whether such potential effects could reduce cancer stem cell numbers and inhibit tumor angiogenesis. We implanted NCI H1437 human lung cancer cells in nude mice and treated the mice with inhalant CBD or placebo. The outcomes were measured by tumor size and imaging, as well as by immunohistochemistry and flow cytometric analysis for CD44, VEGF, and P-selectin. Our findings showed that CBD decreased tumor growth rate and suppressed expression of CD44 and the angiogenic factors VEGF and P-selectin. These results suggest, for the first time, that inhalant CBD can impede lung cancer growth by suppressing CD44 and angiogenesis.

Inhalant Cannabidiol Inhibits Glioblastoma Progression Through Regulation of Tumor Microenvironment.

Introduction: Glioblastoma (GBM) is the most common invasive brain tumor composed of diverse cell types with poor prognosis. The highly complex tumor microenvironment (TME) and its interaction with tumor cells play important roles in the development, progression, and durability of GBM. Angiogenic and immune factors are two major components of TME of GBM; their interplay is a major determinant of tumor vascularization, immune profile, as well as immune unresponsiveness of GBM. Given the ineffectiveness of current standard therapies (surgery, radiotherapy, and concomitant chemotherapy) in managing patients with GBM, it is necessary to develop new ways of treating these lethal brain tumors. Targeting TME, altering tumor ecosystem may be a viable therapeutic strategy with beneficial effects for patients in their fight against GBM. Materials and Methods: Given the potential therapeutic effects of cannabidiol (CBD) in a wide spectrum of diseases, including malignancies, we tested, for the first time, whether inhalant CBD can inhibit GBM tumor growth using a well-established orthotopic murine model. Optical imaging, histology, immunohistochemistry, and flow cytometry were employed to describe the outcomes such as tumor progression, cancer cell signaling pathways, and the TME. Results: Our findings showed that inhalation of CBD was able to not only limit the tumor growth but also to alter the dynamics of TME by repressing P-selectin, apelin, and interleukin (IL)-8, as well as blocking a key immune checkpoint-indoleamine 2,3-dioxygenase (IDO). In addition, CBD enhanced the cluster of differentiation (CD) 103 expression, indicating improved antigen presentation, promoted CD8 immune responses, and reduced innate Lymphoid Cells within the tumor. Conclusion: Overall, our novel findings support the possible therapeutic role of inhaled CBD as an effective, relatively safe, and easy to administer treatment adjunct for GBM with significant impacts on the cellular and molecular signaling of TME, warranting further research.

White-Eyed Orbital Blowout Fracture With Oculocardiac Reflex Secondary to Extraocular Entrapment in a Pediatric Patient.

White-eyed orbital blowout fractures in the pediatric population can present with acute onset diplopia, ophthalmalgia, and abnormal duction. These findings are attributed to the tendency of younger bone to break and reapproximate owing to greater elasticity. This phenomenon, commonly referred to as the greenstick fracture, increases the risk of entrapment of surrounding soft tissue structures in orbital floor fractures. Further concern arises in the presence of an oculocardiac reflex, which requires urgent intervention to prevent serious bradycardia. Prolonged entrapment can go unnoticed and result in irreversible ischemic damage to entrapped tissues. This case discusses the presentation 16-year-old female who sustained a left sided, white-eyed blowout fracture from a face-first ground level fall. On admission, she displayed restrictive strabismus and mild periorbital edema around the left eye. Vertical gaze was restricted when looking inferiorly on the affected side. With sustained upward gaze, her heart rate decreased from 99 to 81 beats per minute. High-resolution non-contrast computed tomography scans of the head showed entrapment of the inferior rectus muscle and periorbital fat. Liberation of entrapped tissues with reduction of bony segments was performed urgently, utilizing a MEDPOR® Titan 3D orbital floor plate and secured with two screws. The patient had an uneventful postoperative period and showed considerable improvements in periorbital edema, duction, and ophthalmalgia on the affected side. In addition, the oculocardiac reflex could no longer be elicited on prolonged upward gaze. Mild and improving paresthesia was noted in the maxillary distribution of the left trigeminal nerve. Sensory deficits like this are the result of fracture communication with the infraorbital canal, which may cause irritation of the infraorbital nerve responsible for sensation by the maxillary division. By postoperative week 7, she had complete resolution of periorbital edema, indiscernible duction abnormalities, and complete healing of surgical incision sites, and an oculocardiac reflex could not be elicited.

