Changes in Intestinal Flora and Serum Metabolites Pre- and Post-Antitumor Drug Therapy in Patients with Non-Small Cell Lung Cancer.

OBJECTIVE: this study aimed to identify the relationships between gut microbiota, metabolism, and non-small cell lung cancer (NSCLC) treatment outcomes, which are presently unclear. METHODS: in this single-center prospective cohort study, we investigated changes in the gut microbiota and serum metabolite profile in 60 patients with NSCLC after four cycles of anticancer therapy. RESULTS: The microbial landscape of the gut exhibited a surge in Proteobacteria and Verrucomicrobiota populations, alongside a decline in Firmicutes, Actinobacteriota, and Bacteroidota. Furthermore, a significant shift in the prevalence of certain bacterial genera was noted, with an increase in Escherichia/Shigella and Klebsiella, contrasted by a reduction in Bifidobacterium. Metabolomic analysis uncovered significant changes in lipid abundances, with certain metabolic pathways markedly altered post-treatment. Correlation assessments identified strong links between certain gut microbial genera and serum metabolite concentrations. Despite these findings, a subgroup analysis delineating patient responses to therapy revealed no significant shifts in the gut microbiome's composition after four cycles of treatment. CONCLUSIONS: This study emphasizes the critical role of gut microbiota changes in NSCLC patients during anticancer treatment. These insights pave the way for managing treatment complications and inform future research to improve patient care by understanding and addressing these microbiota changes.

SN-38, an active metabolite of irinotecan, inhibits transcription of nuclear factor erythroid 2-related factor 2 and enhances drug sensitivity of colorectal cancer cells.

Nuclear factor erythroid 2-related factor 2 (Nrf2) significantly contributes to drug resistance of cancer cells, and Nrf2 inhibitors have been vigorously pursued. Repurposing of existing drugs, especially anticancer drugs, is a straightforward and promising strategy to find clinically available Nrf2 inhibitors and effective drug combinations. Topoisomerase inhibitors SN-38 (an active metabolite of irinotecan), topotecan, mitoxantrone, and epirubicin were found to significantly suppress Nrf2 transcriptional activity in cancer cells. SN-38, the most potent one among them, significantly inhibited the transcription of Nrf2, as indicated by decreased mRNA level and binding of RNA polymerase II to NFE2L2 gene, while no impact on Nrf2 protein or mRNA degradation was observed. SN-38 synergized with Nrf2-sensitive anticancer drugs such as mitomycin C in killing colorectal cancer cells, and irinotecan and mitomycin C synergistically inhibited the growth of SW480 xenografts in nude mice. Our study identified SN-38 and three other topoisomerase inhibitors as Nrf2 inhibitors, revealed the Nrf2-inhibitory mechanism of SN-38, and indicate that clinically feasible drug combinations could be designed based on their interactions with Nrf2 signaling.

Current status and prospect of treatments for recurrent hepatocellular carcinoma.

Owing to its heterogeneous and highly aggressive nature, hepatocellular carcinoma (HCC) has a high recurrence rate, which is a non-negligible problem despite the increasing number of available treatment options. Recent clinical trials have attempted to reduce the recurrence and develop innovative treatment options for patients with recurrent HCC. In the event of liver remnant recurrence, the currently available treatment options include repeat hepatectomy, salvage liver transplantation, tumor ablation, transcatheter arterial chemoembolization, stereotactic body radiotherapy, systemic therapies, and combination therapy. In this review, we summarize the strategies to reduce the recurrence of high-risk tumors and aggressive therapies for recurrent HCC. Additionally, we discuss methods to prevent HCC recurrence and prognostic models constructed based on predictors of recurrence to develop an appropriate surveillance program.

Characteristics and Clinical Implication of UGT1A1 Heterozygous Mutation in Tumor.

