Real world analysis of third-line treatment with anlotinib in combination with radiotherapy for extensive-stage small-cell lung cancer / 中华放射肿瘤学杂志

Objective:To investigate the clinical efficacy and safety of anlotinib combined with radiotherapy as a third-line treatment regimen for extensive stage small-cell lung cancer (ES-SCLC) in a real-world background.Methods:Forty ES-SCLC patients enrolled in a single center of Affiliated Cancer Hospital of Xinjiang Medical University in China between November 2018 and July 2021 were treated with radiotherapy added on anlotinib as a third-line treatment regimen. Overall survival (OS), progression-free survival (PFS), safety, and quality of life were analyzed, and the survival status was statistically analyzed using Kaplan-Meier method.Results:Among the 40 patients, partial remission, stable disease, and progressive disease was confirmed in 7, 24 and 9 patients, respectively. The obtained objective remission rate (ORR) was 18%, the disease control rate (DCR) was 78%, and median PFS and median OS were 4.5 months and 9 months, respectively. The most common adverse reactions included fatigue (28%), bleeding (20%), anorexia (13%), and hand-foot syndrome (8%). Most of them were grade 1-2 in severity, 4 cases were documented as ≥grade 3, and no grade 5 toxicity was recorded.Conclusions:In the real world, radiotherapy added on anlotinib as a third-line regimen can prolong PFS and OS of the ES-SCLC patients, and the adverse reactions are generally tolerated. This combination treatment regimen is worthy of further investigation.

Clinical research of first-line chemotherapy and immunotherapy combined with chest radiotherapy for extensive-stage small cell lung cancer / 中华放射肿瘤学杂志

Objective:To evaluate the safety and efficacy of sequential consolidation thoracic radiotherapy after first-line chemotherapy combined with immunotherapy for extensive-stage small cell lung cancer (SCLC).Methods:A retrospective analysis of patients with extensive-stage SCLC admitted to Jiangsu Cancer Hospital from January 2019 to September 2022 was conducted. Patients who achieved effective chemotherapy combined with immunotherapy received sequential consolidation thoracic radiotherapy. The safety was evaluated according to the common terminology criteria for adverse events (CTCAE) 5.0 standard, and the overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier method.Results:A total of 33 patients were enrolled, with a median age of 66 years (range, 50-79 years). The median follow-up time was 20 months (range, 3-33 months). Fifteen patients (46%) had disease progression, and 12 patients (36%) died. The toxicities mainly included leukopenia, thrombocytopenia, radiation esophagitis, anorexia, and fatigue, etc. Six patients (18%) had grade 4 hematological toxicity, mainly leukopenia. One patient (3%) had grade 3 radiation pneumonitis, and 3 patients (9%) had grade 1-2 radiation pneumonitis. No grade 5 toxicity was observed in all patient groups. The median PFS was 12 months (95% CI=3.9-20.1). The 6-month, 1-year, and 2-year PFS rates were 78%, 49.6%, and 35.6%, respectively. The median OS was 23 months (95% CI=15.98-30.01). The 6-month, 1-year, and 2-year OS rates were 86.2%, 74.5%, and 47.2%, respectively. Conclusions:Sequential consolidation thoracic radiotherapy after first-line chemotherapy combined with immunotherapy is a safe protocol for extensive-stage SCLC. It brings survival benefits to patients by increasing PFS and OS rates.

Application of optimized hippocampus-avoidance prophylactic cranial irradiation in limited-stage small cell lung cancer / 中华放射肿瘤学杂志

Objective:To analyze the treatment efficacy, safety and dose parameters of optimized hippocampus-avoidance prophylactic cranial irradiation (HA-PCI) in limited-stage small cell lung cancer (LS-SCLC) and explore the corresponding dosimetric parameters under the condition of narrowing the hippocampus avoidance region as hippocampus region plus 2 mm in three dimensions.Methods:Clinical data of patients with LS-SCLC receiving HA-PCI (hippocampus avoidance region defined as hippocampus region plus 2 mm in three dimensions) in Cancer Hospital Chinese Academy of Medical Sciences from August 2014 to June 2020 were retrospectively analyzed. Dose parameters of HA-PCI and adverse events were analyzed using descriptive statistics analysis. Changes of neurocognitive function, such as mini-mental state examination (MMSE) and Hopkins verbal learning test-revised (HVLT-R) scores, were evaluated by analysis of variance and Kruskal-Wallis H test. Overall survival (OS), progression-free survival (PFS) and intracranial PFS (iPFS) were calculated using Kaplan-Meier method. The cumulative incidence of local-regional recurrence (LRR), extracranial distant metastases (EDM), and locoregional recurrence (LR) were investigated under competing risk analysis. Results:A total of 112 patients were included, the median follow-up time was 50 months (95% CI: 45.61-54.38). The median volume of hippocampus was 4.85 ml (range: 2.65-8.34 ml), with the average dose ≤9 Gy in 106 patients (94.6%), ≤8 Gy in 92 patients (82.1%). The median volume of hippocampus avoidance area was 15.00 ml (range: 8.61-28.06 ml), with the average dose ≤12 Gy in 109 patients (97.3%), ≤10 Gy in 101 patients (90.2%). The 2-year cumulative LRR, EDM, LR rates were 16.9%, 23.2% and 28.5%, respectively. The 5-year cumulative LRR, EDM, LR rates were 23.2%, 26.9% and 33.3%, respectively. The 2-year iPFS, PFS and OS rates were 66.1% (95% CI: 57.9%-75.4%), 53.6% (95% CI: 45.1%-63.7%) and 80.4% (95% CI: 73.3%-88.1%), respectively. The most common grade I-Ⅱ adverse events were nausea (33.9%) and dizziness (31.3%), and only 1 patient developed grade Ⅲ nausea and dizziness. MMSE ( n=57) and HVLT-R tests ( n=56) showed no significant decline. Conclusions:Optimized HA-PCI can achieve similar dose limitation with favorable efficacy and light toxicity. No significant decline is observed in short-term neurocognitive function in evaluable patients.

