Decision and Practice of End-of-Life Care in Lung Disease Patients with Physicians Orders for Life Sustaining Treatment.

Purpose: The purpose of this study was to analyze end-of-life care practices in lung disease patients with physician orders for life-sustaining treatment (POLSTs). Methods: We retrospectively analyzed data from medical records regarding the end-of-life care practices of POLST decisions for patients with lung disease hospitalized at a tertiary hospital in Seoul, South Korea. Data were collected from January 1 to June 30, 2021. Results: Of 300 total patients, 198 had lung cancer (66.0%) and 102 had non-malignant lung diseases (34.0%). A POLST was written for 187 patients (62.3%), and an advance directive was written for 20 patients (6.7%). Subsequent treatments were hemodialysis in 13 patients (4.3%), surgery in 3 patients (1.0%), and cardiopulmonary cerebral resuscitation in 1 patient (0.3%). Among cancer patients, chemotherapy was performed in 11 patients (3.7%), targeted therapy in 11 patients (3.7%), immunotherapy in 6 patients (2.0%), and radiation therapy in 13 patients (4.3%). Depending on the type of lung disease, types of treatment differed, including hemodialysis, ventilators, bilevel positive airway pressure, high-flow nasal cannulas, nebulizers, enteral nutrition, central line, inotropic agents, and opioids. Conclusion: Although the goals of hospice care are the same whether a patient has lung cancer or a non-malignant lung disease, because the characteristics of the respective diseases differ, end-of-life care practices and hospice approaches must be considered differently.

Refining cell-based assay to detect MOG-IgG in patients with central nervous system inflammatory diseases.

BACKGROUND: Given that the spectrum of myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) associated disease is yet to be fully defined, development of sensitive and highly specific assays to identify MOG-IgG is crucial to precisely define the clinical phenotypes, disease courses and prognosis to describe the full spectrum of MOG-IgG associated diseases. Here, we aim to validate a new in-house live cell-based assay (CBA) for screening MOG-IgG in patients with central nervous system inflammatory diseases. METHODS: We generated a full length MOG transfected HEK293 stable cell line using pIRES2-eGFP vector. Sera from 355 patients with central nervous system inflammatory diseases and 25 healthy individuals were evaluated for MOG-IgG seropositivity using in-house cell-based immunofluorescence assay (CBA-IF). The specificity of IgG (H + L) and IgG1-Fc secondary antibodies as well as IgM binding were determined by cell-based flow cytometry (CBA-FACS). The optimal cut-offs for determining seropositivity in CBA-FACS were calculated and the concordance of CBA-IF score and CBA-FACS was studied. The results of our CBA-IF were compared with the Oxford CBA-IF. RESULTS: 11.5% (41/355) of patients were seropositive for MOG-IgG and had clinical phenotypes that were within the known clinical spectrum of MOG-IgG associated diseases. No typical multiple sclerosis patients, aquaporin-4-IgG positive neuromyelitis optica spectrum disorder or healthy individuals were MOG-IgG seropositive. Using CBA-FACS, the anti-human IgG (H + L) was found to be comparable to IgG1-Fc antibody. No IgM binding was observed in all the samples tested. CBA-IF score and CBA-FACS yielded high correlation. The concordance of the NCC CBA-IF with the Oxford CBA-IF was 98%. CONCLUSION: We have developed MOG-IgG CBAs that have different characteristics and benefits but with high specificity and concordance. The complementary use of two methods and follow-up study with larger cohort will increase the clinical usefulness of MOG-IgG CBAs.

Convenience store visitors recall cigarette advertisements even if they do not purchase cigarettes.

BACKGROUND: This study examined the extent to which visitors to convenience stores remember the cigarette advertisements they encounter in these stores and investigated the relationships between how advertisements are recalled and attitudes toward them. METHODS: Exit surveys of 1007 visitors to three convenience stores located in Seoul, Korea, were conducted between 25 November 2015 and 7 December 2015. RESULTS: Of the respondents, 23.4% (n = 236) freely recalled the cigarette advertisement in the store just visited. However, the percentage of participants who correctly recalled the advertisement increased to 55.2% (n = 556) after we presented them with a card showing options for the advertisement (i.e. a cued recall task). Regardless of sex or purchasing cigarettes, free recall performance was significantly associated with age, number of weekly visits to the convenience store and current smoking status. In addition, free recall increased with having a positive attitude toward cigarette advertisements. CONCLUSIONS: Repeated visits to convenience stores may continue to expose individuals to cigarettes and their advertisements; such exposure may subconsciously affect recall of the advertisements and maintenance of a positive attitude toward cigarette advertisements. Therefore, to denormalize smoking in society, cigarette advertising and displays at points of sale including convenience stores, should be banned.