BACKGROUND: The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1A1 homozygous mutations, but the impact of UGT1A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear. METHODS: A total of 107 patients with UGT1A1 heterozygous mutation or wild-type, who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital, were retrospectively enrolled. The adverse reaction spectra of patients with UGT1A1*6 and UGT1A1*28 mutations were analyzed. Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 5.0. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The genotypes of UGT1A1*6 and UGT1A1*28 were detected by digital fluorescence molecular hybridization. RESULTS: There were 43 patients with UGT1A1*6 heterozygous mutation, 26 patients with UGT1A1*28 heterozygous mutation, 8 patients with UGT1A1*6 and UGT1A1*28 double heterozygous mutations, 61 patients with heterozygous mutation at any gene locus of UGT1A1*6 and UGT1A1*28. Logistic regression analysis showed that the presence or absence of vomiting (P=0.013) and mucositis (P=0.005) was significantly correlated with heterozygous mutation of UGT1A1*28, and the severity of vomiting (P<0.001) and neutropenia (P=0.021) were significantly correlated with heterozygous mutation of UGT1A1*6. In colorectal cancer, UGT1A1*6 was significantly correlated to diarrhea (P=0.005), and the other adverse reactions spectrum was similar to that of the whole patient cohort, and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not. CONCLUSIONS: In clinical use, heterozygous mutations of UGT1A1*6 and UGT1A1*28 are related to the risk and severity of vomiting, diarrhea, neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy. In colorectal cancer, UGT1A1*6 is significantly related to diarrhea post CPT-11 use, efficacy and prognosis is not affected by various genotypes or CPT-11 dosage reduction.

[Clinical Characteristics and Prognosis of 76 Lung Adenocarcinoma Patients 
Harboring EGFR Mutations with Pleural Effusion at Initial Diagnosis: 
A Single-center Retrospective Study].

BACKGROUND: Malignant pleural effusion is one of the common clinical manifestations of patients with lung adenocarcinoma. Patients with pleural effusion at the initial diagnosis of lung adenocarcinoma usually indicate poor prognosis. Epidermal growth factor receptor (EGFR) mutations mainly occur in patients with lung adenocarcinoma. Patients with different mutant subtypes have different prognosis. The clinical characteristics and prognostic factors of patients with EGFR mutated lung adenocarcinoma of different molecular subtypes combined with pleural effusion at initial diagnosis are still unclear. This study was designed to explore the clinical characteristics and prognostic factors of these patients in order to provide management recommendations for them. METHODS: A retrospective analysis of the clinical characteristics, treatment, outcomes and progression-free survival (PFS) of first-line treatment in patients with EGFR mutated lung adenocarcinoma combined with pleural effusion at initial diagnosis admitted to Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital from January 2012 to June 2021 was performed. Pearson's chi-square test or Fisher's exact test were performed for comparison between groups. Kaplan-Meier method was performed for survival analysis and Cox proportional risk regression model was performed for multivariate analysis. RESULTS: 76 patients met the inclusion criteria in this study. The incidences of EGFR classical mutations 19del, 21L858R and non-classical mutations were 46.0%, 38.2% and 15.8%, respectively among these patients. There was no significant difference between the three mutations in terms of gender, age, presence of dyspnea at presentation, whether other distant metastases were combined, site of pleural effusion, volume of pleural effusion, presence of other combined effusions, tumor-node-metastasis (TNM) stage, presence of other gene mutations, and treatment of pleural effusion (P>0.05). In patients with EGFR classical mutations 19del or 21L858R or non-classical mutations subtype, the proportion of chemotherapy in first-line regimens were 17.1%, 20.7% and 58.3%, respectively (P=0.001); and first-line disease control rates were 94.3%, 75.9% and 50%, respectively (P=0.003); pleural effusion control rates were 94.3%, 79.3% and 66.7%, respectively (P=0.04); PFS were 287 d, 327 d and 55 d, respectively (P=0.001). Univariate analysis showed that EGFR mutation subtype, control of pleural effusion, first-line treatment agents, and first-line treatment efficacy were significantly associated with PFS (P<0.05). Cox multifactorial analysis showed that only EGFR mutation subtype and first-line treatment efficacy were independent prognostic factors for PFS (P<0.05). CONCLUSIONS: PFS was significantly better for classical mutations than for non-classical mutations in patients with EGFR mutated lung adenocarcinoma combined with pleural effusion at initial diagnosis. Improving the efficacy of first-line therapy is the key to improve the prognosis of these patients.

Dilemma and solutions of treatment delay in cancer patients during the COVID-19 pandemic: A single-center, prospective survey.