Application value and research progress in thoracic radiotherapy for extensive-stage small cell lung cancer / 中华放射肿瘤学杂志

Small cell lung cancer (SCLC) is characterized by rapid proliferation and high propensity for local recurrence and widespread metastasis, which yields extremely poor prognosis. Approximately 2/3 of patients present with extensive-stage disease (ES-SCLC) at initial diagnosis. For ES-SCLC, the combination platinum-based chemotherapy has been the standard regimen for the past few decades. In the era of chemotherapy, multiple studies have shown the benefit of thoracic radiotherapy (TRT) for patients who responded to chemotherapy. However, with the first-line treatment of ES-SCLC shifting into the immune era, as well as the advances in diagnostic imaging modality and radiation technology, the benefit of TRT has caused a widespread controversy. In this article, the value of TRT for ES-SCLC and the latest progress in the radioimmunotherapy combination mode for ES-SCLC were reviewed.

Consistency comparison of programmed cell death 1-ligand 1 in different immuno-histochemical staining methods / 北京大学学报(医学版)

OBJECTIVE@#To compare the consistency of programmed cell death 1-ligand 1 (PD-L1, clone E1L3N, 22C3, SP263) in different immunohistochemical staining methods.@*METHODS@#The first step was to select the optimal process: The PD-L1(clone E1L3N) antibody recommended process, self-built process ①, self-built process ② and self-built process ③ were used to perform immunohistochemical staining in 5 cases of tonsil tissue. The quality of all slides was scored by expert pathologists (0-6 points). The process with the highest score was selected. The second step was to compare the consistency between the optimal procedure and the two standard procedures. Thirty-two cases of lung non-small cell carcinoma diagnosed by pathology in Peking University First Hospital in the past two years were randomly selected. The 32 cases were stained in parallel with the SP263 and 22C3 standard procedures, and all stained slides were scored by specialized pathologists for tumor proportion score (TPS). The scoring results were grouped according to < 1%, ≥1% to < 10%, ≥10% to < 50%, and ≥50%. The consistency of PD-L1 detection antibody clone E1L3N and 22C3, E1L3N and SP263 staining results was analyzed.@*RESULTS@#Tonsil stained slides scores (0-6 points) were as follows: The recommended protocol was 5, 5, 5, 5 and 5. The self-built process ① was 5, 6, 6, 5 and 6. The self-built process ② was 4, 4, 4, 4 and 4.The self-built process ③ was 3, 3, 3, 3 and 3. The self-built process ① was the best with the highest score. The TPSs of 32 non small cell lung carcinoma (NSCLC) cases were as follows: Of self-built process ①, 6 cases were lower than 1%, 5 cases were from 1% to 10%, 10 cases were from 10% to 50%, and 11 cases were higher than 50%; of 22C3 standard procedure, 5 cases were lower than 1%, 3 cases were from 1% to 10%, 13 cases were from 10% to 50%, 11 cases were higher than 50%; of SP263 standard procedure, 7 cases were lower than 1%, 4 cases were from 1% to 10%, 11 cases were from 10% to 50%, 10 cases were higher than 50%. The results of the consistency test were as follows: The κ value for self-built process ① and 22C3 standard procedure was 0.736 (P < 0.001), the agreement was good; the κ value for self-built process ① and SP263 standard procedure was 0.914 (P < 0.001), the agreement was very good.@*CONCLUSION@#The immunostaining using PD-L1(E1L3N) with validated self-built staining protocol ① by Ventana Benchmark GX platform can obtain high quality of slides, and the TPSs based on these slides are in good agreement with 22C3 and SP263 standard procedures.

Clinical efficacy of anlotinib monotherapy in second-line treatment of extensive stage small cell lung cancer with poor PS score / 国际肿瘤学杂志

Objective:To investigate the clinical efficacy and safety of anlotinib monotherapy in second-line treatment of extensive stage small cell lung cancer (ES-SCLC) with poor performance status (PS) score after treatment failure with first-line standard regimen.Methods:Thirty-three patients with ES-SCLC who failed to receive first-line standard treatment and had poor PS score were selected from Fuyang People's Hospital of Anhui Province from January 2021 to December 2022. All patients were given anrotinib 10 mg orally for second-line treatment, which was taken for 2 weeks and stopped for 1 week, with every 21 days being a cycle period, until the disease progressed or the patient became intolerable. Objective response rate (ORR), disease control rate (DCR) and adverse reactions were observed. Progression-free survival (PFS) was estimated by Kaplan-Meier method, and the influencing factors of PFS were analyzed by Cox regression model.Results:After at least 2 cycles of anlotinib monotherapy, there were no complete remission, 5 cases of partial remission, 17 cases of stable disease, 11 cases of progressive disease. ORR was 15.2% (5/33), DCR was 66.7% (22/33). The median PFS was 3.7 months (95% CI: 2.9-4.5 months). Univariate analysis showed that first-line recurrence time ( χ2=4.90, P=0.027), brain metastases ( χ2=12.42, P<0.001), liver metastases ( χ2=11.05, P=0.001) and controlling nutritional status (CONUT) score ( χ2=12.43, P<0.001) were the influential factors of PFS in ES-SCLC patients with poor PS score and first-line treatment failure of anlotinib monotherapy. Multivariate analysis showed that brain metastases ( HR=3.21, 95% CI: 1.24-8.29, P=0.016), liver metastases ( HR=2.80, 95% CI: 1.03-7.61, P=0.044) and CONUT score ( HR=2.72, 95% CI: 1.16-6.38, P=0.021) were independent influencing factors of PFS in ES-SCLC patients with first-line treatment failure of anlotinib monotherapy and poor PS score. Common adverse reactions were fatigue, hypertension, anorexia, etc. Most of the adverse reactions were grade 1-2, with the incidence of grade 3 adverse reactions being 9.1% (3/33), and no grade 4-5 adverse reactions occurred. Conclusion:The clinical efficacy of anlotinib monotherapy in second-line treatment of ES-SCLC with poor PS score and failure of first-line standard regimen is good, and the adverse reactions are controllable.

