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Abstract Oncogenic RET alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with RET-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients. The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable RET alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes. In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target RET alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms (NCT05278364).

The fibroblast growth factor receptor (FGFR) is a crucial receptor tyrosine kinase involved in essential biological processes, including growth, development, and tissue repair. However, FGFR gene mutations, including amplification, fusion, and mutation, can disrupt epigenetics, transcriptional regulation, and tumor microenvironment interactions, leading to cancer development. Targeting these kinase mutations with small molecule drugs or antibodies has shown clinical benefits. For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Effective screening of FGFR variant patients is crucial for the clinical application of FGFR inhibitors. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

Abstract Immune checkpoint inhibitor (ICI) rechallenge in non‐small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD‐1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

The fusion genes NRG1 and NRG2, members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1-positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2. Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Abstract Immune checkpoint inhibitors (PD‐1/PD‐L1 and CTLA‐4 blockade) have revolutionized the treatment landscape in non‐small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO‐IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

Abstract Background Lung adenocarcinoma (LUAD) is one of the most common subtypes of lung cancer. Finding prognostic biomarkers is helpful in stratifying LUAD patients with different prognosis. Methods We explored the correlation of LUAD prognosis and genes associated with chemotherapy in LUAD and obtained data of LUAD patients from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Drug sensitivity data were acquired from the Genomics of Drug Sensitivity in Cancer (GDSC) database. Differential and enrichment analyses were used to screen the target genes utilizing limma and “clusterProfiler” packages. Then univariate and LASSO Cox analyses were used to select the prognosis‐related genes. Survival analysis was used to estimate the overall survival (OS) of different groups. Results Twenty‐three differentially expressed genes (DEGs) were screened between LUAD samples and healthy samples, and BTK, FGFR2, PIM2, CHEK1, and CDK1 were selected to construct a prognostic signature. The OS of patients in the high‐risk group (risk score higher than 0.69) was worse than that in the low‐risk group (risk score lower than 0.69). Conclusion The risk score model constructed by five genes is a potential prognostic biomarker for LUAD patients.

Abstract Aims To investigate the predictive value of baseline C-reactive protein (CRP) levels on the efficacy of chemotherapy plus immune checkpoint inhibitors (ICI) in patients with advanced lung squamous cell carcinoma (LSCC). Materials and methods In this retrospective multicenter study spanning from January 2016 to December 2020, advanced LSCC patients initially treated with chemotherapy or a combination of chemotherapy and ICI were categorized into normal and elevated CRP subgroups. The relationship between CRP levels and treatment outcomes was analyzed using multivariate Cox proportional hazards models and multivariate logistic regression, focusing primarily on the progression-free survival (PFS) endpoint, and secondarily on overall survival (OS) and objective response rate (ORR) endpoints. Survival curves were generated using the Kaplan-Meier method, with the log-rank test used for comparison between groups. Results Of the 245 patients evaluated, the 105 who received a combination of chemotherapy and ICI with elevated baseline CRP levels exhibited a significant reduction in PFS (median 6.5 months vs. 11.8 months, HR, 1.78; 95% CI: 1.12–2.81; p = 0.013) compared to those with normal CRP levels. Elevated CRP was identified as an independent risk factor for poor PFS through multivariate-adjusted analysis. However, among the 140 patients receiving chemotherapy alone, baseline CRP levels did not significantly influence PFS. Furthermore, within the combination therapy group, there was a notable decrease in the ORR (51% vs. 71%, p = 0.035), coupled with a significantly shorter OS (median 20.9 months vs. 31.5 months, HR, 2.24; 95% CI: 1.13–4.44; p = 0.033). Conclusion In patients with advanced LSCC, elevated baseline CRP levels were identified as an independent predictive factor for the efficacy of combination therapy with chemotherapy and ICI, but not in chemotherapy alone. This suggests that CRP may be a valuable biomarker for guiding treatment strategies.