INTRODUCTION: During the COVID-19 pandemic, the protective and medical resources were limited, while a limited number of studies have concentrated on the influences of COVID-19 on the treatment of cancer patients. This survey aimed to explore the protective awareness about COVID-19, the incidence and factors influencing treatment delay, and expected treatment modality of cancer patients, so as to assist cancer patients. METHODS: A current prospective, online survey was conducted through the WeChat platform on cancer outpatients at the Department of Peking University Third Hospital in China from March 4 to April 4, 2020. RESULTS: A total of 141 patients completed the survey after excluding 35 patients with an incomplete questionnaire. Note that 100% of the patients wore masks and paid attention to hand hygiene during the hospital visits, 73.0% of the patients had a strong desire to treat cancer, and 41.8% experienced treatment delay. The rate of treatment delay among the patients treated in other departments was markedly higher than that in our department (64.7% vs. 38.7%, p = .042). The results of logistic regression analysis showed that the previous treatment department was independently correlated with treatment delay. Moreover, 51.8% of the patients preferred to receive chemotherapy in the day ward, 54.6% hoped to receive a strong contact with doctors, and 83.7% would like to receive online therapeutic consultation. CONCLUSION: The rate of treatment delay was remarkable, which may be related to previous treatment departments. Promotion of "active management of attending physician" and "telemedicine" may be highly advantageous for cancer patients during the COVID-19 pandemic.

A Novel Circular RNA circPTCD3 Promotes Breast Cancer Progression Through Sponging miR-198.

INTRODUCTION: Circular RNAs (circRNAs), a new type of non-coding RNA, have been demonstrated to play critical roles in the progression of various of malignant cancers. However, the function of circRNAs in breast cancer is not clearly understood. METHODS: qPCR was used to evaluate the gene expression. Function studies including MTT, transwell, wound healing and colony formation assay were performed to evaluate the function of circPTCD3 in breast cancer. Luciferase and RNA pull-down assays were used to verify the interaction between circPTCD3 and miR-198. The xenograft model was established to evaluate the function of circPTCD3 in vivo. RESULTS: In the present study, we identified a novel circRNA termed as circPTCD3 which was indicated to be significantly up-regulated in breast cancer tissues and cell lines. The results revealed that ectopic expression of circPTCD3 promoted the cell proliferation, migration and colony formation ability of breast cancer cells. Constantly, silencing of circPTCD3 inhibited those of breast cancer cells. Furthermore, we identified that circPTCD3 was able to target miR-198 in breast cancer cell. miR-198 has the function of inhibiting proliferation and migration of breast cancer cells which can be reversed by circPTCD3. CONCLUSION: Taken together, our findings for the first time identified a novel circRNA (circPTCD3) and revealed its oncogenic role in breast cancer. Mechanically, we reported that circPTCD3 served as a competing endogenous RNA (ceRNA) to sponge miR-198. These findings provide insights into breast cancer progression and also potential new targets for diagnosis or treatment of breast cancer.

Compromise or not? A case report of successful treatment of pembrolizumab-induced hepatitis in a patient with non-small cell lung cancer with low-dose methylprednisolone and bicyclol.

Pembrolizumab, an anti-programmed cell death protein 1 (PD-1) antibody, has been shown to improve survival in patients with non-small cell lung cancer (NSCLC) with high expression of programmed death-ligand 1 (PD-L1). Corticosteroids are the mainstay for most high-grade immune-related adverse events (irAEs) such as pembrolizumab-induced hepatitis. However, the dose and duration of corticosteroid therapy are not well defined. The objective of this case report was to describe a new treatment pattern for severe immune checkpoint inhibitor-associated hepatitis. Here, we report the case of a patient with metastatic lung adenocarcinoma who developed grade 3 immunotherapy-induced hepatitis after the first cycle of pembrolizumab. Alanine aminotransferase (ALT) levels peaked at 233 U/L. Hepatitis was alleviated after the administration of methylprednisolone. Therefore, we retreated the patient with pembrolizumab. However, aminotransferase levels increased again after the initiation of low-dose methylprednisolone or the reuse of pembrolizumab. Finally, hepatitis was controlled with low-dose methylprednisolone plus bicyclol, a Chinese hepatoprotective agent. Although the patient had been on low-dose methylprednisolone therapy for about six months, he showed a prompt response. During this period, we also found a dramatic decrease in the neutrophil-lymphocyte ratio (NLR), senescent T cells (CD8+ CD28- CD57+ ), and myeloid-derived suppressor cells (MDSCs) in the peripheral blood of the patient. To our knowledge, this is the first case report of successful management of grade 3 pembrolizumab-induced hepatitis with a combination of low-dose corticosteroids and bicyclol. The durable clinical response and changes in blood biomarkers indicate that low doses of corticosteroids do not compromise the efficacy of immune checkpoint inhibitors (ICIs). Therefore, this case may provide a new treatment pattern for severe immunotherapy-induced hepatitis.