Sexual Dimorphism in the Polarization of Cardiac ILCs through Elabela.

Elabela is a component of the apelinergic system and may exert a cardioprotective role by regulating the innate immune responses. Innate lymphoid cells (ILCs) have a significant role in initiating and progressing immune-inflammatory responses. While ILCs have been intensively investigated during the last decade, little is known about their relationship with the apelinergic system and their cardiac diversity in a gender-based paradigm. In this study, we investigated the polarization of cardiac ILCs by Elabela in males versus females in a mouse model. Using flow cytometry and immunohistochemistry analyses, we showed a potential interplay between Elabela and cardiac ILCs and whether such interactions depend on sexual dimorphism. Our findings showed, for the first time, that Elabela is expressed by cardiac ILCs, and its expression is higher in females' ILC class 3 (ILC3s) compared to males. Females had higher frequencies of ILC1s, and Elabela was able to suppress T-cell activation and the expression of co-stimulatory CD28 in a mixed lymphocyte reaction assay (MLR). In conclusion, our results suggest, for the first time, a protective role for Elabela through its interplay with ILCs and that it can be used as an immunotherapeutic target in the treatment of cardiovascular disorders in a gender-based fashion.

Inflammaging and Cannabinoids.

Aging is a complex phenomenon associated with a wide spectrum of physical and physiological changes affecting every part of all metazoans, if they escape death prior to reaching maturity. Critical to survival, the immune system evolved as the principal component of response to injury and defense against pathogen invasions. Because how significantly immune system affects and is affected by aging, several neologisms now appear to encapsulate these reciprocal relationships, such as Immunosenescence. The central part of Immunosenescence is Inflammaging -a sustained, low-grade, sterile inflammation occurring after reaching reproductive prime. Once initiated, the impact of Inflammaging and its adverse effects determine the direction and magnitudes of further Inflammaging. In this article, we review the nature of this vicious cycle, we will propose that phytocannabinoids as immune regulators may possess the potential as effective adjunctive therapies to slow and, in certain cases, reverse the pathologic senescence to permit a more healthy aging.

A potential role for cannabichromene in modulating TRP channels during acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening clinical syndrome whose potential to become one of the most grievous challenges of the healthcare system evidenced by the COVID-19 pandemic. Considering the lack of target-specific treatment for ARDS, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve quality of life and outcomes for ARDS patients. ARDS is a systemic inflammatory disease starting with the pulmonary system and involves all other organs in a morbid bidirectional fashion. Mounting evidence including our findings supporting the notion that cannabinoids have potential to be targeted as regulatory therapeutic modalities in the treatment of inflammatory diseases. Therefore, it is plausible to test their capabilities as alternative therapies in the treatment of ARDS. In this study, we investigated the potential protective effects of cannabichromene (CBC) in an experimental model of ARDS. METHODS: We used, for the first time, an inhalant CBC treatment as a potential therapeutic target in a murine model of ARDS-like symptoms. ARDS was induced by intranasal administration of Poly(I:C), a synthetic mismatched double-stranded RNA, into the C57BL/6 mice (6-10 male mice/group, including sham, placebo, and CBC treated), three once-daily doses followed by a daily dose of inhalant CBC or placebo for the period of 8 days starting the first dose 2 h after the second Poly(I:C) treatment. We employed histologic, immunohistochemistry, and flow cytometry methods to assess the findings. Statistical analysis was performed by using one way analysis of variance (ANOVA) followed by Newman-Keuls post hoc test to determine the differences among the means of all experimental groups and to establish significance (p < 0.05) among all groups. RESULTS: Our data showed that CBC was able to reverse the hypoxia (increasing blood O2 saturation by 8%), ameliorate the symptoms of ARDS (reducing the pro-inflammatory cytokines by 50% in lung and blood), and protect the lung tissues from further destruction. Further analysis showed that CBC may wield its protective effects through transient receptor potential (TRP) cation channels, TRPA1 and TRPV1, increasing their expression by 5-folds in lung tissues compared to sham and untreated mice, re-establishing the homeostasis and immune balance. CONCLUSION: Our findings suggest that inhalant CBC may be an effective alternative therapeutic target in the treatment of ARDS. In addition, Increased expression of TRPs cation channels after CBC treatment proposes a novel role for TRPs (TRPA1 and TRPV2) as new potential mechanism to interpret the beneficial effects of CBC as well as other cannabinoids in the treatment of ARDS as well as other inflammatory diseases. Importantly, delivering CBC through an inhaler device is a translational model supporting the feasibility of trial with human subjects, authorizing further research.