Whole-brain radiotherapy plus SIB or SRS for brain metastases in small cell lung cancer / 中华放射肿瘤学杂志

Objective:To evaluate the value of whole-brain radiotherapy (WBRT) combined with simultaneous integrated boost (SIB) and WBRT plus sequential stereotactic radiosurgery (SRS) in the treatment of small-cell lung cancer (SCLC) patients with brain metastases (BM).Methods:A retrospective analysis was performed among 135 SCLC patients with BM who were admitted to Tianjin Medical University Cancer Institute and Hospital from 2007 to 2023. They all received cisplatin- or carboplatin-based first-line chemotherapy and WBRT with 94 patients receiving thoracic radiotherapy after chemotherapy. All patients were divided into the WBRT+SIB ( n=66) and WBRT+SRS groups ( n=69) according to the treatment methods. After propensity score matching (PSM), 63 patients were assigned into each group. The primary endpoints were overall survival (OS) and brain metastasis-related local control (BMRLC) rates. Categorical data, such as gender and age, were compared by Chi-square test. OS and BMRLC were calculated by Kaplan-Meier method. The survival curves between two groups were compared by log-rank test. The risk factors of OS and BMRLC were assessed by multivariate Cox regression models. Results:In all the patients, the median follow-up time was 24.9 (range 6.30-109.57) months. The 2-year OS and BMRLC rates were 49.0% and 85.0%, respectively. Cerebral necrosis occurred in 2 patients. Multivariate analysis revealed that shorter time interval of BM after diagnosis (≤10 months) ( P=0.041), control of extracranial progression ( P=0.029), and lower diagnosis-specific graded prognostic assessment (DS-GPA) (≥2) ( P=0.006) significantly improved OS. After PSM, the 2-year OS rate in the WBRT+SIB group was significantly higher than that in the WBRT+SRS group ( P=0.041), while the 2-year BMRLC rate was not significantly improved ( P=0.203). In the DS-GPA<2 subgroup, the OS in the WBRT+SIB group was significantly higher than that in the WBRT+SRS group ( P=0.016), whereas no significant difference was observed in BMRLC between two groups ( P=0.205). In the DS-GPA≥2 subgroup, no significant difference was found in OS between two groups ( P=0.266), while BMRLC in the WBRT+SIB group was significantly lower compared with that in the WBRT+SRS group ( P=0.027). Conclusions:WBRT+SIB is more suitable for SCLC patients with BM than WBRT+SRS. However, WBRT+SRS yields higher local control for DS-GPA≥2 patients.

Efficacy and safety of angiogenesis inhibitor combined with erlotinib in the targeted treatment of EGFR-mutated advanced non-small cell lung carcinoma:a Meta-analysis / 肿瘤

Objective:To evaluate the efficacy and safety of angiogenesis inhibitor combined with erlotinib versus erlotinib alone in the targeted treatment of epidermal growth factor receptor(EGFR)-mutated advanced non-small cell lung carcinoma. Methods:A computer-based online search was performed using PubMed,Cochrane Library,Excerpta Medica Database(Embase),Web of Science,VIP,China National Knowledge Infrastructure(CNKI),and WANFANG databases.The retrieval time is from the establishment of the database to March 2022.After literature screening and rigorous data extraction,Meta-analysis was performed using RevMan 5.4 software.The primary endpoints of this study were median progression free survival(mPFS),median overall survival(mOS),objective response rate(ORR)and safety. Results:A total of 11 articles containing data of 3 805 patients was included in this study.Meta-analysis results showed that compared with the treatment of erlotinib alone(control group),the treatment of angiogenesis inhibitors combined with erlotinib(experimental group)could effectively improve the mPFS[hazard ratio(HR)=0.64,95％confidence interval(CI)=0.58-0.70,P＜0.000 01]and ORR[odds ratio(OR)=1.2 5,95％CI=1.02-1.54,P=0.03]in advanced non-small cell lung cancer patients,while it did not show an advantage in improving mOS(HR=0.91,95％CI=0.78-1.07,P=0.26)and the difference was not statistically significant.In terms of safety,adverse events(AE)of grade 3 and above are higher in experimental group than that in control group(OR=2.09,95％CI=1.70-2.58,P＜0.00001),the experimental group had a higher rate of hypertension(OR=5.48,95％CI=2.78-1 0.8,P＜0.000 01),dermatitis acneiform and rash(OR=2.27,95％CI=1.33-3.89,P=0.003),diarrhea(OR=3.78,95％CI=2.13-6.69,P＜0.000 01),and proteinuria(OR=5.71,95％CI=1.73-18.82,P=0.004).There was no statistically significant difference in bleeding events(OR=1.37,95％CI=0.79-2.38,P=0.26)or hepatic injury(OR=1.08,95％CI=0.77-1.52,P=0.65)between the 2 groups. Conclusion:Compared with erlotinib alone,the combination of angiogenesis inhibitors could effectively improve the ORR and mPFS in patients with EGFR-mutated advanced non-small cell lung cancer.However,the combination of angiogenesis inhibitors with erlotinib increased the incidence of several grade 3 treatment-related AE,such as hypertension,dermatitis acneiform and rash,diarrhea,and proteinuria,compared to erlotinib treatment alone.