Background: Although immune checkpoint inhibitor treatment for advanced thymic carcinoma exhibits promising efficacy, factors that affect the efficacy and prognosis, including metastases sites, remain uncertain. Objectives: Our study aimed to investigate the determinants of survival among patients with advanced thymic carcinoma who underwent immunotherapy in real-world settings, with implications for clinical practice. Designs: Different therapy regimens of immunotherapy were produced to analyze the influence of liver metastases on survival and prognosis for advanced thymic carcinoma patients. Methods: Data for advanced thymic carcinoma patients receiving immunotherapy and their metastases sites were collected for analysis from seven different hospitals between January 2015 and January 2023. Progression-free survival (PFS) and overall survival (OS) analyses were performed using the Kaplan–Meier method. Cox analysis was used to evaluate factors influencing survival. Results: The present study analyzed 136 advanced thymic carcinoma patients from seven different hospitals. The PFS for all patients receiving immunotherapy was 6.4 months, while the OS was 24.0 months. The objective response rate was different for patients with liver and non-liver metastases (11.9% versus 37.2%, p = 0.003). The disease control rate values were also different between the two groups (47.6% versus 80.9%, p = 0.037). The PFS for patients with liver metastases demonstrated poor immunotherapy efficacy compared to patients with non-liver metastases (3.0 versus 8.0 months, p

Background: While targeted therapy has become the standard treatment for certain non-small-cell lung cancer (NSCLC) patients with gene mutation positivity, there remains a lack of enough reports of the efficacy of mesenchymal–epithelial transition (MET) alterations in the real world. Objectives: We aimed to explore the efficacy and toxicity of targeted therapy in NSCLC patients with different types of MET alterations and hope to provide more clinical medication guidance. Design: Designed different subgroups to compare the efficacy and safety of targeted therapy in NSCLC patients with MET alterations. Methods: We conducted analyses on the efficacy and safety of mesenchymal–epithelial transition factor-tyrosine kinase inhibitor (MET-TKI) therapy in NSCLC patients with MET alterations. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors version 1.1 criteria, and both progression-free survival (PFS) and overall survival were determined using the Kaplan–Meier method. Results: Our study encompassed 116 NSCLC patients with MET alterations, including MET ex14 skipping mutation ( n = 50), MET primary amplification (amp) ( n = 25), and secondary amp ( n = 41). Among treated patients, 34 achieved a partial response, while 52 exhibited stable disease. The overall response rate for the entire cohort was 29.31%, with a disease control rate of 74.14%. A significant difference was observed in the median PFS among patients with MET ex14 skipping mutation, MET primary amplification (amp), and secondary amp (10.4 versus 6.6 versus 4.5 months, p = 0.002). In all, 69 patients experienced drug-related adverse effects, with the most common being peripheral edema (35.34%), nausea and vomiting (21.55%), and fatigue (10.34%). In total, 29 patients (25%) encountered drug-related adverse reactions of grade 3 or higher. Conclusion: MET-TKI therapy works better for MET ex14 skipping mutation than other types of MET gene alteration. In the two MET amplified groups, the secondary amp was less effective. This study may provide more research support for the treatment of these patients.

Abstract The rearranged during transfection (RET) gene is one of the receptor tyrosine kinases and cell‐surface molecules responsible for transmitting signals that regulate cell growth and differentiation. In non‐small cell lung cancer (NSCLC), RET fusion is a rare driver gene alteration associated with a poor prognosis. Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. These inhibitors have shown the ability to overcome resistance to multikinase inhibitors (MKIs). Furthermore, ongoing clinical trials are investigating several second‐generation sRETis that are specifically designed to target solvent front mutations, which pose a challenge for first‐generation sRETis. The effective screening of patients is the first crucial step in the clinical application of RET‐targeted therapy. Currently, four methods are widely used for detecting gene rearrangements: next‐generation sequencing (NGS), reverse transcription‐polymerase chain reaction (RT‐PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). Each of these methods has its advantages and limitations. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.

