Risk factors and actionable molecular signatures in COVID-19-associated lung adenocarcinoma and lung squamous cell carcinoma patients.

The molecular mechanism of the pathological impact of COVID-19 in lung cancer patients remains poorly understood to date. In this study, we used differential gene expression pattern analysis to try to figure out the possible disease mechanism of COVID-19 and its associated risk factors in patients with the two most common types of non-small-cell lung cancer, namely, lung adenocarcinoma and lung squamous cell carcinoma. We also used network-based approaches to identify potential diagnostic and molecular targets for COVID-19-infected lung cancer patients. Our study showed that lung cancer and COVID-19 patients share 36 genes that are expressed differently and in common. Most of these genes are expressed in lung tissues and are mostly involved in the pathogenesis of different respiratory tract diseases. Additionally, we also found that COVID-19 may affect the expression of several cancer-associated genes in lung cancer patients, such as the oncogenes JUN, TNC, and POU2AF1. Moreover, our findings suggest that COVID-19 may predispose lung cancer patients to other diseases like acute liver failure and respiratory distress syndrome. Additionally, our findings, in concert with published literature, suggest that molecular signatures, such as hsa-mir-93-5p, CCNB2, IRF1, CD163, and different immune cell-based approaches could help both diagnose and treat this group of patients. Altogether, the scientific findings of this study will help formulate appropriate management measures and guide the development of diagnostic and therapeutic measures for COVID-19-infected lung cancer patients.

Expert Consensus on Prevention and Treatment of COVID-19 Infection in Patients with Lung Cancer.

Corona virus disease 2019 (COVID-19) infection has become a major public health issue affecting human health. The main goal of epidemic prevention and control at the current stage in China is to "protect people's health and prevent severe cases". Patients with lung cancer who receive antitumor therapy have low immunity, and the risk of severe illness and death once infected is much higher than healthy people, so they are vulnerable to COVID-19 infection. At present, less attention has been paid to the prevention and treatment of COVID-19 infection in patients with lung cancer in domestic guidelines and consensus. Based on the published data in China and abroad, we proposed recommendations and formed expert consensus on the vaccination of COVID-19, the use of neutralizing antibodies and small molecule antiviral drugs for patients with lung cancer, for physician's reference.

Risk factors of SARS-CoV-2 infection and complications from COVID-19 in lung cancer patients.

BACKGROUND: Identifying lung cancer patients at an increased risk of getting SARS-CoV-2-related complications will facilitate tailored therapy to maximize the benefit of anti-cancer therapy, while decreasing the likelihood of COVID-19 complications. This analysis aimed to identify the characteristics of lung cancer patients that predict for increased risk of death or serious SARS-CoV-2 infection. PATIENTS AND METHODS: This was a retrospective cohort study of patients with lung cancer diagnosed October 1, 2015, and December 1, 2020, and a diagnosis of COVID-19 between February 2, 2020, and December 1, 2020, within the Veterans Health Administration. Serious SARS-CoV-2 infection was defined as hospitalization, ICU admission, or mechanical ventilation or intubation within 2 weeks of COVID-19 diagnosis. For categorical variables, differences were assessed using Χ2 tests, while Kruskal-Wallis rank-sum test was used for continuous variables. Multivariable logistic regression models were fit relative to onset of serious SARS-CoV-2 infection and death from SARS-CoV-2 infection. RESULTS: COVID-19 infection was diagnosed in 352 lung cancer patients. Of these, 61 patients (17.3%) died within four weeks of diagnosis with COVID-19, and 42 others (11.9%) experienced a severe infection. Patients who had fatal or severe infection were older and had lower hemoglobin levels than those with mild or moderate infection. Factors associated with death from SARS-CoV-2 infection included increasing age, immune checkpoint inhibitor therapy and low hemoglobin level. CONCLUSIONS:  The mortality of lung cancer patients from COVID-19 disease in the present cohort was less than previously reported in the literature. The identification of risk factors associated with severe or fatal outcomes informs management of patients with lung cancer who develop COVID-19 disease.

[Preliminary Recommendations on the Timing of Lung Surgery after 
Novel Coronavirus Infection in Patients with Pulmonary Nodules and Lung Cancer].