Value of derived neutrophil-to-lymphocyte ratio in predicting prognosis of extensive-stage small cell lung cancer patients treated with the first-line atezolizumab immunotherapy and chemotherapy / 肿瘤研究与临床

Objective:To investigate the value of derived neutrophil-to-lymphocyte ratio (dNLR) in predicting the prognosis of extensive-stage small cell lung cancer (ES-SCLC) patients treated with the first-line atezolizumab immunotherapy and chemotherapy.Methods:From the Project Data Sphere platform, the clinical data and laboratory test data of 53 ES-SCLC patients who received the first-line atezolizumab immunotherapy and chemotherapy in the global multicenter phase Ⅱ prospective study NCT03041311 from February 2017 to February 2022 were collected. The Contal-O'Quigley method was used to calculate the optimal cut-off value of baseline dNLR for determining the overall survival (OS) of patients. The dNLR higher than or equal to the optimal cut-off value was defined as high dNLR, and less than the optimal cut-off value was defined as low dNLR. According to optimal cut-off value, the dNLR levels at baseline and after 4 cycles of chemotherapy were determined, and dynamic dNLR grouping was performed (low risk: low dNLR at baseline and after 4 cycles of chemotherapy; intermediate risk: high dNLR at baseline or after 4 cycles of chemotherapy; high risk: high dNLR at baseline and after 4 cycles of chemotherapy). The differences in clinicopathological features between the baseline high dNLR group and low dNLR group were analyzed. Kaplan-Meier method was used to draw the OS and progression-free survival (PFS) curves, and log-rank test was used to compare the differences between the two groups. Univariate Cox proportional hazards model was used to analyze the influencing factors of OS and PFS. The time-dependent receiver operating characteristic (ROC) curve was used to evaluate the predictive value of baseline dNLR grouping and dynamic dNLR grouping for 1-year OS rate in ES-SCLC patients receiving the first-line atezolizumab immunotherapy and chemotherapy.Results:Among the 53 patients, 34 (64.20%) were male and 19 (35.80%) were female; 27 (50.90%) were < 65 years old and 26 (49.10%) were ≥65 years old. The optimal cut-off value of baseline dNLR for determining the OS was 1.79. There were 17 cases in low dNLR group and 36 cases in high dNLR group at baseline. The proportion of patients with elevated serum lactate dehydrogenase (LDH) in the baseline high dNLR group was higher than that in the baseline low dNLR group [58.33% (21/36) vs. 17.65% (3/17), χ2 = 7.72, P = 0.005]. The 1-year OS rates of the baseline high and low dNLR groups were 44.0% and 81.9%, and the 1-year PFS rates were 2.5% and 17.6%. The differences in OS and PFS between the two groups were statistically significant (both P < 0.05). There were 38 patients with complete dynamic dNLR data, including 9 cases of low-risk, 19 cases of medium-risk and 10 cases of high-risk, and the 1-year OS rates of the three groups were 90.0%, 67.5% and 33.3%, the difference in OS between the three groups was statistically significant ( P = 0.011). Univariate Cox regression analysis showed that baseline dNLR (low dNLR vs. high dNLR) was the influencing factor for OS of patients ( HR = 0.163, 95% CI 0.057-0.469, P = 0.001) and PFS ( HR = 0.505, 95% CI 0.268-0.952, P = 0.035). Time-dependent ROC curve analysis showed that the area under the curve (AUC) of baseline dNLR grouping and dynamic dNLR grouping for predicting 1-year OS rate of ES-SCLC patients receiving the first-line atezolizumab combined with chemotherapy was 0.674 (95% CI 0.575-0.887) and 0.731 (95% CI 0.529-0.765). Conclusions:Baseline and dynamic dNLR grouping may be effective markers for predicting the prognosis of ES-SCLC patients receiving the first-line atezolizumab immunotherapy and chemotherapy.

Expression and clinical significance of SSTR2, ADAM-12 and FLI-1 in small cell lung cancer tissue / 中国基层医药