High Levels of Interferon-Alpha Expressing Macrophages in Human Breast Milk During SARS-CoV-2 Infection: A Case Report.

Introduction: In addition to hand washing and wearing masks, social distancing and reducing exposure time to <15 minutes are the most effective measures against the spread of COVID-19. Unfortunately, three of these guidelines are very difficult, if not impossible, for nursing babies: they cannot wear masks, stay six feet away from the lactating breasts, nor consistently finish within 15 minutes while nursing. We report a case of a nursing mother with SARS-CoV-2 infection, documenting changes of immune cells and cytokines in breast milk with and without the infection. Case Description: With Institutional Review Board (IRB) approval, we obtained expressed breast milk samples from a lactating mother before and during SARS-CoV-2 infection as documented by reverse transcription-PCR. Using flow cytometry analysis, we measured the immune cell profiles and expression of cytokines such as interferon alpha (IFNα) in milk leukocytes before and during infection. Results: There was an eightfold increase in IFNα+ milk leukocytes, from 1% before SARS-CoV-2 infection to 8% when actively infected. The milk macrophages showed the highest increase in IFNα expression. Both T and B lymphocytes showed mild increase. Innate lymphoid cells, neutrophils, and natural killer cells showed no increase in IFNα expression and the dendritic cells actually showed a reduction. Conclusion: We document the presence and high expression of IFNα in the breast milk macrophages of a lactating mother with confirmed COVID-19, compared with her milk before the infection.

Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer's Disease.

There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.

Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome.

Considering lack of target-specific antiviral treatment and vaccination for COVID-19, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve COVID-19-infected patient outcomes. In a follow-up study to our recent findings indicating the potential of Cannabidiol (CBD) in the treatment of acute respiratory distress syndrome (ARDS), here we show for the first time that CBD may ameliorate the symptoms of ARDS through up-regulation of apelin, a peptide with significant role in the central and peripheral regulation of immunity, CNS, metabolic and cardiovascular system. By administering intranasal Poly (I:C), a synthetic viral dsRNA, while we were able to mimic the symptoms of ARDS in a murine model, interestingly, there was a significant decrease in the expression of apelin in both blood and lung tissues. CBD treatment was able to reverse the symptoms of ARDS towards a normal level. Importantly, CBD treatment increased the apelin expression significantly, suggesting a potential crosstalk between apelinergic system and CBD may be the therapeutic target in the treatment of inflammatory diseases such as COVID-19 and many other pathologic conditions.

Cannabidiol Modulates Cytokine Storm in Acute Respiratory Distress Syndrome Induced by Simulated Viral Infection Using Synthetic RNA.

