Lazertinib as a frontline treatment in patients with EGFR-mutated advanced non-small cell lung cancer: Long-term follow-up results from LASER201.

OBJECTIVE: This analysis of the first-line cohort of LASER201 study evaluated the efficacy and safety of lazertinib 240 mg as a frontline therapy for epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). METHODS: A total of 43 patients, with EGFR mutation-positive (Exon19Del, n = 24; L858R, n = 18; G719X, n = 1) locally advanced or metastatic NSCLC who had not previously received EGFR tyrosine kinase inhibitor (EGFR TKI) therapy, received once-daily lazertinib 240 mg. EGFR mutation status was confirmed by local or central testing. The primary endpoint was objective response rate (ORR) assessed by blinded independent central review. Secondary efficacy endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), tumor shrinkage, and overall survival (OS). RESULTS: At the primary data cut-off (DCO; January 8, 2021), the ORR was 70 % (95 % confidence interval [CI]: 56.0-83.5), DCR was 86 % (95 % CI: 75.7-96.4) and the median DoR was 23.5 (95 % CI: 12.5-not reached) months. The median PFS was 24.6 (95 % CI: 12.2-30.2) months. At the final DCO (March 30, 2023), the median OS was not estimable and the median follow-up duration for OS was 55.2 [95 % CI: 22.8-55.7] months. OS rates at 36 months and 54 months were 66 % (95 % CI: 47.5-79.3 %) and 55 % (95 % CI: 36.6-70.7 %), respectively. The most commonly reported TEAEs were rash (54 %), diarrhea (47 %), pruritus (35 %), and paresthesia (35 %). No drug-related rash or pruritus TEAEs of grade 3 or higher were reported. Diarrhea and paresthesia of grade 3 or higher were reported in 3 (7 %) and 1 (2 %) patients, respectively. CONCLUSION: This analysis demonstrated long-term clinical benefit with lazertinib 240 mg in patients with EGFR-mutated NSCLC who had not previously received EGFR TKIs. The safety profile for lazertinib was tolerable and consistent with that previously reported.

Molluscum Contagiosum-Associated Epidermal Cyst at the Great Toe / 대한피부과학회지

no abstract available.

Lymphangioma Circumscriptum of the Vulva Mimicking Condyloma Acuminatum in a Patient with Crohn’s Disease / 대한피부과학회지

While lymphangioma circumscriptum may present anywhere on the body, the vulva is a rare site. However, vulvar involvement can occur in some clinical settings, and Crohn’s disease is one of the underlying etiologies of acquired lymphangioma circumscriptum. A 31-year-old woman presented with an 8-year history of widespread verruciform plaques on her vulva. She complained of a mild itching sensation at the lesion site. She was diagnosed with Crohn’s disease 11 years prior but had not been treated. She had no history of trauma or surgery in the perineal area and no familial history of cancer or hereditary disorders. The histopathologic findings were consistent with lymphangioma. Based on the clinicopathologic findings, the patient was diagnosed with lymphangioma circumscriptum on the vulva. Herein, we report a rare case of acquired lymphangioma circumscriptum of the vulva mimicking condyloma acuminatum in a patient with Crohn’s disease.

Risk of Cardiovascular Disease in Patients with Behçet Disease:A Population-based Retrospective Cohort Study in Korea / 대한피부과학회지

Background@#Few studies have investigated the association between Behçet disease (BD) and cardiovascular disease (CVD). The aim of this study was to investigate the risk of various CVDs in patients with BD. @*Objective@#The aim of this study was to investigate the risk of various CVD in patients with BD. @*Methods@#Between 2003 and 2015, we performed a retrospective cohort study involving patients with BD selected from Korea’s National Health Insurance Service-National Sample Cohort database and age- and sex-matched controls. Age- and sex-matched controls were selected randomly from the NHIS-NSC database at a frequency of 1:5. @*Results@#Among the 998 patients with BD and the 4,990 controls studied, patients with BD showed significantly higher risk for angina pectoris (adjusted Hazard Ratio [HR] 1.522, 95% confidence interval [CI] 1.020∼2.273;p=0.04) and peripheral arterial disease (adjusted HR 2.939, 95% CI 1.296∼6.664; p=0.01) than the controls. The cumulative incidence rates of these diseases in patients with BD were also significantly higher than those in the controls. @*Conclusion@#Patients with BD showed independent risk for angina pectoris and peripheral arterial disease.