Differences in visual fixation duration according to the position of graphic health warning labels: An eye-tracking approach.

INTRODUCTION: The Framework Convention on Tobacco Control (FCTC) recommends that graphic health warning labels (GHWLs) be positioned at the top of the principal area of cigarette packs, rather than at the bottom, to increase visibility. However, during the legislative process of introducing GHWLs in South Korea, the position of GHWLs has become a contested issue. The pro-tobacco industry group argued that the warnings should be placed at the bottom of cigarette packs because evidence for the effectiveness of the upper position was insufficient. Therefore, this study investigated whether the position of the GHWL affects eye movement. METHODS: Participants (30 daily smokers and 24 non-smokers) were shown six cigarette packs in random order with different position combinations (top, middle, bottom) and image concepts (skin aging, toxic constituents). Participants' eye movements were recorded using eye-tracking equipment to measure visual fixation duration in milliseconds (ms). RESULTS: Participants visually fixated longer on the health warning area than on the tobacco branding area (p<0.05). Mean fixation duration on the health warning area was significantly longer at the top or middle positions compared to the bottom, by 28% (mean difference=340 ms, p=0.006) and by 30% (mean difference=368 ms, p=0.002), respectively. By contrast, mean fixation duration on the branding area was longer with the warning at the bottom compared to top or middle positions by 25% and 33%, with mean differences of 157 ms (p=0.100) and 212 ms (p=0.026), respectively. No significant difference in fixation time was observed between the top and middle positions (p>0.05). CONCLUSIONS: The duration of visual fixation on GHWLs was longer when they were displayed at the top and middle, rather than at the bottom. Therefore, GHWLs should be positioned from the top to the middle of the tobacco package.

Tobacco company strategies for maintaining cigarette advertisements and displays in retail chain stores: In-depth interviews with Korean convenience store owners.

INTRODUCTION: This study gathered data from store owners regarding the advertising and display of, and the contractual arrangements and promotional activities related to, the sale of tobacco products in convenience stores. METHODS: In-depth interviews were conducted with three owners of convenience stores in South Korea: to examine the procedures for managing the sale of tobacco products; for allocating the advertising allowance for such products; and for coordinating the promotional activities of tobacco companies. RESULTS: All tobacco advertisements and displays in convenience stores are installed and managed in accordance with the contract between the tobacco companies and the convenience store headquarters. The headquarters receives an allowance from the tobacco company in return for maintaining and displaying their product and promotional materials. The headquarters then pays a monthly advertising allowance to each franchisee as an operating subsidy. However, the owners also stated that tobacco companies provide financial incentives directly to them to engage in illegal promotional activities. CONCLUSIONS: Because tobacco advertisements and displays at convenience stores are related to the profitability of these products, the participants in these relationships have become increasingly entangled. Illegal promotional activities must be monitored to limit tobacco sales and advertising. Furthermore, efforts to ban the advertising and display of tobacco products at the point of sale must be based on the development of policies emerging from an understanding of the roles of the major stakeholders.

CTLA4-CD28 chimera gene modification of T cells enhances the therapeutic efficacy of donor lymphocyte infusion for hematological malignancy.

Donor lymphocyte infusion (DLI) followed by hematopoietic stem cell transplantation has served as an effective prevention/treatment modality against the relapse of some hematologic tumors, such as chronic myeloid leukemia (CML). However, the therapeutic efficacies of DLI for other types of leukemia, including acute lymphocytic leukemia (ALL), have been limited thus far. Therefore, we examined whether increasing the reactivity of donor T cells by gene modification could enhance the therapeutic efficacy of DLI in a murine model of ALL. When a CTLA4-CD28 chimera gene (CTC28) in which the intracellular signaling domain of CTLA4 was replaced with the CD28 signaling domain was introduced into CD4 and CD8 T cells in DLI, the graft-versus-tumor (GVT) effect was significantly increased. This effect was correlated with an increased expansion of donor CD8 T cells in vivo, and the depletion of CD8 T cells abolished this effect. The CD8 T cell expansion and the enhanced GVT effect were dependent on the transduction of both CD4 and CD8 T cells with CTC28, which emphasizes the role of dual modification in this therapeutic effect. The CTC28-transduced T cells that expanded in vivo also exhibited enhanced functionality. Although the potentiation of the GVT effect mediated by the CTC28 gene modification of T cells was accompanied by an increase of graft-versus-host disease (GVHD), the GVHD was not lethal and was mitigated by treatment with IL-10 gene-modified third-party mesenchymal stem cells. Thus, the combined genetic modification of CD4 and CD8 donor T cells with CTC28 could be a promising strategy for enhancing the therapeutic efficacy of DLI.