In recent years, the corona virus disease 2019 (COVID-19) pandemic has had a huge impact on the global medical, political and economic fields. Since the beginning of the COVID-19 epidemic, our understanding of the impact of COVID-19 has grown exponentially. Recently, the COVID-19 epidemic has changed rapidly in China, and there has been controversy over how to carry out surgical operations for patients with lung neoplastic lesions. Some studies have shown that lung cancer patients undergoing surgery are more likely to experience respiratory failure and perioperative death after contracting COVID-19 than the general population, however, delays in cancer treatment are also associated with increased mortality among these patients. In particular, the novel coronavirus Omikron variant has a higher transmissibility and may escape the immunity obtained through the previous novel coronavirus infection and vaccination. In order to minimize the risk of novel coronavirus infection in surgical patients, it is necessary to develop new treatment guidelines, expert consensus and preventive measures. However, the current rapid change of the epidemic situation has led to insufficient time and evidence to develop guidelines and consensus. Therefore, thoracic surgeons need to evaluate specific patient populations at higher risk of severe complications before surgery and weigh the benefit of surgical treatment against the risk of novel coronavirus infection. We try to give some recommendations on lung surgery during the current domestic epidemic situation based on the guidelines and consensus of oncology and thoracic surgery organizations in different regions on lung surgery.
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Severe Post-COVID-19 Organizing Pneumonia during Cancer Immunochemotherapy.

A 44-year-old man developed coronavirus disease 2019 (COVID-19) pneumonia during immunochemotherapy consisting of carboplatin, paclitaxel, and pembrolizumab for non-small cell lung cancer. Low-grade fever, followed by mild hypoxemia, and febrile neutropenia, were observed, and granulocyte colony-stimulating factor (G-CSF) was administered until the recovery of neutropenia, when he developed a high fever, severe hypoxemia, and hypotension accompanied by consolidation in the bilateral lungs. His conditions promptly improved after treatment including hydrocortisone and the primary and metastatic tumors remained regressed for 10 months without further treatment. Post-COVID-19 organizing pneumonia during cancer immunochemotherapy can be aggravated by immune-checkpoint inhibitors and G-CSF.

Optic neuritis in lung adenocarcinoma: A challenging diagnosis.

Optic neuritis with CRMP-5 IgG is a paraneoplastic inflammation of the optic nerve associated with lung cancer, mostly small-cell lung cancer. We present the case of a patient with lung adenocarcinoma who developed progressive bilateral visual loss a few months after immune-chemotherapy with pembrolizumab and after Covid-19 vaccination. Positive CRMP-5 IgG were detected in blood sample and complete work-up - including brain MRI - did not show any progression. High dose systemic corticoids were administered with transient improving, followed by intravenous immunoglobulins, methotrexate and rituximab but despite negativization of CRMP-5 IgG, the patient had a progressive visual loss.

Identification of the effects of COVID-19 on patients with pulmonary fibrosis and lung cancer: a bioinformatics analysis and literature review.

Coronavirus disease 2019 (COVID-19) poses a serious threat to human health and life. The effective prevention and treatment of COVID-19 complications have become crucial to saving patients' lives. During the phase of mass spread of the epidemic, a large number of patients with pulmonary fibrosis and lung cancers were inevitably infected with the SARS-CoV-2 virus. Lung cancers have the highest tumor morbidity and mortality rates worldwide, and pulmonary fibrosis itself is one of the complications of COVID-19. Idiopathic lung fibrosis (IPF) and various lung cancers (primary and metastatic) become risk factors for complications of COVID-19 and significantly increase mortality in patients. Therefore, we applied bioinformatics and systems biology approaches to identify molecular biomarkers and common pathways in COVID-19, IPF, colorectal cancer (CRC) lung metastasis, SCLC and NSCLC. We identified 79 DEGs between COVID-19, IPF, CRC lung metastasis, SCLC and NSCLC. Meanwhile, based on the transcriptome features of DSigDB and common DEGs, we identified 10 drug candidates. In this study, 79 DEGs are the common core genes of the 5 diseases. The 10 drugs were found to have positive effects in treating COVID-19 and lung cancer, potentially reducing the risk of pulmonary fibrosis.

Clinical characteristics and outcomes of lung cancer patients with COVID-19: A systematic review and meta-analysis protocol.

BACKGROUND: COVID-19 is spreading rapidly worldwide, and the population is generally susceptible to SARS-CoV-2, especially those with cancer. Hence, our study aims to design a protocol for a systematic review and meta-analysis of the clinical characteristics and prognoses of lung cancer patients with COVID-19. METHODS: The protocol is prepared following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The literature will be searched in Embase, Pubmed, the Cochrane Library, LitCovid, and CNKI for potentially eligible articles. The quality of the articles will be used in the Newcastle-Ottawa Quality Assessment Scale (NOS) and Cochrane Handbook for Systematic Reviews of Interventions. Statistical analysis will be performed through RevMan 5 software. This review protocol has been registered in PROSPERO (CRD42022306866). DISCUSSION: To clarify whether COVID-19 affects the clinical symptoms and prognoses of lung cancer patients. Further study is needed to establish the best evidence-based for the management of lung cancer patients with COVID-19. CONCLUSION: The definitive conclusion will be important to physicians effectively manage lung cancer patients with COVID-19.