Objective:To investigate the expression and clinical significance of somatostatin receptor 2 (SSTR2), a disintegrin and metalloproteinase-12 (ADAM-12), and friend leukemia virus integration-1 (FLI-1) in small cell lung cancer tissue.Methods:Eighty-two patients with small cell lung cancer who received treatment in Haiyang People's Hospital from January 2020 to January 2021 were included in this study. All patients underwent radical surgical resection. Small cell lung cancer tissues and adjacent tissues more than 2 cm from the edge of cancer tissues were harvested. The positive expression rates of SSTR2, ADAM-12, and FLI-1 in cancer tissues and adjacent tissues were determined by immunohistochemistry. The relationship between SSTR2, ADAM-12, FLI-1, and clinical characteristics were analyzed. The 1-year survival rate of patients with small cell lung cancer was calculated.Results:The positive rates of SSTR2, ADAM-12, and FLI-1 in small cell lung cancer tissue were 79.27% (65/82), 76.83% (63/82), and 78.05% (64/82), respectively, which were significantly higher than 19.51% (16/82), 17.07% (14/82), 20.73% (17/82) in the adjacent tissue ( χ2 = 58.57, 58.78, 53.90, all P < 0.05). SSTR2, ADAM-12, and FLI-1 were positively associated with lymph node metastasis, clinical stage, tissue invasion, tumor size, and histological grade (all P < 0.05). After controlling for gender, age, and others, SSTR2, ADAM-12, and FLI-1 were associated with lymph node metastasis, clinical stage, tissue invasion, tumor size, and histological grade (all P < 0.05). All patients were followed up for 1 year. Six patients were lost to follow-up. The 1-year survival rate of 76 patients with small cell lung cancer was 67.11% (51/76). The survival rate of patients with positive SSTR2, ADAM-12, and FLI-1 expression were lower than that of patients with negative SSTR2, ADAM-12, and FLI-1 expression ( χ2 = 3.93, 6.43, 7.52, all P < 0.05). Conclusion:SSTR2, ADAM-12, and FLI-1 are highly expressed in small cell lung cancer tissue. Combined detection of SSTR2, ADAM-12, and FLI-1 is conducive to the prognosis and evaluation of small cell lung cancer in patients. This study is innovative and scientific.

Interpretation of CT images of pulmonary mucinous adenocarcinoma / 中国综合临床

Pulmonary mucinous adenocarcinoma (PMA) is relatively rare. On chest CT, it can be divided into two types: mass type and pneumonia type. Mass type PMA is more common and is difficult to distinguish from other nonsmall cell lung cancer. It is a solid or partial solid nodule or mass, predominantly located in the peripheral field of the lung with lobulation, spiculation, and more prone “vacuole sign”. Pneumonia type PMA has a poor prognosis and is more likely to develop into diffuse, multifocal and multilobular lesions similar to inflammatory manifestations, indicating dissemination along the airway. Typical signs include large areas of low density, low enhancement consolidation, and “dead tree sign”.

The value of radiomics for individualized prophylactic cranial irradiation in limited-stage small cell lung cancer / 中华放射肿瘤学杂志

Objective:To investigate the predictive value of enhanced CT-based radiomics for brain metastasis (BM) and selective use of prophylactic cranial irradiation (PCI) in limited-stage small cell lung cancer (LS-SCLC).Methods:Clinical data of 97 patients diagnosed with LS-SCLC confirmed by pathological and imaging examination in Shanxi Provincial Cancer Hospital from January 2012 to December 2018 were retrospectively analyzed. The least absolute shrinkage and selection operator (LASSO) Cox and Spearman correlation tests were used to select the radiomics features significantly associated with the incidence of BM and calculate the radiomics score. The calibration curve, the area under the receiver operating characteristic (ROC) curve (AUC), 5-fold cross-validation, decision curve analysis (DCA), and integrated Brier score (IBS) were employed to evaluate the predictive power and clinical benefits of the radiomics score. Kaplan-Meier method and log-rank test were adopted to draw survival curves and assess differences between two groups.Results:A total of 1272 radiomics features were extracted from enhanced CT. After the LASSO Cox regression and Spearman correlation tests, 8 radiomics features associated with the incidence of BM were used to calculate the radiomics score. The AUCs of radiomics scores to predict 1-year and 2-year BM were 0.845 (95% CI=0.746-0.943) and 0.878 (95% CI=0.774-0.983), respectively. The 5-fold cross validation, calibration curve, DCA and IBS also demonstrated that the radiomics model yielded good predictive performance and net clinical benefit. Patients were divided into the high-risk and low-risk cohorts based on the radiomics score. For patients at high risk, the 1-year and 2-year cumulative incidence rates of BM were 0% and 18.2% in the PCI group, and 61.8% and 75.4% in the non-PCI group, respectively ( P<0.001). In the PCI group, the 1-year and 2-year overall survival rates were 92.9% and 78.6%, and 85.3% and 36.8% in the non-PCI group, respectively ( P=0.023). For patients at low risk, the 1-year and 2-year cumulative incidence rates of BM were 0% and 0% in the PCI group, and 10.0% and 20.2% in the non-PCI group, respectively ( P=0.062). In the PCI group, the 1-year and 2-year overall survival rates were 100% and 77.0%, and 96.7% and 79.3% in the non-PCI group, respectively ( P=0.670). Conclusion:The radiomics model based on enhanced CT images yields excellent performance for predicting BM and individualized PCI.

Radiation dose and fractionation regimen for limited stage small cell lung cancer: a survey of current practice patterns of Chinese radiation oncologists / 中华放射肿瘤学杂志

Objective:To investigate the radiation dose and fractionation regimens for limited stage small cell lung cancer (LS-SCLC) in Chinese radiation oncologists.Methods:Over 500 radiation oncologists were surveyed through questionnaire for radiation dose and fractionation regimens for LS-SCLC and 216 valid samples were collected for further analysis. All data were collected by online questionnaire designed by WJX software. Data collection and statistical analysis were performed by SPSS 25.0 statistical software. The differences in categorical variables among different groups were analyzed by Chi-square test and Fisher's exact test. Results:Among 216 participants, 94.9% preferred early concurrent chemoradiotherapy, 69.4% recommended conventional fractionation, 70.8% preferred a total dose of 60 Gy when delivering conventional radiotherapy and 78.7% recommended 45 Gy when administering hyperfractionated radiotherapy.Conclusions:Despite differences in LS-SCLC treatment plans, most of Chinese radiation oncologists prefer to choose 60 Gy conventional fractionated radiotherapy as the main treatment strategy for LS-SCLC patients. Chinese Society of Clinical Oncology (CSCO), National Comprehensive Cancer Network (NCCN) and Chinese Medical Association guidelines or expert consensus play a critical role in guiding treatment decision-making.