Introduction: In the absence of effective antivirals and vaccination, the pandemic of COVID-19 remains the most significant challenge to our health care system in decades. There is an urgent need for definitive therapeutic intervention. Clinical reports indicate that the cytokine storm associated with acute respiratory distress syndrome (ARDS) is the leading cause of mortality in severe cases of some respiratory viral infections, including COVID-19. In recent years, cannabinoids have been investigated extensively due to their potential effects on the human body. Among all cannabinoids, cannabidiol (CBD) has demonstrated potent anti-inflammatory effects in a variety of pathological conditions. Therefore, it is logical to explore whether CBD can reduce the cytokine storm and treat ARDS. Materials and Methods: In this study, we show that intranasal application of Poly(I:C), a synthetic analogue of viral double-stranded RNA, simulated symptoms of severe viral infections inducing signs of ARDS and cytokine storm. Discussion: The administration of CBD downregulated the level of proinflammatory cytokines and ameliorated the clinical symptoms of Poly I:C-induced ARDS. Conclusion: Our results suggest a potential protective role for CBD during ARDS that may extend CBD as part of the treatment of COVID-19 by reducing the cytokine storm, protecting pulmonary tissues, and re-establishing inflammatory homeostasis.

Whole Body Vibration-Induced Omental Macrophage Polarization and Fecal Microbiome Modification in a Murine Model.

Human nutrient metabolism, developed millions of years ago, is anachronistic. Adaptive features that offered survival advantages are now great liabilities. The current dietary pattern, coupled with massively reduced physical activities, causes an epidemic of obesity and chronic metabolic diseases, such as type 2 diabetes mellitus. Chronic inflammation is a major contributing factor to the initiation and progression of most metabolic and cardiovascular diseases. Among all components of an innate immune system, due to their dual roles as phagocytic as well as antigen-presenting cells, macrophages play an important role in the regulation of inflammatory responses, affecting the body's microenvironment and homeostasis. Earlier studies have established the beneficial, anti-inflammatory effects of whole body vibration (WBV) as a partial exercise mimetic, including reversing the effects of glucose intolerance and hepatic steatosis. Here for the first time, we describe potential mechanisms by which WBV may improve metabolic status and ameliorate the adverse consequences through macrophage polarization and altering the fecal microbiome.

Innate immunity and oral microbiome: a personalized, predictive, and preventive approach to the management of oral diseases.

Three recent advances in immunology, genetics, and microbiology have ushered in a new era in the continued efforts to better understand and treat oral diseases, moving ever closer to the three Ps of modern healthcare: personalized, predictive, and preventive medicine (PPPM). The discovery of now 15 subtypes of innate lymphoid cells, the refinement of DNA sequencing, and culture-independent characterization of the entire microbial community begin to reveal this complex adaptive network. All these advances warrant a systematic review as they have changed and will continue to change dental medicine. We will update dental professionals on these advances as related to oral diseases and associated pathologies in other organ systems such as premature labor, arthrosclerosis, and cancer. The five objectives are:Introduce the concept of microbiota and microbiomeExplain how we study microbiota and microbiomeDescribe the types and functions of innate lymphoid cellsInventory the unique demands of the oral cavityProvide a heuristic model to integrate the aboveConclusions and expert recommendations.

Cannabinoids as a Potential New and Novel Treatment for Melanoma: A Pilot Study in a Murine Model.