A case of cytokine release syndrome accompanied with COVID-19 infection during treatment with immune checkpoint inhibitors for non-small cell lung cancer.

Cytokine release syndrome (CRS) is a systemic inflammatory disease caused by a variety of factors, including infections and certain drugs. A 70-year-old man who was diagnosed with a postoperative recurrence of lung adenocarcinoma received nivolumab, ipilimumab, pemetrexed and carboplatin every 3 weeks for two cycles followed by nivolumab and ipilimumab, which resulted in a partial response. Four days after the dose of nivolumab, the patient returned with diarrhea and fever. The patient was diagnosed with COVID-19 infection accompanied by severe colitis. Although intensive care was performed, the patient suddenly went into cardiopulmonary arrest. Examination revealed an abnormally high interleukin-6 level, suggesting CRS. This is the first report of a patient with CRS accompanied with COVID-19 infection during treatment with ICIs. Cytokine release syndrome (CRS) is a systemic inflammatory disease caused by a variety of factors, including infections and certain drugs. Here, we report a case of non-small cell lung cancer with CRS caused by COVID-19 infection during treatment with nivolumab and ipilimumab. Fever is a common event in cancer patients, especially in COVID-19-infected patients, but when fever develops during cancer immunotherapy, CRS should always be kept in mind.

Exploring the potential mechanism of emetine against coronavirus disease 2019 combined with lung adenocarcinoma: bioinformatics and molecular simulation analyses.

BACKGROUND: Patients with lung adenocarcinoma (LUAD) may be more predisposed to coronavirus disease 2019 (COVID-19) and have a poorer prognosis. Currently, there is still a lack of effective anti-LUAD/COVID-19 drugs. Thus, this study aimed to screen for an effective anti-LUAD/COVID-19 drug and explore the potential mechanisms. METHODS: Firstly, we performed differentially expressed gene (DEG) analysis on LUAD transcriptome profiling data in The Cancer Genome Atlas (TCGA), where intersections with COVID-19-related genes were screened out. Then, we conducted Cox proportional hazards analyses on these LUAD/COVID-19 DEGs to construct a risk score. Next, LUAD/COVID-19 DEGs were uploaded on Connectivity Map to obtain drugs for anti-LUAD/COVID-19. Finally, we used network pharmacology, molecular docking, and molecular dynamics (MD) simulation to explore the drug's therapeutic targets and potential mechanisms for anti-LUAD/COVID-19. RESULTS: We identified 230 LUAD/COVID-19 DEGs and constructed a risk score containing 7 genes (BTK, CCL20, FURIN, LDHA, TRPA1, ZIC5, and SDK1) that could classify LUAD patients into two risk groups. Then, we screened emetine as an effective drug for anti-LUAD/COVID-19. Network pharmacology analyses identified 6 potential targets (IL6, DPP4, MIF, PRF1, SERPING1, and SLC6A4) for emetine in anti-LUAD/COVID-19. Molecular docking and MD simulation analyses showed that emetine exhibited excellent binding capacities to DDP4 and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). CONCLUSIONS: This study found that emetine may inhibit the entry and replication of SARS-CoV-2 and enhance tumor immunity by bounding to DDP4 and Mpro.

Risk factors for pneumonitis in advanced extrapulmonary cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune-mediated pneumonitis has a high mortality rate; however, information regarding the related risk factors remains limited. This study aimed to analyze risk factors for pneumonitis, including smoking and lung metastasis (LM), in patients with extrapulmonary primary tumors. METHODS: Data of 110 patients treated with immune checkpoint inhibitors (ICIs) (nivolumab/pembrolizumab) for treating extrapulmonary primary tumors at the Shiga University of Medical Science Hospital between January 2015 and December 2019 were retrospectively collected. The association between the onset of pneumonitis and treatment-related factors was analyzed by logistic regression. The severity of pneumonitis was graded according to the Common Terminology Criteria for Adverse Events version 5.0. Risk factors, such as the absence or presence of interstitial lung disease (ILD) and LM, or other clinical factors, including smoking status before ICI administration, were analyzed. RESULTS: Multivariate analyses indicated that the amount of smoking was significantly associated with an increase in the development of all-grade pneumonitis types (odds ratio (OR) = 20.33, 95% confidence interval (CI) = 20.03-20.66; p = 0.029). LM and ILD were significantly related to an increase in the development of symptomatic pneumonitis (≥ Grade 2) (OR = 10.08, 95% CI = 1.69-199.81; p = 0.076, and OR = 6.76, 95% CI = 1.13-40.63; p = 0.037, respectively). CONCLUSIONS: Pre-screening for ILD and LM and recognizing patients' smoking history is important for determining the risk of ICI-induced pneumonitis and allowing safe ICI administration.