Abstract Identifying the primary site of metastatic cancer is critical to guiding the subsequent treatment. Approximately 3–9% of metastatic patients are diagnosed with cancer of unknown primary sites (CUP) even after a comprehensive diagnostic workup. However, a widely accepted molecular test is still not available. Here, we report a method that applies formalin-fixed, paraffin-embedded tissues to construct reduced representation bisulfite sequencing libraries (FFPE-RRBS). We then generate and systematically evaluate 28 molecular classifiers, built on four DNA methylation scoring methods and seven machine learning approaches, using the RRBS library dataset of 498 fresh-frozen tumor tissues from primary cancer patients. Among these classifiers, the beta value-based linear support vector (BELIVE) performs the best, achieving overall accuracies of 81-93% for identifying the primary sites in 215 metastatic patients using top-k predictions (k = 1, 2, 3). Coincidentally, BELIVE also successfully predicts the tissue of origin in 81-93% of CUP patients (n = 68).

Abstract Malignant pleural mesothelioma (MPM) is a malignant tumor originating from the pleura, and its incidence has been increasing in recent years. Due to the insidious onset and strong local invasiveness of MPM, most patients are diagnosed in the late stage and early screening and treatment for high‐risk populations are crucial. The treatment of MPM mainly includes surgery, chemotherapy, and radiotherapy. Immunotherapy and electric field therapy have also been applied, leading to further improvements in patient survival. The Mesothelioma Group of the Yangtze River Delta Lung Cancer Cooperation Group (East China LUng caNcer Group, ECLUNG; Youth Committee) developed a national consensus on the clinical diagnosis and treatment of MPM based on existing clinical research evidence and the opinions of national experts. This consensus aims to promote the homogenization and standardization of MPM diagnosis and treatment in China, covering epidemiology, diagnosis, treatment, and follow‐up.

Abstract Background The efficacy of definite for non‐small‐cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations has been preliminarily demonstrated. However, there is a paucity of data with which to compare the efficacy and safety of second‐ and third‐generation TKIs in patients with NSCLC carrying uncommon EGFR mutations. Methods We compared the efficacy and safety of second‐ and third‐generation TKIs in all NSCLC patients in whom next‐generation sequencing confirmed uncommon EGFR mutations, including G719X, S768I, and L861Q. The parameters analyzed included the objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and overall survival (OS). The rate of treatment‐related adverse events (AEs) reflected the safety of these TKIs. Results Eighty‐four NSCLC patients with uncommon EGFR mutations were enrolled between April 2016 and May 2022 at Zhejiang Cancer Hospital, including 63 treated with second‐generation TKIs and 21 treated with third‐generation TKIs. The ORR for all patients receiving TKIs was 47.6%, and the DCR was 86.9%. The median PFS for NSCLC patients with uncommon EGFR mutations receiving TKIs was 11.9 months and OS was 30.6 months. There was no significant difference in PFS after treatment with second‐ or third‐generation TKIs (13.3 vs. 11.0 months, respectively, P = 0.910) or in OS (30.6 vs. 24.6 months, respectively P = 0.623). The third‐generation TKIs showed no severe toxicity. Conclusions The efficacy of second‐ and third‐generation TKIs for NSCLC with uncommon EGFR mutations does not differ, and so can be used to treat NSCLC patients with these mutations.