Prediction of Treatment Response of Verruca Vulgaris Based on Lesion Hardening / 대한피부과학회지

Background@#Verruca vulgaris is a common cutaneous viral infectious disease caused by human papilloma virus (HPV). The main treatment modalities are cryotherapy, immunotherapy, laser therapy, intralesional injection of bleomycin, and salicylic acid therapy. However, there is no definitive tool for predicting clinical improvement or treatment response. @*Objective@#This study was designed to evaluate clinical treatment response according to the hardness of verruca vulgaris skin lesions. We developed a new prediction tool called the “hardening sign” that divides the course of treatment into four categories based on inspection and palpation. @*Methods@#We conducted a retrospective medical chart review of patients who visited Hanyang University Guri Hospital between January 2016 and January 2017 and were clinically diagnosed with verruca vulgaris. We divided the patients into four groups according to the grade of rigidity of their lesions. @*Results@#Forty-seven patients (24 male and 23 female) were identified. The mean age at diagnosis was 17.2±8.5 years, and the mean duration of treatment was 28.8±27.7 weeks. The mean number of hospital visits was 16.5±12.4. Eleven patients underwent only cryotherapy, while 36 patients underwent combined cryotherapy and immunotherapy. We observed significantly shorter durations of treatment for patients with higher grades of hardening. There was no correlation between the hardening grade and the number of treatments required for patients to be completely cured. @*Conclusion@#This study suggests that the therapeutic response of verruca vulgaris warts to cryotherapy can be easily predicted by careful consideration of the “hardening sign”.

Treatment of Recalcitrant Viral Warts with Combination Therapy of Systemic Acitretin and Diphenylcyclopropenone Immunotherapy

Viral warts are benign proliferations of the epithelium caused by human papilloma virus (HPV) infection. Diverse therapeutic options are available for viral warts, depending on extension and severity of the disease. We report a case of a 19-year-old man who presented with multiple viral warts on hands and feet for 5 years. He was treated at other clinics before visiting our hospital, but there was no improvement. We treated the lesions with a combination therapy of systemic acitretin and diphenylcyclopropenone (DPCP) immunotherapy for 6 months. A significant improvement was observed during the 12th week of therapy. Herein, we report a case of recalcitrant viral warts showing complete regression when a combination therapy of oral acitretin and immunotherapy was administered.

A Case of Livedoid Vasculopathy Successfully Treated with Sulodexide

We report a 29-year-old female with a one-month history of non-healing multiple erythematous to violaceous plaques with crusts over both legs and feet. Tender, scarring ulcers with surrounding erythema were present. The clinical manifestation, together with histopathologic findings of fibrinoid plugs within vascular lumens and walls, as well as red blood cell extravasation, led to diagnosis of livedoid vasculopathy.The patient experienced recurrent painful violaceous plaques with ulcerations during the two years of treatment with oral pentoxifylline 400 mg three times daily. The cutaneous lesions and symptoms dramatically improved after the treatment regimen changed to oral sulodexide (250 lipasemic units) three times daily. Sulodexide, a highly purified mixture of glycosaminoglycans including dermatan sulfate and lowmolecular weight heparin, could be an effective therapy for recalcitrant livedoid vasculopathy. Herein, we report a case of livedoid vasculopathy treated with sulodexide, which has not previously been reported.