Large-Scale in-House Cell-Based Assay for Evaluating the Serostatus in Patients with Neuromyelitis Optica Spectrum Disorder Based on New Diagnostic Criteria.

BACKGROUND AND PURPOSE: The detection of aquaporin 4-IgG (AQP4-IgG) is now a critical diagnostic criterion for neuromyelitis optica spectrum disorder (NMOSD). To evaluate the serostatus of NMOSD patients based on the 2015 new diagnostic criteria using a new in-house cell-based assay (CBA). METHODS: We generated a stable cell line using internal ribosome entry site-containing bicistronic vectors, which allow the simultaneous expression of two proteins (AQP4 and green fluorescent protein) separately from the same RNA transcript. We performed in-house CBA using serum from 386 patients: 178 NMOSD patients diagnosed according to the new diagnostic criteria without AQP4-IgG, 63 high risk NMOSD patients presenting 1 of the 6 core clinical characteristics of NMOSD but not fulfilling dissemination in space, and 145 patients with other neurological diseases, including 66 with multiple sclerosis. The serostatus of 111 definite and high risk NMOSD patients were also tested using a commercial CBA kit with identical serum to evaluate the correlation between the 2 methods. All assays were performed by two independent and blinded investigators. RESULTS: Our in-house assay yielded a specificity of 100% and sensitivities of 80% (142 of 178) and 76% (48 of 63) when detecting definite- and high risk NMOSD patients, respectively. The comparison with the commercial CBA kit revealed a correlation for 102 of the 111 patients: no correlation was present in 7 patients who were seronegative using the commercial method but seropositive using the in-house method, and in 2 patients who were seropositive using the commercial method but seronegative using the in-house method. CONCLUSIONS: These results demonstrate that our in-house CBA is a highly specific and sensitive method for detecting AQP4-IgG in NMOSD patients.

Ndrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2.

Induction of T-cell clonal anergy involves serial activation of transcription factors, including NFAT and Egr2/3. However, downstream effector mechanisms of these transcription factors are not fully understood yet. Here we identify Ndrg1 as an anergy factor induced by Egr2. Ndrg1 is upregulated by anergic signalling and maintained at high levels in resting anergic T cells. Overexpression of Ndrg1 mimics the anergic state and knockout of the gene prevents anergy induction. Interestingly, Ndrg1 is phosphorylated and degraded by CD28 signalling in a proteasome-dependent manner, explaining the costimulation dependence of anergy prevention. Similarly, IL-2 treatment of anergic T cells, under conditions that lead to the reversal of anergy, also induces Ndrg1 phosphorylation and degradation. Finally, older Ndrg1-deficient mice show T-cell hyperresponsiveness and Ndrg1-deficient T cells aggravate inducible autoimmune inflammation. Thus, Ndrg1 contributes to the maintenance of clonal anergy and inhibition of T-cell-mediated inflammation.

A Patient with Duodenal Mucinous Adenocarcinoma Presenting as a Laterally Spreading Tumor.

Primary duodenal carcinoma is rare. Duodenal mucinous adenocarcinoma (DMA) is even rarer, and its associated manifestations and typical endoscopic or imaging findings are not well characterized. Herein, we report a case of primary DMA in an asymptomatic 58-year-old man who visited our hospital for a regular health screening. Upper endoscopy revealed an approximately 4-cm lesion in the second portion of the duodenum, but the mass was not visualized on computed tomography. Biopsies revealed a tubular adenoma that was subsequently resected. Frozen biopsies demonstrated DMA with a background of low-grade tubular adenoma for which we performed Roux-en-Y duodenojejunostomy and jejunojejunostomy. To our knowledge, this is the first report of a patient with DMA in Korea.

[A case of pleomorphic liposarcoma in a patient with Crohn's disease taking azathioprine].

Azathioprine is frequently used for the treatment of inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. Lymphomas, squamous cell carcinomas, and undifferentiated pleomorphic sarcomas have been reported among patients receiving azathioprine therapy. Herein, we report a case of pleomorphic liposarcoma of chest wall which occurred in a 44-year-old man with Crohn's disease taking azathioprine. He was diagnosed with Crohn's disease 3 years ago after suffering from abdominal pain and hematochezia for 12 years. He had been taking 50 mg of azathioprine per day for 23 months when he visited the thoracic and cardiovascular surgery clinic due to right chest palpable mass that had rapidly grown during the past 2 months. Excisional biopsy was performed and the mass was diagnosed as pleomorphic liposarcoma. Therefore, he underwent radical excision of the right chest wall mass, which measured 11.0 × 6.5 cm in size. He is scheduled to receive radiation therapy and chemotherapy.

[Is it useful to perform additional colonoscopy to detect unmatched lesion between positron emission tomography/computed tomography and colonoscopy?].