The correlation between skeletal muscle index of the L3 vertebral body and malnutrition in patients with advanced lung cancer.

BACKGROUND: Studies have shown that the skeletal muscle index at the third lumbar vertebra (L3 SMI) had reasonable specificity and sensitivity in nutritional assessment and prognostic prediction in digestive system cancers, but its performance in lung cancer needs further investigation. METHODS: A retrospective study was performed on 110 patients with advanced lung cancer. The L3 SMI, the Patient-Generated Subjective Global Assessment score (PG-SGA score), body mass index (BMI), and serological indicators were analyzed. According to PG-SGA scores, patients were divided into severe malnutrition (≥9 points), mild to moderate malnutrition (≥3 points and ≤ 8 points), and no malnutrition (≤2 points) groups. Pearson correlation and logistic regression analysis were adopted to find factors related to malnutrition, and a forest plot was drawn. The receiver operating characteristic (ROC) curve was performed to compare the diagnostic values of malnutrition among factors, which were expressed by the area under curve (AUC). RESULTS: 1. The age of patients in the severe malnutrition group, the mild to moderate malnutrition group, and the no malnutrition group significantly differed, with mean ages of 63.46 ± 10.01 years, 60.42 ± 8.76 years, and 55.03 ± 10.40 years, respectively (OR = 1.062, 95%CI: 1.008 ~ 1.118, P = 0.024; OR = 1.100, 95%CI: 1.034 ~ 1.170, P = 0.002). Furthermore, the neutrophil to lymphocyte ratio (NLR) of the severe malnutrition group was significantly higher than that of the no malnutrition group, with statistical significance. The difference between the mild to moderate malnutrition group and the no malnutrition group were not statistically significant, with NLR of 4.07 ± 3.34 and 2.47 ± 0.92, respectively (OR = 1.657,95%CI: 1.036 ~ 2.649, P = 0.035). The L3 SMI of patients in the severe malnutrition and mild to moderate malnutrition groups were significantly lower than that of the patients in the no malnutrition group, with statistical significance. The L3 SMI of patients in the severe malnutrition group, mild to moderate malnutrition group, and no malnutrition group were 27.40 ± 4.25 cm2/m2, 38.19 ± 6.17 cm2/m2, and 47.96 ± 5.02 cm2/m2, respectively (OR = 0.600, 95%CI: 0.462 ~ 0.777, P < 0.001; OR = 0.431, 95%CI: 0.320 ~ 0.581, P < 0.001). 2. The Pearson correlation analysis showed that the PG-SGA score positively correlated with age (r = 0.296, P < 0.05) but negatively correlated with L3 SMI (r = - 0.857, P < 0.05). The L3 SMI was also negatively correlated with age (r = - 0.240, P < 0.05). 3. The multivariate analysis showed that the L3 SMI was an independent risk factor for malnutrition (OR = 0.446, 95%CI: 0.258 ~ 0.773, P = 0.004; OR = 0.289, 95%CI: 0.159 ~ 0.524, P < 0.001). CONCLUSION: 1. The differences in the L3 SMI was statistically significant among advanced lung cancer patients with different nutritional statuses. 2. In the nutritional assessment of patients with lung cancer, the L3 SMI was consistent with the PG-SGA. 3. The L3 SMI is an independent predictor of malnutrition in patients with advanced lung cancer.

Daratumumab for Refractory IgD Multiple Myeloma with Lung Cancer and Persistent Thrombocytopenia: a Case Report.

BACKGROUND: Immunoglobulin D multiple myeloma (IgD-MM) is a rare but aggressive disease. The safety and effectiveness of anti-CD38 monoclonal antibody (daratumumab) have not been known in either IgD-MM or MM complicated with secondary neoplasm. METHODS: A fragile IgD-MM patient had an aggressively relapsed disease concurrent with lung cancer and severe thrombocytopenia, which led to a dilemma for management. After a failure of ixazomib-based chemotherapy, a salvage therapy with daratumumab unexpectedly induced complete remission and platelet recovery, and the patient successfully proceeded to lung cancer surgery. CONCLUSIONS: Our case indicates daratumumab is both safe and effective for refractory IgD-MM with severe complications.

Early outcomes of lung resections in non-small cell lung cancer after COVID-19 pneumonia.