Lymphangioma Circumscriptum of the Vulva Mimicking Condyloma Acuminatum in a Patient with Crohn’s Disease / 대한피부과학회지

While lymphangioma circumscriptum may present anywhere on the body, the vulva is a rare site. However, vulvar involvement can occur in some clinical settings, and Crohn’s disease is one of the underlying etiologies of acquired lymphangioma circumscriptum. A 31-year-old woman presented with an 8-year history of widespread verruciform plaques on her vulva. She complained of a mild itching sensation at the lesion site. She was diagnosed with Crohn’s disease 11 years prior but had not been treated. She had no history of trauma or surgery in the perineal area and no familial history of cancer or hereditary disorders. The histopathologic findings were consistent with lymphangioma. Based on the clinicopathologic findings, the patient was diagnosed with lymphangioma circumscriptum on the vulva. Herein, we report a rare case of acquired lymphangioma circumscriptum of the vulva mimicking condyloma acuminatum in a patient with Crohn’s disease.

Primary Cutaneous Solitary Fibrous Tumor on the Back

Solitary fibrous tumors (SFT) are uncommon mesenchymal tumors. SFT have several synonyms including localized fibrous tumor, benign mesothelioma, localized fibrous mesothelioma, and submesothelial fibroma. SFT usually occur in the pleura or other serosal surfaces, but SFT can also develop in extrapleural areas including the nasal cavity, orbit, retroperitoneum, and pelvis. Cutaneous SFT is extremely rare, and more likely to occur in the head and neck region. Histologically, this tumor can mimic a variety of benign and malignant tumors such as dermatofibroma, dermatofibrosarcoma protuberans, spindle cell lipoma or other mesenchymal tumors. Most cases of SFT show non-aggressive clinical courses, with low recurrence rates. Herein, we describe a case of primary cutaneous SFT which presented with huge mass on the back.

Generalized Cutaneous Metastasis of Breast Ductal Carcinoma / 대한피부과학회지

No abstract available.

Concurrent Leukemia Cutis and Sweet Syndrome in a Patient with Acute Myeloid Leukemia / 대한피부과학회지

No abstract available.

A Case of Peripheral T-cell Lymphoma, Unspecified Presenting as Multiple Ulcerative Tumors / 대한피부과학회지

Peripheral T cell lymphoma, unspecified (PTCL-U) comprises a heterogenous group of mature T-cell lymphomas that do not match with any defined T-cell entities in the current classification system. A 68-year-old man presented with extensive erythematous to brownish ulcerative tumors with yellowish discharge on the neck, trunk, and both upper extremities that had persisted for the past 7 months. Histological findings showed medium- to large-sized pleomorphic lymphocytes with cellular atypia infiltrating the deep dermis and subcutis. Immunohistochemical analysis of specimens from this patient revealed positive staining for CD2, CD45, and granzyme B and mildly positive staining for CD3, CD4, CD30, and CD79a. Based on these clinico-pathological findings, the patient was finally diagnosed with PTCL-U. We report herein a rare case of PTCL-U presenting as multiple ulcerative tumors.

TAK1 inhibition-induced RIP1-dependent apoptosis in murine macrophages relies on constitutive TNF-α signaling and ROS production.

BACKGROUND: Transforming growth factor-ß (TGF-ß)-activated kinase 1 (TAK1) is a key regulator of signal cascades of TNF-α receptor and TLR4, and can induce NF-κB activation for preventing cell apoptosis and eliciting inflammation response. RESULTS: TAK1 inhibitor (TAKI) can decrease the cell viability of murine bone marrow-derived macrophages (BMDM), RAW264.7 and BV-2 cells, but not dermal microvascular endothelial cells, normal human epidermal keratinocytes, THP-1 monocytes, human retinal pigment epithelial cells, microglia CHME3 cells, and some cancer cell lines (CL1.0, HeLa and HCT116). In BMDM, TAKI-induced caspase activation and cell apoptosis were enhanced by lipopolysaccharide (LPS). Moreover, TAKI treatment increased the cytosolic and mitochondrial reactive oxygen species (ROS) production, and ROS scavengers NAC and BHA can inhibit cell death caused by TAKI. In addition, RIP1 inhibitor (necrostatin-1) can protect cells against TAKI-induced mitochondrial ROS production and cell apoptosis. We also observed the mitochondrial membrane potential loss after TAKI treatment and deterioration of oxygen consumption upon combination with LPS. Notably TNF-α neutralization antibody and inhibitor enbrel can decrease the cell death caused by TAKI. CONCLUSIONS: TAKI-induced cytotoxicity is cell context specific, and apoptosis observed in macrophages is dependent on the constitutive autocrine action of TNF-α for RIP1 activation and ROS production.