BACKGROUND/AIMS: Incidentally detected focal 18F-fluorodeoxyglucose (FDG) uptake was compared with colonoscopy. We investigated the characteristics of colon adenomas which were revealed on PET/CT. Then we identified whether additional colonoscopy was necessary in patients with lesions which were revealed on PET/CT but had no matched lesions on colonoscopy. METHODS: We retrospectively reviewed 95 patients who underwent colonoscopy within a 6 month interval after they had focal FDG uptake from January 2010 to May 2012 at National Police Hospital in Korea. Also, we analyzed 30 patients who underwent additional colonoscopy within 2 years after they had no matched lesions on primary colonoscopy. RESULTS: PET/CT depicted 54.6% (41/75) of adenomas and adenocarcinomas. The PET visibility of colon adenoma was significantly associated with degree of dysplasia (p=0.027), histologic type (p=0.040), and the size (p=0.038). The positivity rate was increased with higher degree of dysplasia (low-grade dysplasia, 47%; high-grade dysplasia, 78%; adenocarcinoma, 100%) and villous patterns of histologic type (tubular, 46.8%; tubulovillous, 87.5%; villous, 100%). Patients with adenomas larger than 10 mm (87.5%) had higher detection rate compared to those with adenomas smaller than 10 mm (49.0%). Among the 30 patients who underwent additional colonoscopy, only one patient had a 6 mm sized tubular adenoma (low-grade dysplasia). CONCLUSIONS: Incidental focal colonic uptake may indicate advanced adenoma or adenocarcinoma. Thus, it justifies performing colonoscopy for identifying the presence of colon neoplasms. However, in case of unmatched lesions between PET/CT and colonoscopy, there was little evidence that additional colonoscopy would yield benefits.

Positive conversion of negative signaling of CTLA4 potentiates antitumor efficacy of adoptive T-cell therapy in murine tumor models.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been known to be a strong tolerance-inducing inhibitory receptor on T-cell surface. Systemic blocking of CTLA4 function with blocking antibodies has been regarded as an attractive strategy to enhance antitumor immunity. However, this strategy accompanies systemic autoimmune side effects that are sometimes problematic. Therefore, we developed a novel CTLA4 mutant that could be expressed in tumor antigen-specific T cells to enhance antitumor effect without systemic autoimmunity. This mutant, named CTLA4-CD28 chimera, consists of extracellular and transmembrane domains of CTLA4, linked with cytoplasmic CD28 domain. Overexpression of CTLA4-CD28 chimera in T cells delivered stimulatory signals rather than inhibitory signals of CTLA4 and significantly enhanced T-cell reactivity. Although this effect was observed in both CD4 and CD8 T cells, the effect on CD4 T cells was predominant. CTLA4-CD28 chimera gene modification of CD4 T cells significantly enhanced antitumor effect of unmodified CD8 T cells. Nonetheless, the gene modification of CD8 T cells along with CD4 T cells further maximized antitumor effect of T cells in 2 different murine tumor models. Thus, CTLA4-CD28 chimera gene modification of both tumor antigen-specific CD4 and CD8 T cells would be an ideal way of modulating CTLA4 function to enhance tumor-specific T-cell reactivity.

Recruitment of Sprouty1 to immune synapse regulates T cell receptor signaling.

TCR stimulation not only initiates positive signals for T cell activation, but also induces negative signals that down-regulate T cells. We previously reported that Sprouty1, a negative regulator of Ras-MAPK pathway of receptor tyrosine kinases, was induced by TCR signal and inhibited TCR signaling in CD4+ T cell clones. In this study, we addressed the mechanism underlying Sprouty1 inhibition of T cells. When overexpressed in Jurkat T cells, Sprouty1 inhibited TCR signal-induced IL-2 transcription, and also AP-1, NFAT, and NF-kappaB activation, which suggests that Sprouty1 acts at proximal TCR signalosome. Accordingly, we found that Sprouty1 translocated to immune synapse upon TCR engagement in both Jurkat cells and activated primary T cells and interacted with various signaling molecules in the TCR signalosome, such as linker for activation of T cells (LAT), phospholipase C-gamma1 (PLC-gamma1), c-Cbl/Cbl-b, and HPK1. Sprouty1 inhibited LAT phosphorylation, leading to decreased MAPK activation and IL-2 production. Deletion of C-terminal 54 amino acids in Sprouty1 abolished its inhibitory effect and this deletion mutant was unable to translocate to immune synapse and interact with LAT. Overall, our data suggest that Sprouty1 induced by TCR signal negatively regulates further TCR signaling by interacting with proximal signaling molecules in immune synapse, providing a novel regulatory mechanism of T cells.