[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

CA : A Cancer Journal for Clinicians

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Purpose
The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).

Patients and Methods
In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).

Results
A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.

Conclusion
Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

Epithelial to mesenchymal transition (EMT) is essential for driving plasticity during development, but is an unintentional behaviour of cells during cancer progression. The EMT-associated reprogramming of cells not only suggests that fundamental changes may occur to several regulatory networks but also that an intimate interplay exists between them. Disturbance of a controlled epithelial balance is triggered by altering several layers of regulation, including the transcriptional and translational machinery, expression of non-coding RNAs, alternative splicing and protein stability.

Regulatory networks defining EMT during cancer initiation and progression

The discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the outbreak of coronavirus disease 2019 (COVID-19) are causing public health emergencies. A handful pieces of literature have summarized its clinical and radiologic features, whereas therapies for COVID-19 are rather limited. To evaluate the efficacy of convalescent plasma therapy in COVID-19 patients, we did this timely descriptive study. Six laboratory-confirmed COVID-19 patients were enrolled and received the transfusion of ABO-compatible convalescent plasma. The efficacy of this intervention was determined by the alleviation of symptoms, changes in radiologic abnormalities and laboratory tests. No obvious adverse effect observed during the treatment. Transfusion of convalescent plasma led to a resolution of ground-glass opacities and consolidation in patients #1, #2, #3, #4, and #6. In patients #1 and #5 who presented with SARS-CoV-2 in throat swab, convalescent plasma therapy elicited an elimination of the virus. Serologic analysis indicated an immediate increase in anti-SARS-CoV-2 antibody titers in patients #2 and #3, but not in patient #1. This study indicates that convalescent plasma therapy is effective and specific for COVID-19. This intervention has a special significance for eliminating SARS-CoV-2 and is believed to be a promising state-of-the-art therapy during COVID-19 pandemic crisis.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25882

Treatment with convalescent plasma for COVID-19 patients in Wuhan, China.

With great interest, we read the paper “Nervous system involvement after infection with COVID-19 and other coronaviruses”. The authors speculated that SARS-CoV-2 may cause neurological damages (Wu et al., 2020). Herein, we provided clinical evidence showing the central nervous system (CNS) involvement for SARS-CoV-2. A Wuhan male had fever, shortness of breath, and myalgia since Jan 28. On Feb 10, his disease deteriorated and his consciousness suddenly progressed to confusion. Laboratory test indicated low WBC count (3.3 × 10/L) and lymphopenia (0.8 × 10/L). Skull computer tomography (CT) was normal (Fig. 1A), while chest CT showed multiple subpleural ground glass opacities (GGOs) (Fig. 1B). The patient was positive for SARS-CoV-2 and sent to our institution. On physical examination, vital signs were stable without altered consciousness. Meningeal irritation signs (including nuchal rigidity, Kernig sign and Brudzinski sign) and extensor plantar response were present. Arterial blood gas analysis indicted PO2/FiO2 ratio of 240 mmHg. This COVID19 patient was treated with arbidol and oxygen therapy, whereas his consciousness was not improved. Lumbar puncture was performed on Feb 16, and the cerebrospinal fluid (CSF) pressure was 220 mmHg. Laboratory tests with CSF showed WBC (0.001 × 10/L), protein (0.27 g/L), ADA (0.17 U/L) and sugar (3.14 mmol/L) contents within normal limits. The CSF specimen was further tested for SARS-CoV-2 but the result was negative. This patient did not have evidence of bacterial or tuberculous infection of the CNS. After careful evaluation by neurologic experts, encephalitis associated with SARS-CoV-2 infection was concluded. Treatment at this moment was largely supportive, including mannitol infusion. Intriguingly, the patient’s consciousness generally ameliorated since Feb 20, and chest CT suggested a resolution of GGOs (Fig. 1B). His consciousness was completely clear on Feb 24. Two consecutive throat swab tests were negative for SARS-CoV-2. The patient was discharged from hospital on Feb 27. This letter describes a COVID-19 case who presented as encephalitis. To the best of our knowledge, this is an unusual manifestation of COVID-19. Fortunately, encephalitic associate with SARS-CoV-2 is selflimited. Although the definitive diagnosis of viral encephalitis largely depends on virus isolation, this is difficult for COVID-19 because SARSCoV-2 dissemination is transient and its CSF titer may be extremely low. Consistently, anti-SARS-CoV-2 IgM and IgG were not detectable in the patient’s CSF sample (unpublished data). Therefore, physical evaluation of neurological symptom is important to lead a presumptive diagnosis, as we have mentioned in this case. The pathophysiological characteristic of SARS-CoV-2 associated encephalitis is not fully understood. In agreement with Wu and colleagues (Wu et al., 2020), we speculate that SARS-CoV-2-induced immunologic response may cause inflammatory injury and edema, as a consequence, leading to alterations in consciousness. With the clearance of virus and the use of mannitol, the CSF pressure gradually reduces and the patient’s consciousness gradually improves. This might be a rational explanation for the self-limited property of SARS-CoV-2 associated encephalitis. Collectively, this report indicated that CNS may be involved in COVID-19 and highlights the diagnostic and therapeutic approaches to SARS-CoV-2 associated encephalitis.