[The Effects and Management of Viral Pneumonia on Lung Cancer Patients].

The worldwide epidemic of three coronaviruses and one influenza virus in 21st century have seriously threatened human health. Infection with these viruses can cause respiratory symptoms. The patients with lung cancer are more susceptible to viral infection and have a worse prognosis due to the advanced age and the systemic immunosuppressive state caused by malignancy itself and the anticancer treatments. In addition, without sufficient clinical awareness, a missed diagnosis of viral pneumonia may occur due to the fever and respiratory symptoms caused by lung cancer and its secondary diseases. Furthermore, control measures against viral outbreaks may interfere with routine diagnosis and treatment of lung cancer patients. Therefore, scientific protection and individualized management of lung cancer patients are particularly important during virus epidemic prevention and control. Here, we systematically reviewed the epidemiological and clinical characteristics of viral pneumonia, its impact on patients with lung cancer and the differential diagnosis of lung cancer-related respiratory manifestations, aiming to provide guidance for the individual management of lung cancer patients during the prevention and control of viral pneumonia epidemic.

[Retrospective Analysis of Risk Factors for Venous Thromboembolism in 283 Patients with Lung Cancer during Systemic Therapy].

BACKGROUND: Patients with lung cancer have high risk of developing venous thromboembolism (VTE), which has been shown to have a significant impact on mortality. This study was to identify the incidence of VTE in lung cancer patients during systemic therapy and to analyze the risk factors associated with it. METHODS: We retrospectively analyzed the cases of 283 patients with lung cancer who received systemic therapy in the Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, from January 2016 to December 2018. Chi-square test and multivariate analyses were used to assess the correlation between clinical features and VTE. RESULTS: Of the patients we observed, 34 developed VTE, with an incidence of 12.01% (34/283). In patients with lower extremity varicose vein (LVV), there was an increase in the incidence of VTE (50.00% vs 9.89%, P=0.001). The incidence VTE in patients with distant metastasis was higher than that in patients without distant metastasis, and higher than that in patients with tumor-free (14.05% vs 14.00% vs 2.08%, P=0.024). The incidence of VTE in patients with active tumor was also significantly higher than that in patients without it (16.93% vs 8.18%, P=0.025). Patients with hypoalbuminemia (albumin <35 g/L) had more VTE events more than those without did (22.00% vs 9.87%, P=0.017), and patients with an elevated D-dimer level (>0.3 µg/mL) developed more VTE than those without did (17.93% vs 5.80%, P=0.006). There were no significant correlations between pathological types, blood cell count before systemic therapy including leukocyte, hemoglobin and platelet, or antiangiogenic drugs and VTE. Multivariate analysis showed that LVV, hypoalbuminemia and elevated level of D-dimer were independent risk factors of VTE. CONCLUSIONS: LVV, serum albumin and D-dimer level may be potential and more effective predictors of VTE in lung cancer patients during systemic therapy. Basing on these factors, new predictive model can be built, and further study to validate its efficacy is required.

[A Single Center, Retrospective Analysis of Prognosis in Non-small Cell Lung Cancer Patients with Peritoneal Carcinomatosis].