Abstract Background Radical resection plus lymph node dissection is a common treatment for patients with T1-3N0M0 non-small cell lung cancer (NSCLC). Few models predicted the survival outcomes of these patients. This study aimed to developed a nomogram for predicting their overall survival (OS). Materials and methods This study involved 3002 patients with T1-3N0M0 NSCLC after curative resection between January 1999 and October 2013. 1525 Patients from Sun Yat-sen University Cancer Center were randomly allocated to training cohort and internal validation cohort in a ratio of 7:3. 1477 patients from ten institutions were recruited as external validation cohort. A nomogram was constructed based on the training cohort and validated by internal and external validation cohort to predict the OS of these patients. The accuracy and practicability were tested by Harrell's C-indexes, calibration plots and decision curve analyses (DCA). Results Age, sex, histological classification, pathological T stage, and HI standard were independent factors for OS and were included in our nomogram. The C-index of the nomogram for OS estimates were 0.671 (95% CI, 0.637–0.705),0.632 (95% CI, 0.581–0.683), and 0.645 (95% CI, 0.617–0.673) in the training cohorts, internal validation cohorts, and external validation cohort, respectively. The calibration plots and DCA for predictions of OS were in excellent agreement. An online version of the nomogram was built for convenient clinical practice. Conclusions Our nomogram can predict the OS of patients with T1-3N0M0 NSCLC after curative resection. The online version of our nomogram offer opportunities for fast personalized risk stratification and prognosis prediction in clinical practice.

Abstract EGFR exon 20 insertion (20ins)-positive non-small-cell lung cancer (NSCLC) is an uncommon disease with limited therapeutic options and dismal prognosis. Here we report the activity, tolerability, potential mechanisms of response and resistance for dual targeting EGFR 20ins with JMT101 (anti-EGFR monoclonal antibody) plus osimertinib from preclinical models and an open label, multi-center phase 1b trial (NCT04448379). Primary endpoint of the trial is tolerability. Secondary endpoints include objective response rate, duration of response, disease control rate, progression free survival, overall survival, the pharmacokinetic profile of JMT101, occurrence of anti-drug antibodies and correlation between biomarkers and clinical outcomes. A total of 121 patients are enrolled to receive JMT101 plus osimertinib 160 mg. The most common adverse events are rash (76.9%) and diarrhea (63.6%). The confirmed objective response rate is 36.4%. Median progression-free survival is 8.2 months. Median duration of response is unreached. Subgroup analyses were performed by clinicopathological features and prior treatments. In patients with platinum-refractory diseases (n = 53), confirmed objective response rate is 34.0%, median progression-free survival is 9.2 months and median duration of response is 13.3 months. Responses are observed in distinct 20ins variants and intracranial lesions. Intracranial disease control rate is 87.5%. Confirmed intracranial objective response rate is 25%.

Summary: The evolutionarily conserved Notch pathway, involved in cancer stem cell capacity and cancer immunity, may predict the benefit from immune checkpoint inhibitors (ICIs) in clear cell renal cell carcinoma (ccRCC). In the TCGA dataset, mRNA expression of Notch pathway genes identified three clusters with different prognoses and molecular characteristics. Based on the differentially expressed Notch pathway genes between clusters, we constructed the Notch-score, correlated with Notch activation, angiogenesis, PI3K-AKT-mTOR activity, and sensitivities to VEGFR/mTOR inhibitors. A high Notch-score was linked with more “resting”/“anti-inflammatory” rather than “activated”/“pro-inflammatory” tumor-infiltrating immune cells, inactivated immune pathways, and scarce any benefits from ICI-based therapies over VEGFR/mTOR inhibitors in the JAVELIN Renal 101 (avelumab plus axitinib vs. sunitinib) and the CheckMate-009/010/025 trials (nivolumab vs. everolimus). For the Notch-activated ccRCCs, ICIs provide limited advantages and might not be strongly recommended, by which the cost-effectiveness of treatments in ccRCCs may be potentially improved.