Encephalitis as a clinical manifestation of COVID-19.

Background
Lysine specific demethylase 1 (LSD1) has been identified and biochemically characterized in epigenetics, but the pathological roles of its dysfunction in lung cancer remain to be elucidated. The aim of this study was to evaluate the prognostic significance of LSD1 expression in patients with non-small cell lung cancer (NSCLC) and to define its exact role in lung cancer proliferation, migration and invasion.

/pdf/over-expression-of-lsd1-promotes-proliferation-migration-and-5ci8zgd6d8.pdf

Over-Expression of LSD1 Promotes Proliferation, Migration and Invasion in Non-Small Cell Lung Cancer

A few studies have reported the long shedding of SARS-CoV-2 RNA. However, the duration of RNA shedding in Wuhan is rarely known and the meaning of the prolonged shedding is still under investigation. Almost 10% patients diagnosed of COVID-19 had a RNA shedding longer than 30 days even if the symptom elimination. The IgM was in a high level in the 9th week after symptom onset in these prolonged-RNA-shedding patients. Further study should be conducted to know the infectivity of the virus and the relationship between RNA shedding and antibody expression. This article is protected by copyright. All rights reserved.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25952

Prolonged SARS-CoV-2 RNA shedding: Not a rare phenomenon.

Gasdermin D (GSDMD) is a newly discovered pyroptosis executive protein, which can be cleaved by inflammatory caspases and is essential for secretion of IL-1β, making it a critical mediator of inflammation. However, the precise role of GSDMD in carcinogenesis remains nearly unknown. Considering the vital role of inflammation in tumorigenesis, we investigated the biological function of GSDMD in non-small cell lung cancer (NSCLC). Our study demonstrated that the GSDMD protein levels were significantly upregulated in NSCLC compared to these levels in matched adjacent tumor specimens. Higher GSDMD expression was associated with aggressive traits including larger tumor size and more advanced tumor-node-metastasis (TNM) stages. In addition, high GSDMD expression indicated a poor prognosis in lung adenocarcinoma (LUAD), but not in squamous cell carcinoma (LUSC). Knockdown of GSDMD restricted tumor growth in vitro and in vivo. Notably, intrinsic and extrinsic activation of pyroptotic (NLRP3/caspase-1) signaling in GSDMD-deficient tumor cells induced another type of programmed cell death (apoptosis), instead of pyroptosis. GSDMD depletion activated the cleavage of caspase-3 and PARP, and promoted cancer cell death via intrinsic mitochondrial apoptotic pathways. In addition, co-expression analyses indicated a correlation between GSDMD and EGFR/Akt signaling. Collectively, our results revealed a crosstalk between pyroptotic signaling and apoptosis in tumor cells. Knockdown of GSDMD attenuated tumor proliferation by promoting apoptosis and inhibiting EGFR/Akt signaling in NSCLC. In conclution, GSDMD is an independent prognostic biomarker for LUAD.

/pdf/downregulation-of-gsdmd-attenuates-tumor-proliferation-via-8sqcmkfotl.pdf

Downregulation of GSDMD attenuates tumor proliferation via the intrinsic mitochondrial apoptotic pathway and inhibition of EGFR/Akt signaling and predicts a good prognosis in non‑small cell lung cancer.

Tangfeng Lv

Papers

Treatment with convalescent plasma for COVID-19 patients in Wuhan, China.

Encephalitis as a clinical manifestation of COVID-19.

Over-Expression of LSD1 Promotes Proliferation, Migration and Invasion in Non-Small Cell Lung Cancer

Prolonged SARS-CoV-2 RNA shedding: Not a rare phenomenon.

Downregulation of GSDMD attenuates tumor proliferation via the intrinsic mitochondrial apoptotic pathway and inhibition of EGFR/Akt signaling and predicts a good prognosis in non‑small cell lung cancer.