BACKGROUND: Peritoneal carcinomatosis is a rare clinical event in lung cancer and the prognosis is very poor. There are limited data on what factors predict peritoneal progression and affect the outcome. The aim of this study is to investigate investigate the factors associated with peritoneal carcinomatosis. METHODS: The patients with non-small cell lung cancer (NSCLC) from the Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital were eligible for retrospective analysis between August 2010 and August 2018. Clinical factors such as age, gender, histology, pleural effusion and gene mutations with epidermal growth factor receptor/anaplastic lymphoma kinase/ROS proto-oncogene 1 receptor tyrosine kinase (EGFR/ALK/ROS1) were analyzed. Overall survival (OS) was calculated by the Kaplan-Meier method. RESULTS: 1.44% (12/836) patients in this study developed peritoneal carcinomatosis and 12 patients with adenocarcinoma had metachronous NSCLC diagnosis and PC. Malignant pleural effusion rates at baseline and at PC diagnosis were separately 50% (6/12) and 100.0% (12/12). Among the 12 patients, 9 patients harbored EGFR/ALK/ROS1 mutation. The outcome of patients with EGFR/ALK/ROS1 mutation was significantly better than that of patients without EGFR/ALK/ROS1 mutation, the mOS1 and mOS2 were separately 26.0 months and 6.0 months versus 10.0 months and 1.5 months (P<0.05). The mOS2 of patients with aggressive treatment after PC diagnosis was 6.0 months, significantly better than 1.0 month of patients with best supportive care (P<0.05). The mOS2 of the patients with angiogenesis inhibitors based-treatment after PC diagnosis was 8.5 months, significantly longer than that of patients with other treatments (P<0.05). CONCLUSIONS: Adenocarcinoma and malignant pleural effusion are highly associated with peritoneal carcinomatosis in patients with advanced NSCLC. Aggressive treatment for lung cancer with PC is encouraged when possible. More patients with PC may benefit from the treatment strategies with angiogenesis inhibitors. Further prospective trials are urgently needed.

[Impact of the Pretreatment or Posttreatment NLR and PLR on the Response of First Line Chemotherapy and the Outcomes in Patients with Advanced Non-small Cell Lung Cancer].

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), indexes of systemic inflammation, have been associated with worse survival for many types of cancer. The aim of this study is to investigate the impact of NLR and PLR on overall survival (OS) and to explore the value of changes in the NLR and PLR with treatment as a response indicator in non-small cell lung cancer (NSCLC). METHODS: A total of 68 NSCLC patients in Peking University Third Hospital were eligible for retrospective analysis between April 2008 and April 2015. The pretreatment and posttreatment NLR and PLR in all patients were calculated based on complete blood counts. Potential prognostic factors such as age, gender, performance status, histology, stage, response to chemotherapy, NLR and PLR were analyzed. NLR and PLR were assessed at baseline and during chemotherapy treatment. OS was calculated by the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to determine the associations of the PLR, NLR and clinical features with OS. RESULTS: Among the 68 cases, the values of the posttreatment NLR after two cycles of chemotherapy (NLR2) and the pretreatment NLR (NLR0) were (2.69±2.06) and (3.94±2.12), respectively. NLR2 was significantly lower than NLR0 (P=0.000). There was no difference between the pretreatment PLR (PLR0) and the posttreatment PLR after two cycles of chemotherapy (PLR2) (P<0.05). NLR2 significantly correlated with the response of first line treatment with two or four cycles of chemotherapy. The proportion of high NLR2 in the patients with progression disease was 100.0%, significantly higher than the proportion of high NLR2 in the patients with partial response or stable disease. NLR0, PLR0 and NLR2 were significantly correlated with the OS (P<0.05), but not with age, performance status, histology, stage, status and regimens of treatment (P>0.05). According to univariate analysis, the OS was significantly associated with NLR0, PLR0, NLR2, the response of 2 and 4 cycles of first line chemotherapy, status and regimens of second line treatment (P<0.05), but not with stage, status of third line or beyond treatment and radiotherapy (P>0.05). The multivariate analysis showed that NLR0 (P=0.004), the response with 4 cycles of first line chemotherapy (P=0.022) and status of second line treatment (P=0.007) were independent prognostic indicators in the 68 patients. CONCLUSIONS: The study showed that NLR0 was well connected with outcomes and NLR2 was well connected with the response to first line chemotherapy in patients with advanced non-small cell lung cancer. Therefore, NLR may be a biomarker for predicting the outcomes and response of first line chemotherapy and a potential target for management of non-small cell lung cancer.