Background: Adrenal insufficiency (AI) caused by immune checkpoint inhibitors (ICIs) is an extremely rare immune-related adverse event (irAE). The detailed clinical characteristics and outcomes of patients with ICI-induced AI are unavailable. This study aimed to explore the clinical characteristics and efficacy of treatment in patients with ICI-induced AI. Methods: We retrospectively collected information on patients diagnosed with AI caused by ICIs at LiShui Municipal Central Hospital and Zhejiang Cancer Hospital, including baseline characteristics, laboratory results, symptoms, treatment outcomes of AI, and hormone use. Survival outcomes were calculated using the Kaplan–Meier method and stratified according to the different situations. Results: From December 2020 to February 2023, among 1014 patients treated with ICI therapy, a total of twenty patients were diagnosed with ICI-induced AI. Most of the patients were men (80%, n = 16), with a performance status (PS) of 0 − 1 (95%, n = 19). The median (range) age was 65.9 (49−80) years and 14 patients (70%) were treated with ICIs as first-line therapy. The majority of the patients (70%, n = 14) experienced grade 3 − 4 AI. All patients received corticosteroid replacement therapy, and only 7 patients recovered. The median time to the diagnosis of AI after starting ICI therapy was 5.2 (3.0 − 7.5) months. The objective response rate was 70% and median progression-free survival in these patients was 16.0 months (95% confidence interval: 11.7 − 20.3 months). Conclusions: ICI-induced AI is a rare irAE, and close monitoring of cortisol levels is important. Patients diagnosed with AI after receiving immunotherapy seem to have a favorable outcome.

Abstract Background We aimed to determine the clinical. outcomes of various immune checkpoint inhibitor (ICI) combinations for the treatment of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. The results predicted the treatment efficacy of these combinations. Methods From July 15, 2016 to March 22, 2022, 85 NSCLC patients with EGFR mutations, enrolled at the Zhejiang Cancer Hospital, received ICI combinations after resistance to prior EGFR-tyrosine kinase inhibitors (EGFR-TKIs). These patients were diagnosed with EGFR mutations using an amplification refractory mutation system PCR (ARMS-PCR) and next-generation sequencing (NGS). Survival times were analyzed using the Kaplan–Meier method and log-rank test. Results Patients who received ICIs combined with anti-angiogenic therapy had longer progression-free survival (PFS) and overall survival (OS) than patients who received ICIs combined with chemotherapy. There was no significant difference in survival time between patients who received ICIs combined with chemotherapy and anti-angiogenic therapy and patients who received ICIs combined with anti-angiogenic therapy or ICIs combined with chemotherapy, which was due to the limitation sample size of patients who received ICIs combined with chemotherapy and anti-angiogenic therapy. Patients with L858R mutations had a longer PFS and OS than patients with exon 19 deletions. T790M negative patients benefited more from ICI combinations, compared with T790M positive patients. In addition, there was no significant difference in PFS and OS between patients with TP53 co-mutations and patients without a TP53 co-mutation. We also found that patients with prior first-generation EGFR-TKI resistance had longer PFS and OS than prior third-generation EGFR-TKI resistance patients. There was no new adverse event in this study. Conclusions EGFR-mutated patients who received ICIs combined with anti-angiogenic therapy had longer PFS and OS than patients with ICIs combined with chemotherapy. Patients with L858R or without T790M mutation benefited more from ICI combinations. Besides, patients with prior first-generation EGFR-TKI resistance could benefit more from ICIs combinations than prior third-generation EGFR-TKI resistance patients.

Abstract Thymic epithelial tumors (TETs) are a relatively rare type of thoracic tumor, accounting for less than 1% of all tumors. The incidence of TETs is about 3.93/10000 in China, slightly higher than that of European and American countries. For resectable TETs, complete surgical resection is recommended. Radiotherapy or chemotherapy may be used as postoperative adjuvant treatment. Treatment for advanced, unresectable TETs consist mainly of radiotherapy and chemotherapy, but there is a lack of standard first‐ and second‐line treatment regimens. Recently, targeted therapies and immune checkpoint inhibitors have shown promising outcomes in TETs. Based on the currently available clinical evidences and the opinions of the national experts, the Thymic Oncology Group of Yangtze River Delta Lung Cancer Cooperation Group (East China LUng caNcer Group, ECLUNG; Youth Committee) established this Chinese expert consensus on the clinical diagnosis and treatment of TETs, covering the epidemiology, diagnosis, treatment, prognosis and follow‐up of TETs.