Syk is involved in NLRP3 inflammasome-mediated caspase-1 activation through adaptor ASC phosphorylation and enhanced oligomerization.

NLRP3 is the most crucial member of the NLR family, as it detects the existence of pathogen invasion and self-derived molecules associated with cellular damage. Several studies have reported that excessive NLRP3 inflammasome-mediated caspase-1 activation is a key factor in the development of diseases. Recent studies have reported that Syk is involved in pathogen-induced NLRP3 inflammasome activation; however, the detailed mechanism linking Syk to NLRP3 inflammasome remains unclear. In this study, we showed that Syk mediates NLRP3 stimuli-induced processing of procaspase-1 and the consequent activation of caspase-1. Moreover, the kinase activity of Syk is required to potentiate caspase-1 activation in a reconstituted NLRP3 inflammasome system in HEK293T cells. The adaptor protein ASC bridges NLRP3 with the effector protein caspase-1. Herein, we find that Syk can associate directly with ASC and NLRP3 by its kinase domain but interact indirectly with procaspase-1. Syk can phosphorylate ASC at Y146 and Y187 residues, and the phosphorylation of both residues is critical to enhance ASC oligomerization and the recruitment of procaspase-1. Together, our results reveal a new molecular pathway through which Syk promotes NLRP3 inflammasome formation, resulting from the phosphorylation of ASC. Thus, the control of Syk activity might be effective to modulate NLRP3 inflammasome activation and treat NLRP3-related immune diseases.

Liver Stem Cells / 한양의대학술지

Liver transplantation has been regarded as the definitive curative approach for pathologic liver conditions from the acute stage to the chronic end stage for decades. Recently, translational research has been focused on liver stem cell transplantation, using various cell therapies, due to the potential benefit of natural host liver regeneration. Many studies are ongoing utilizing and evaluating the use of either fetal-liver-derived stem cells or oval cells, however many obstacles still remain. Extensive research identifying and characterizimg stem/progenitor cells for potential application to in vitro cell therapy, whereas many questions remain concerning the isolation and identification of adult liver stem cells with adequate capacity for proliferation and the regeneration of injured liver. Recent approaches to liver regeneration include the production of hepatocyte-like cells from other stem cell sources such as mesenchymal stem cells and embryonic stems cells. Another major target for liver regeneration studies include the generation of liver stem cells from induced pluripotent stem cells (IPSC) We review the current data concerning characterization of stem cells and progenitor cells for their capacity to support their potential for re-population and regeneration of normal adult liver from liver damaged due to injury and/or disease.

Regulation of c-Fos gene expression by NF-κB: a p65 homodimer binding site in mouse embryonic fibroblasts but not human HEK293 cells.