OBJECTIVE: There is limited literature on patients with a history of COVID-19 pneumonia who underwent anatomical lung resection for non-small cell lung cancer (NSCLC). This study was aimed to share the early postoperative outcomes in patients who underwent lung resection after COVID-19 pneumonia. MATERIALS AND METHODS: We retrospectively evaluated 30 patients who underwent lobectomy with thoracotomy and systematic mediastinal lymph node dissection due to NSCLC in a single center between November 2018 and September 2021. The patients were divided into two groups regarding COVID-19 pneumonia history; the COVID-19 group consisted of 14 patients (46.7%) and the non-COVID-19 group 16 (53.3%) patients. The patients' age, gender, comorbidity, Charlson Comorbidity Index (CCI) score, forced expiratory volume in 1 s (FEV1) value, tumor type and size, resection type, postoperative air leak duration, total drainage volume, drain removal time, postoperative complications, and length of stay (LOS) were recorded. RESULTS: 9 (30%) patients were female, and 21 (70%) were male. The mean age was 62.1 ± 8.91 years. Our comparison of postoperative air leak duration, total drainage volume, time to drain removal, postoperative complications, and LOS between the COVID-19 and non-COVID-19 groups revealed no statistically significant difference. CONCLUSION: Anatomical lung resection can be performed safely in NSCLC patients with a history of COVID-19 pneumonia without significant difference in early postoperative morbidity and mortality.

Implications of the Immune Landscape in COPD and Lung Cancer: Smoking Versus Other Causes.

Cigarette smoking is reported in about one third of adults worldwide. A strong relationship between cigarette smoke exposure and chronic obstructive pulmonary disease (COPD) as well as lung cancer has been proven. However, about 15% of lung cancer cases, and between one fourth and one third of COPD cases, occur in never-smokers. The effects of cigarette smoke on the innate as well as the adaptive immune system have been widely investigated. It is assumed that certain immunologic features contribute to lung cancer and COPD development in the absence of smoking as the major risk factor. In this article, we review different immunological aspects of lung cancer and COPD with a special focus on non-smoking related risk factors.

Protein expression of transmembrane protease serine 4 in the gastrointestinal tract and in healthy, cancer, and SARS­CoV­2 infected lungs.

In addition to the angiotensin­converting enzyme 2 (ACE2), a number of host cell entry mediators have been identified for severe acute respiratory syndrome coronavirus­2 (SARS­CoV­2), including transmembrane protease serine 4 (TMPRSS4). The authors have recently demonstrated the upregulation of TMPRSS4 in 11 different cancers, as well as its specific expression within the central nervous system using in silico tools. The present study aimed to expand the initial observations and, using immunohistochemistry, TMPRSS4 protein expression in the gastrointestinal (GI) tract and lungs was further mapped. Immunohistochemistry was performed on tissue arrays and lung tissues of patients with non­small cell lung cancer with concurrent coronavirus disease 2019 (COVID­19) infection using TMPRSS4 antibody. The results revealed that TMPRSS4 was abundantly expressed in the oesophagus, stomach, small intestine, jejunum, ileum, colon, liver and pancreas. Moreover, the extensive TMPRSS4 protein expression in the lungs of a deceased patient with COVID­19 with chronic obstructive pulmonary disease and bronchial carcinoma, as well in the adjacent normal tissue, was demonstrated for the first time, at least to the best of our knowledge. On the whole, the immunohistochemistry data of the present study suggest that TMPRSS4 may be implicated in the broader (pulmonary and extra­pulmonary) COVID­19 symptomatology; thus, it may be responsible for the tropism of this coronavirus both in the GI tract and lungs.

Mortality Among Adults With Cancer Undergoing Chemotherapy or Immunotherapy and Infected With COVID-19.

Importance: Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality. Objective: To evaluate whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality. Design, Setting, and Participants: The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients (≥18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis. Exposures: SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated. Main Outcomes and Measures: The primary end point was all-cause mortality within the primary hospitalization. Results: Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38% (966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) and myeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19-related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86). Conclusions and Relevance: The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed.

Diabetic ketoacidosis shortly after COVID-19 vaccination in a non-small-cell lung cancer patient receiving combination of PD-1 and CTLA-4 inhibitors: A case report.

We describe a case of diabetic ketoacidosis (DKA) shortly after the SARS-CoV-2 (COVID-19) vaccination in a 65-year-old woman with non-small-cell lung cancer under a combination treatment of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. She had no history of diabetic mellitus. A few days after the second shot of COVID-19 vaccination, she developed DKA. We speculate that the immune-related adverse event and immunogenicity of vaccination synergistically induced DKA.