Abstract Background Prostate cancer is one of the most common cancers in men with notable interpatient heterogeneity. Implications of the immune microenvironment in predicting the biochemical recurrence-free survival (BCRFS) after radical prostatectomy and the efficacy of systemic therapies in prostate cancer remain ambiguous. Methods The tumor immune contexture score (TICS) involving eight immune contexture-related signatures was developed using seven cohorts of 1120 patients treated with radical prostatectomy (training: GSE46602, GSE54460, GSE70769, and GSE94767; validation: GSE70768, DKFZ2018, and TCGA). The association between the TICS and treatment efficacy was investigated in GSE111177 (androgen deprivation therapy [ADT]) and EGAS00001004050 (ipilimumab). Results A high TICS was associated with prolonged BCRFS after radical prostatectomy in the training (HR = 0.32, 95% CI 0.24–0.45, P

Abstract Background Immunotherapy has exhibited efficacy in thymic carcinoma patients; however, there are insufficient data to confirm this efficacy in thymoma. The toxicity of immunotherapy also remains to be determined. Methods The efficacy and safety of immunotherapy were analyzed in 11 thymoma patients who received PD‐1 inhibitors according to a range of relevant indexes including the objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), and immunotherapy‐related adverse events. Results The PFS and OS rates for all patients were 12.8 and 56.5 months, respectively. No difference in efficacy was detected between monotherapy and combination therapy (PFS: 12.8 vs 2.2 months, P = 0.787; OS: 73.8 vs 56.5 months, P = 0.367). The ORRs and DCRs for all patients were 27.3% and 90.9%, respectively. The incidence of adverse events was 45.5% among the 11 thymoma patients, including immune‐related myocarditis (36.4%), immune‐related liver damage (18.2%), and myasthenia gravis (18.2%). In the whole cohort of patients, the rate of adverse events of grade 3 or higher was 36.4%. The rates of adverse events of grade 3 or 4 in B3‐type and non‐B3‐type thymoma patients were 0% and 62.5%, respectively. Conclusions Immunotherapy elicited a response in thymoma patients; however, more attention should be paid to the immune‐related adverse events.

Lung squamous cell carcinoma (LSCC) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases and is the second most common histological type of lung cancer. Anaplastic lymphoma kinase (ALK)-positive NSCLC accounts for only 2%-5% of all NSCLC cases, and is almost exclusively detected in patients with lung adenocarcinoma. Thus, ALK testing is not routinely performed in the LSCC population, and the efficacy of such treatment for ALK-rearranged LSCC remains unknown. Echinoderm microtubule associated protein like 4 (EML4)-ALK (V1) and TP53 co-mutations were identified by next generation sequencing (NGS) in this patient with advanced LSCC. On December 3, 2020, Ensatinib was taken orally and the efficacy was evaluated as partial response (PR). The progression-free survival (PFS) was 19 months. When the disease progressed, the medication was changed to Loratinib. To our knowledge, Enshatinib created the longest PFS of ALK-mutant LSCC patients treated with targeted therapy since literature review. Herein, we described one case treated by Enshatinib involving a patient with both EML4-ALK and TP53 positive LSCC, and the relevant literatures were reviewed for discussing the treatment of this rare disease.