The immediate early gene c-Fos is reported to be regulated by Elk-1 and cAMP response element-binding protein (CREB), but whether nuclear factor (NF)-κB is also required for controlling c-Fos expression is unclear. In this study, we determined how NF-κB's coordination with Elk/serum response factor (SRF) regulates c-fos transcription. We report that PMA strongly induced c-Fos expression, but tumor necrosis factor (TNF)-α did not. In mouse embryonic fibroblasts, the PMA induction of c-Fos was suppressed by a deficiency in IKKα, IKKß, IKKγ, or p65. By contrast, in human embryonic kidney 293 cells, PMA induced c-Fos independently of p65. In accordance with these results, we identified an NF-κB binding site in the mouse but not human c-fos promoter. Under PMA stimulation, IKKα/ß mediated p65 phosphorylation and the binding of the p65 homodimer to the NF-κB site in the mouse c-fos promoter. Furthermore, our studies demonstrated independent but coordinated functions of the IKKα/ß-p65 and extracellular signal-regulated kinase (ERK)-Elk-1 pathways in the PMA induction of c-Fos. Collectively, these results reveal the distinct requirement of NF-κB for mouse and human c-fos regulation. Binding of the p65 homodimer to the κB site was indispensable for mouse c-fos expression, whereas the κB binding site was not present in the human c-fos promoter. Because of an inability to evoke sufficient ERK activation and Elk-1 phosphorylation, TNF-α induces c-Fos more weakly than PMA does in both mouse and human cells.

Regulation of inflammatory response by 3-methyladenine involves the coordinative actions on Akt and glycogen synthase kinase 3ß rather than autophagy.

3-Methyladenine (3-MA) is one of the most commonly used inhibitors in autophagy research today. However, rather than inhibiting class III PI3K that is involved in autophagy suppression, 3-MA might also interfere with class I PI3K and consequently augment autophagy flux. In this study, we aim to get a thorough understanding on the action mechanisms of 3-MA in TLR4-mediated inflammatory responses in RAW264.7 macrophages and, moreover, to decipher the action of 3-MA in modulation of autophagy. We found that 3-MA could enhance LPS-induced NF-κB activation and production of TNF-α, inducible NO synthase (iNOS), cyclooxygenase-2, IL-1ß, and IL-12. In contrast, 3-MA suppressed LPS-induced IFN-ß production and STAT signaling. Studies revealed that 3-MA can, through inhibition of Akt as a result of class I PI3K interference, positively regulate p38, JNK, and p65, but negatively regulate TANK-binding kinase 1 and IFN regulatory factor 3 mediated by TLR4. As glycogen synthase kinase 3ß (GSK3ß) is an important Akt substrate, we further explored its involvement in the actions of 3-MA. 3-MA was found to enhance LPS-induced NF-κB activation, iNOS, and pro-IL-1ß expression, and these actions were reversed by either GSK3ß inhibitors or small interfering GSK3ß. Lastly, we demonstrated that 3-MA acts as an autophagy inducer in RAW264.7 macrophages, but the stimulating effects on NF-κB activation and iNOS and cyclooxygenase-2 expression were not affected in LPS-stimulated macrophages with small interfering autophagy protein-5 treatment. These results not only shed new light on the action mechanisms of 3-MA to differentially regulate inflammatory outcomes derived from TLR4-mediated MyD88 and Toll/IL-1R domain-containing adapter inducing IFN-ß pathways, but also highlight the necessity to check autophagy status upon taking 3-MA as a general autophagy inhibitor.

Cell type-specific effects of Adenosine 5'-triphosphate and pyrophosphate on the antitumor activity of doxorubicin.

Extracellular ATP is an important signaling molecule mediating quite divergent specific biological effects. Even though recent studies suggest a potential role of ATP in cancer progress, its real impact in chemotherapeutic efficacy remains unclear. In the present study, we investigated the effect of ATP on the cytotoxicity of doxorubicin in various cancer cell types and found that ATP had no effect on doxorubicin cytotoxicity in colon, prostate, breast, and cervical cancers or in osteosarcoma. In contrast, ATP has divergent effects on lung cancer cells: it can protect against doxorubicin-induced cell death in non-metastatic lung cancer CL1.0 cells, but not in highly metastatic CL1.5 cells. Both apoptotic (characterized by sub-G(1) peak, caspase 3 activation, poly(ADP-ribose) polymerase-1 cleavage) and necrotic (characterized by propidium iodide uptake and ROS production) features induced by doxorubicin in CL1.0 cells were reduced by ATP. In addition, ATP attenuated p53 accumulation, DNA damage (assessed by poly(ADP-ribose) formation and the comet assay) and topoisomerase II inhibition after doxorubicin treatment, and doxorubicin cytotoxicity was diminished by the p53 inhibitor pifithrin-α. Moreover, UTP, UDP, ADP, and pyrophosphate sodium pyrophosphate tetrabasic decahydrate diminished the antitumor effect of doxorubicin in CL1.0 cells, whereas purinergic P2 receptors antagonists did not abrogate the action of ATP. In summary, ATP fails to alter the antitumor efficacy of doxorubicin in most cancer cell types, except in CL1.0 cells, in which pyrophosphate mediates the cell protection afforded by ATP via attenuation of reactive oxygen species production, DNA damage, p53 accumulation, and caspase activation.