Analysis of survival time and benefits of postoperative radiotherapy in resected small cell lung cancer patients / 中华放射肿瘤学杂志

Objective:To analyze the survival time, prognostic factors and the value of postoperative thoracic radiotherapy in resected small cell lung cancer (SCLC) patients.Methods:Clinic opathological data of SCLC patients who received surgical treatment in Cancer Hospital & General Hospital of Ningxia Medical University from April 2014 to September 2021 were enrolled in this retrospective study. All patients were subject to follow-up. The survival time of SCLC patients was evaluated by Kaplan-Meier method. Univariate and multivariate analyses of prognostic factors were performed by Cox proportional hazard model.Results:A total of 64 patients with SCLC were enrolled in the study. The 5-year overall survival (OS) rate was 43.5%. Univariate analysis showed that TNM staging ( P=0.027), postoperative neutrophil-lymphocyte ratio (NLR) ( P=0.039) and adjuvant thoracic radiotherapy ( P=0.041) were the prognostic factors. Multivariate analysis showed that TNM staging ( P=0.038) and adjuvant thoracic radiotherapy ( P=0.022) were the prognostic factors in patients with SCLC. The 5-year OS rates of patients with and without adjuvant thoracic radiotherapy were 71.6% and 35.4% ( P=0.028), respectively. There was a statistically significant difference in the 5-year OS rates between pathological stage N 2 SCLC patients with or without adjuvant thoracic radiotherapy (75.0% vs. 0%, P=0.030). Conclusions:TNM staging and postoperative adjuvant thoracic radiotherapy are prognostic factors in patients with SCLC undergoing surgical treatment. Pathological stage N 2 SCLC patients can benefit from adjuvant thoracic radiotherapy.

Prognosis and risk factors of brain metastases from limited-stage small cell lung cancer after complete resection / 中华放射肿瘤学杂志

Objective:To analyze the prognosis and risk factors for brain metastases (BM) in patients with limited-stage small cell lung cancer (LS-SCLC) after complete resection, aiming to identify those most likely to benefit from prophylactic cranial irradiation (PCI).Methods:Clinical data of 94 patients with LS-SCLC treated in Cangzhou Integrated Traditional Chinese and Western Medicine Hospital from January 2005 to December 2018 who underwent complete resection were retrospectively analyzed, including 31 cases treated with PCI and 63 without PCI. Prognostic factors and risk factors of BM were analyzed by Kaplan-Meier method. The differences between two groups were analyzed by log-rank test. Independent risk factors of overall survival (OS) and BM were assessed by multivariate Cox regression model.Results:The 2-year and 5-year OS rates were 80.6% and 61.3% in the PCI group, and 61.9% and 46.0% in the non-PCI group, respectively ( P=0.001). The 2-year and 5-year brain metastasis-free survival (BMFS) rates were 80.6% and 54.8% in the PCI group, and 57.1% and 42.9% in the non-PCI group, respectively ( P=0.045). The 2-year and 5-year progression-free survival (PFS) rates were 71.0% and 48.4% in the PCI group, and 49.2% and 34.9% in the non-PCI group, respectively ( P=0.016). PCI could improve OS in patients with pII/III stage LS-SCLC ( P=0.039, P=0.013), but the OS benefit in patients with pI stage LS-SCLC was not significant ( P=0.167). BM occurred in 3 patients (9.7%) in the PCI group, which was significantly lower than that in the non-PCI group ( n=17, 27.0%; P=0.044); there was no significant difference in the BM rate of patients with pI and pII stage LS-SCLC between PCI and non-PCI groups ( P=0.285, P=0.468); and the BM rate of patients with pIII stage LS-SCLC in the PCI group was significantly lower than that in the non-PCI group ( P=0.041). Multivariate analysis showed age ≥60 ( HR=2.803, P=0.001), BM ( HR=2.239, P=0.022), no PCI ( HR=0.341, P=0.004) and pathological stage pII/III ( HR=4.963, P=0.002) were the independent high-risk factors affecting OS; and pathological stage pII/III ( HR=11.665, P=0.007) was an independent high-risk factor affecting BM. Conclusions:LS-SCLC patients with pII-III stage have a higher risk of developing BM and poor prognosis after complete resection, and should receive PCI treatment. However, LS-SCLC patients with pI stage may not benefit significantly.

Prognostic impacts of the estimated dose of radiation to immune cells (EDRIC) on limited-stage small-cell lung cancer with different tumor burdens / 中华放射肿瘤学杂志