BACKGROUND: Malignant melanoma is a complex malignancy with significant morbidity and mortality. The incidence continues to rise, and despite advances in treatment, the prognosis is poor. Thus, it is necessary to develop novel strategies to treat this aggressive cancer. Synthetic cannabinoids have been implicated in inhibiting cancer cell proliferation, reducing tumor growth, and reducing metastasis. We developed a unique study focusing on the effects of treatment with a cannabinoid derivative on malignant melanoma tumors in a murine model. METHODS: Murine B16F10 melanoma tumors were established subcutaneously in C57BL/6 mice. Mice were then treated with intraperitoneal injections of vehicle twice per week (control-group 1, n = 6), Cisplatin 5 mg/kg/wk (group 2; n = 6), and Cannabidiol (CBD) 5 mg/kg twice per week (group 3; n = 6). Tumors were measured and volume calculated as (4π/3) × (width/2)2 × (length/2). Tumor size and survival curves were measured. Results were compared using a one-way ANOVA with multiple comparison test. RESULTS: A significant decrease in tumor size was detected in mice treated with CBD when compared with the control group (P = 0.01). The survival curve of melanoma tumors treated with CBD increased when compared with the control group and was statistically significant (P = 0.04). The growth curve and survival curve of melanoma tumors treated with Cisplatin were significantly decreased and increased, respectively, when compared with the control and CBD-treated groups. Mice treated with Cisplatin demonstrated the longest survival time, but the quality of life and movement of CBD-treated mice were observed to be better. CONCLUSIONS: We demonstrate a potential beneficial therapeutic effect of cannabinoids, which could influence the course of melanoma in a murine model. Increased survival and less tumorgenicity are novel findings that should guide research to better understand the mechanisms by which cannabinoids could be utilized as adjunctive treatment of cancer, specifically melanoma. Further studies are necessary to evaluate this potentially new and novel treatment of malignant melanoma.

Innate Immunity of Neonates and Infants.

Many important events occur at birth. The fetus is suddenly removed from a protected intra-uterine environment that is aquatic, warm, and nearly sterile, to the dry, cold external world laden with microbes. To survive, the neonate must interact with many organisms, making use of some, while vigorously defending against the others like a nation conducting trade with friendly countries and guarding against hostile ones from invading it, waging wars if necessary. Although, the neonatal immune system is plastic, however, it is highly tolerant which is due to both the fetal development during gestation as well as significant sudden changes in fetal environment and enormous exposure to the new antigens and intestinal bacteria and their products. This "quiescent mode" of innate immune system is part of a highly regulated process to fulfill all requirements of multi-layered process of early life, implemented effectively through the cells of innate immune system. While, most of the neonatal innate immune cells (e.g., neutrophils and monocytes) present contained activity and lower frequencies compared to their adult counterparts, innate lymphoid cells (ILCs), a distinct cellular component of innate immunity, show higher level of activity and presence during period of infancy compared to later stages of life and adulthood, which may suggest a role for ILCs in variable susceptibility to certain conditions during life time. In this review, while we focus on the characteristics and status of ILCs in neonatal immune system, we also draw an analogy from a national defense perspective because of the great similarities between that and the immune system by providing the known biological counterparts of all five core operational elements, the five Ds of defense, detection, discrimination, deployment, destruction, and de-escalation, with special focus on innate immunity, maternal support, and influence during the neonatal and infancy periods.

Aesthetic Unit Boundary Approach to Large Fibroadenoma Resection.

BACKGROUND: Fibroadenomas are the most common benign breast tumors in adolescents. Surgical excision is indicated when the tumor becomes large or symptomatic. Multiple approaches have been described. However, unsightly scars, excess skin, and breast asymmetry are common challenges after tumor resection. The aims of our study were to describe a concentric circumareolar approach combining the round-block technique and geometric principles in the management of large benign breast tumors. METHODS: This was a retrospective review of pediatric patients who have undergone excision of large fibroadenoma with concentric circumareolar approach from June 2007 to May 2017. Preoperatively, the excess skin that needed to be resected was marked based on geometric principles. Under general anesthesia, circumareolar deepithelialization of the excess skin and tumor resection were performed. Purse-string suture technique was used to achieve the proper nipple-areola complex size. RESULTS: Satisfactory breast symmetry and minimal scarring were achieved in all 6 patients. One patient developed a small seroma, which resolved spontaneously without intervention. CONCLUSIONS: Concentric circumareolar approach can be used to resect large benign breast tumors while concealing the scar along the aesthetic unit boundary of the breast. The cosmetic outcome and recovery were promising. The approach is simple to execute, highly reproducible, and less dependent on intuition.