zVAD-induced autophagic cell death requires c-Src-dependent ERK and JNK activation and reactive oxygen species generation.

The treatment of L929 fibrosarcoma cells with zVAD has been shown to induce necroptosis. However, whether autophagy is involved or not in this event remains controversial. In this study, we re-examined the role of autophagy in zVAD-induced cell death in L929 cells and further elucidated the signaling pathways triggered by caspase inhibition and contributing to autophagic death. First, we found that zVAD can stimulate LC3-II formation, autophagosome and autolysosome formation, and ROS accumulation. Antioxidants, beclin 1 or Atg5 silencing, and class III PtdIns3K inhibitors all effectively blocked ROS production and cell death, suggesting ROS accumulation downstream of autophagy contributes to cell necrosis. zVAD also stimulated PARP activation, and the PARP inhibitor DPQ can reduce zVAD-induced cell death, but did not affect ROS production, suggesting the increased ROS leads to PARP activation and cell death. Notably, our data also indicated the involvement of Src-dependent JNK and ERK in zVAD-induced ROS production and autophagic death. We found caspase 8 is associated with c-Src at the resting state, and upon zVAD treatment this association was decreased and accompanied by c-Src activation. In conclusion, we confirm the autophagic death in zVAD-treated L929 cells, and define a new molecular pathway in which Src-dependent ERK and JNK activation can link a signal from caspase inhibition to autophagy, which in turn induce ROS production and PARP activation, eventually leading to necroptosis. Thus, in addition to initiating proteolytic activity for cell apoptosis, inactivated caspase 8 also functions as a signaling molecule for autophagic death.

Celecoxib induces heme oxygenase-1 expression in macrophages and vascular smooth muscle cells via ROS-dependent signaling pathway.

The multiple cytoprotective mechanisms of heme oxygenase (HO)-1 make it a promising therapeutic target. This study investigated whether the selective cyclooxygenase (COX)-2 inhibitor, celecoxib, can upregulate HO-1 expression. Murine J774 macrophages and rat aortic vascular smooth muscle cells (VSMCs) were used to study the effect of celecoxib on HO-1 expression. A signal transduction pathway involving reactive oxygen species (ROS) was also investigated. We found that celecoxib can upregulate HO-1 gene and protein expressions in J774 macrophages and VSMCs. This effect was not diminished by prostaglandin E(2) or 15dPGJ(2), while it was additive to hypoxia-induced HO-1 expression, suggesting an event independent of COX-2 activity or hypoxia-inducible factor-1α. Moreover, celecoxib activated ERK, p38, Akt, and Nrf2 as well as increased ROS production. All these events contributed to the increase in the expression of HO-1 caused by celecoxib. In this study, we also, for the first time, demonstrated that AMP-activated protein kinase (AMPK) can mediate HO-1 expression via the downstream activation of p38 and Akt. However, the HO-1-inducing actions of celecoxib and hypoxia were not associated with AMPK. This study demonstrates a COX-2-independent action of celecoxib in upregulating HO-1 in macrophages and VSMCs. This action is dependent on ROS, Akt, ERK, p38, and Nrf2 activation. These findings provide new insights into the action mechanism of celecoxib with broad implications for anti-inflammation therapy.