Objective:To investigate the effects of estimated dose of radiation to immune cells (EDRIC) on overall survival (OS), local progression-free survival (LPFS) and distant metastasis-free survival (DMFS) in limited-stage small-cell lung cancer (LS-SCLC) with different tumor burdens.Methods:Clinical data of 216 patients with LS-SCLC who initially received conventional fractionated radiotherapy of the chest for radical treatment in Tianjin Medical University Cancer Institute and Hospital from 2013 to 2019 were retrospectively analyzed. EDRIC was calculated based on the model developed by Jin et al. and tumor burdens were assessed by gross tumor volume (GTV) or clinical stage. The study endpoints were OS, LPFS and DMFS, which were calculated from the date of diagnosis. The optimal cut-off value of EDRIC was calculated by R language. The correlation between EDRIC and tumor burdens was analyzed using Spearman's correlations. Survival analysis was performed by Cox proportional hazards regression model and Kaplan-Meier curve. Results:The median follow-up time for the whole group was 47.8 months, and the median OS and DMFS was 34.6 months and 18.5 months, respectively, while the median LPFS did not reach. The optimal cut-off value of EDRIC was 6.8 Gy. Cox multivariate analysis showed that EDRIC was an independent prognostic factor affecting OS and DMFS. EDRIC was weakly correlated with GTV or clinical stage. Stratified by the median GTV, OS ( P=0.021) and DMFS ( P=0.030) were significantly shortened and LPFS had a tendency of shortening ( P=0.107) when EDRIC>6.8 Gy compared with those when EDRIC ≤ 6.8 Gy in the GTV ≤ 34.6 cm 3 group; EDRIC had little effect on OS, LPFS, and DMFS ( P=0.133, 0.420, 0.374) in the GTV>34.6 cm 3 group. Stratified by clinical stage, OS ( P=0.003) and DMFS ( P=0.032) were significantly shortened and LPFS ( P=0.125) tended to shorten when EDRIC>6.8 Gy in stage I, II and IIIA groups; EDRIC exerted slight effect on OS, LPFS, and DMFS ( P=0.377, 0.439, 0.484) in stage IIIB and IIIC groups. Conclusion:EDRIC is an important factor affecting prognosis and exerts more significant impact on prognosis in patients with smaller tumor burden.

Predictive value of metabolic tumor volume and total lesion glycolysis in 18F-FDG PET/CT imaging for prognosis in patients with extensive-stage small cell lung cancer / 中华核医学与分子影像杂志

Objective:To investigate the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with extensive-stage small cell lung cancer (ES-SCLC).Methods:From March 2019 to June 2020, 69 patients (55 males, 14 females, age: 38-87 years) with ES-SCLC who underwent pretreatment 18F-FDG PET/CT in First Affiliated Hospital of Zhengzhou University were retrospectively enrolled. The variables including gender, age, smoking, weight loss, liver metastasis, bone metastasis, malignant effusion, SUV max of the primary tumor, whole-body MTV (wbMTV) and whole-body TLG (wbTLG) (including wbMTV 40%, wbTLG 40%, wbMTV 2.5 and wbTLG 2.5) were analyzed. The predictors of overall survival (OS) were analyzed by using Kaplan-Meier method (log-rank test). Results:Of 69 ES-SCLC patients, 43(62%) died and 26(38%) were still alive by the end of follow-up, with a median survival time of 15.0(95% CI: 11.7-18.3) months. Univariate analysis revealed that age ( χ2=4.53, P=0.033), bone metastasis ( χ2=18.05, P<0.001), liver metastasis ( χ2=27.94, P<0.001), wbMTV 2.5 ( χ2=3.98, P=0.046), and wbTLG 2.5( χ2=5.80, P=0.016) were significant predictors of OS. Conclusion:wbMTV 2.5 and wbTLG 2.5 are assosciated with OS and may provide some reference value for predicting the prognosis of ES-SCLC patients.

Value of 18F-FDG PET/CT combined with tumor markers ProGRP and NSE in diagnosis and differential diagnosis of stageⅠA small cell lung cancer / 中华核医学与分子影像杂志

Objective:To explore the value of 18F-FDG PET/CT combined with pro-gastrin-releasing peptide (ProGRP) and neuron-specific enolase (NSE) in diagnosis and differential diagnosis of stageⅠA small cell lung cancer (SCLC). Methods:From June 2017 to October 2021, 113 patients (75 males, 38 females; age 32-79 years) with stageⅠA lung cancer (70 with adenocarcinoma, 25 with squamous cell carcinoma, 18 with SCLC; patients with adenocarcinoma and squamous cell carcinoma were combined into non-SCLC (NSCLC) group) and 30 patients with benign pulmonary nodule (21 males, 9 females; age 37-77 years) from the Affiliated Qingdao Central Hospital of Qingdao University were retrospectively analyzed. All patients were examined by 18F-FDG PET/CT and serum tumor markers associated with lung cancer. Differences of the clinical, imaging and tumor markers data among different groups were analyzed by χ2 test, Fisher exact test and Kruskal-Wallis rank sum test. Independent risk factors were analyzed by logistic regression analysis and ROC curve analysis was used to analyze the value of different predictive factors in diagnosis and differential diagnosis of SCLC. Results:There were significant differences in SUV max, lobulation sign, spiculation sign, calcification, pleural traction sign, ProGRP, NSE and carcinoembryonic antigen (CEA) among SCLC, NSCLC and benign nodules groups ( H values: 14.06-20.54, χ2 values: 8.16-14.95, all P<0.05), in which lobulation sign of SCLC was more than that of benign nodules (12/18 vs 26.7%(8/30); χ2=7.41, P=0.007), spiculation sign (2/18 vs 51.6%(49/95); χ2=10.01, P=0.002) and pleural traction sign (1/18 vs 35.8%(34/95); χ2=6.47, P=0.011) were less than those of NSCLC, SUV max was higher than that of benign nodules (7.4(5.8, 9.0) vs 2.3(1.4, 5.1); H=51.82, P<0.001), ProGRP was higher than that of NSCLC and benign nodules (64.0(40.1, 84.8) vs 38.7(26.9, 47.6), 36.7(29.1, 40.5) ng/L; H values: 36.13, 43.96, P values: 0.002, 0.001) and NSE was higher than that of benign nodules (12.4(10.9, 14.5) vs 7.4(5.4, 11.8) μg/L; H=40.53, P=0.001). When differentiated SCLC from NSCLC, spiculation sign (odds ratio ( OR)=0.043, 95% CI: 0.004-0.450, P=0.009) and ProGRP ( OR=1.083, 95% CI: 1.035-1.133, P<0.001) were independent risk factors for SCLC, and the AUC of the two factors combination was 0.875, with the sensitivity and specificity of 14/18 and 84.2%(80/95). When differentiated SCLC from benign nodules, SUV max( OR=2.706, 95% CI: 1.099-6.662, P=0.030), ProGRP ( OR=1.165, 95% CI: 1.009-1.344, P=0.038) and NSE ( OR=1.639, 95% CI: 1.016-2.645, P=0.043) were independent risk factors for SCLC, and the AUC of the three factors combination was 0.985, with the sensitivity and specificity of 17/18 and 96.7%(29/30). Conclusion:18F-FDG PET/CT combined with tumor markers ProGRP and NSE is helpful to improve the diagnosis and differential diagnosis of stage ⅠA SCLC.

Deubiquitinating enzyme JOSD2 affects susceptibility of non-small cell lung carcinoma cells to anti-cancer drugs through DNA damage repair / 浙江大学学报·医学版

OBJECTIVES@#To investigate the effects and mechanisms of deubiquitinating enzyme Josephin domain containing 2 (JOSD2) on susceptibility of non-small cell lung carcinoma (NSCLC) cells to anti-cancer drugs.@*METHODS@#The transcriptome expression and clinical data of NSCLC were downloaded from the Gene Expression Omnibus. Principal component analysis and limma analysis were used to investigate the deubiquitinating enzymes up-regulated in NSCLC tissues. Kaplan-Meier analysis was used to investigate the relationship between the expression of deubiquitinating enzymes and overall survival of NSCLC patients. Gene ontology enrichment and gene set enrichment analysis (GSEA) were used to analyze the activation of signaling pathways in NSCLC patients with high expression of JOSD2. Gene set variation analysis and Pearson correlation were used to investigate the correlation between JOSD2 expression levels and DNA damage response (DDR) pathway. Western blotting was performed to examine the expression levels of JOSD2 and proteins associated with the DDR pathway. Immunofluorescence was used to detect the localization of JOSD2. Sulforhodamine B staining was used to examine the sensitivity of JOSD2-knock-down NSCLC cells to DNA damaging drugs.@*RESULTS@#Compared with adjacent tissues, the expression level of JOSD2 was significantly up-regulated in NSCLC tissues (P<0.05), and was significantly correlated with the prognosis in NSCLC patients (P<0.05). Compared with the tissues with low expression of JOSD2, the DDR-related pathways were significantly upregulated in NSCLC tissues with high expression of JOSD2 (all P<0.05). In addition, the expression of JOSD2 was positively correlated with the activation of DDR-related pathways (all P<0.01). Compared with the control group, overexpression of JOSD2 significantly promoted the DDR in NSCLC cells. In addition, DNA damaging agents significantly increase the nuclear localization of JOSD2, whereas depletion of JOSD2 significantly enhanced the sensitivity of NSCLC cells to DNA damaging agents (all P<0.05).@*CONCLUSIONS@#Deubiquitinating enzyme JOSD2 may regulate the malignant progression of NSCLC by promoting DNA damage repair pathway, and depletion of JOSD2 significantly enhances the sensitivity of NSCLC cells to DNA damaging agents.

The effect of PLK1 inhibitor in osimertinib resistant non-small cell lung carcinoma cells / 浙江大学学报·医学版

OBJECTIVES@#To investigate the effects of PLK1 inhibitors on osimertinib-resistant non-small cell lung carcinoma (NSCLC) cells and the anti-tumor effect combined with osimertinib.@*METHODS@#An osimertinib resistant NCI-H1975 cell line was induced by exposure to gradually increasing drug concentrations. Osimertinib-resistant cells were co-treated with compounds from classical tumor pathway inhibitor library and osimertinib to screen for compounds with synergistic effects with osimertinib. The Gene Set Enrichment Analysis (GSEA) was used to investigate the activated signaling pathways in osimertinib-resistant cells; sulforhodamine B (SRB) staining was used to investigate the effect of PLK1 inhibitors on osimertinib-resistant cells and the synergistic effect of PLK1 inhibitors combined with osimertinib.@*RESULTS@#Osimertinib-resistance in NCI-H1975 cell (resistance index=43.45) was successfully established. The PLK1 inhibitors GSK 461364 and BI 2536 had synergistic effect with osimertinib. Compared with osimertinib-sensitive cells, PLK1 regulatory pathway and cell cycle pathway were significantly activated in osimertinib-resistant cells. In NSCLC patients with epidermal growth factor receptor mutations treated with osimertinib, PLK1 mRNA levels were negatively correlated with progression free survival of patients (R=－0.62, P<0.05), indicating that excessive activation of PLK1 in NSCLC cells may cause cell resistant to osimertinib. Further in vitro experiments showed that IC50 of PLK1 inhibitors BI 6727 and GSK 461364 in osimertinib-resistant cells were lower than those in sensitive ones. Compared with the mono treatment of osimertinib, PLK1 inhibitors combined with osimertinib behaved significantly stronger effect on the proliferation of osimertinib-resistant cells.@*CONCLUSIONS@#PLK1 inhibitors have a synergistic effect with osimertinib on osimertinib-resistant NSCLC cells which indicates that they may have potential clinical value in the treatment of NSCLC patients with osimertinib resistance.