Abstract Human epidermal growth factor receptor 2 (HER2) possesses tyrosine kinase activity and participates in cell growth, differentiation and migration, and survival. Its alterations, mainly including mutations, amplifications, and overexpression are associated with poor prognosis and are one of the major drivers in non–small cell lung cancer (NSCLC). Several clinical trials had been investigating on the treatments of HER2‐altered NSCLC, including conventional chemotherapy, programmed death 1 (PD‐1) inhibitors, tyrosine kinase inhibitors (TKIs) and antibody‐drug conjugates (ADCs), however, the results were either disappointing or encouraging, but inconsistent. Trastuzumab deruxtecan (T‐DXd) was recently approved by the Food and Drug Administration as the first targeted agent for treating HER2‐mutant NSCLC. Effective screening of patients is the key to the clinical application of HER2‐targeted agents such as TKIs and ADCs. Various testing methods are nowadays available, including polymerase chain reaction (PCR), next‐generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), etc. Each method has its pros and cons and should be reasonably assigned to appropriate patients for diagnosis and guiding treatment decisions. To help standardize the clinical workflow, our expert group reached a consensus on the clinical management of HER2‐altered NSCLC, focusing on the diagnosis and treatment strategies.

Background: B3 type thymoma is defined as a well-differentiated thymic carcinoma and is similar to a thymic carcinoma. However, the differences between them are not well defined. In addition, the data to compare the efficacy and safety of platinum-based chemotherapy as first-line therapy between B3 thymoma and thymic carcinoma are lacking. Methods: The efficacy and safety of platinum-based chemotherapy as first-line therapy was retrospectively compared between a group of 36 patients with type B3 thymoma and a group of 127 patients with thymic carcinoma treated between January 2009 and March 2022 at the Zhejiang Cancer Hospital. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events were analyzed. Results: The ORRs for B3 thymoma and thymic carcinoma were 36.1% and 28.3%, respectively (p = 0.370). Among all patients, the difference in PFS between B3 thymoma and thymic carcinoma was not significant (11.3 vs. 10.1 months, p = 0.118). The squamous carcinoma subgroup did not exhibit any differences in PFS compared to B3 thymoma (11.7 vs. 11.3 months, p = 0.161). The result for the non-squamous carcinoma subgroup was similar (6.5 vs. 11.3 months, p = 0.128). Furthermore, the OS values for B3 thymoma and thymic carcinoma were not significantly different (58.3 vs. 35.1 months, p = 0.067). However, there were differences in OS between B3 thymoma and non-squamous carcinoma (58.3 vs. 30.6 months, p = 0.031). Conclusions: B3 thymoma and especially squamous carcinoma patients may be treated using a similar therapy scheme as that utilized for thymic carcinoma.

Abstract Immune checkpoint inhibitors (ICIs) have successfully treated a number of different types of cancer, which is of great significance for cancer treatment. With the widespread use of ICIs in clinical practice, the increasing checkpoint inhibitor pneumonia (CIP) will be a challenge to clinicians. To guide the diagnosis and treatment of CIP, we conducted in‐depth discussions based on the latest evidence, forming a consensus among Chinese experts on the multidisciplinary management of CIP.

Abstract Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first “tumor agnostic” drugs approved for pan‐cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second‐generation drugs designed to overcome first‐generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription‐polymerase chain reaction, and (DNA and/or RNA‐based) next‐generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first‐ and second‐generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

IntroductionHepatocellular carcinoma (HCC) is one of the most invasive cancers with a low 5-year survival rate. Pyroptosis, a specialized form of cell death, has shown its association with cancer progression. However, its role in the prognosis of HCC has not been fully understood.MethodsIn our study, clinical information and mRNA expression for 1076 patients with HCC were obtained from the five public cohorts. Pyroptotic clusters were generated by unsupervised clustering based on 40 pyroptosis-related genes (PRGs) in the TCGA and ICGC cohort. A pyroptosis-related signature was constructed using least absolute shrinkage and selection operator (LASSO) regression according to differentially expressed genes (DEGs) of pyroptotic clusters. The signature was then tested in the validation cohorts (GES10142 and GSE14520) and subsequently validated in the CPTAC cohort (n=159) at both mRNA and protein levels. Response to sorafenib was explored in GSE109211.ResultsThree clusters were identified based on the 40 PRGs in the TCGA cohort. A total of 24 genes were selected based on DEGs of the above three pyroptotic clusters to construct the pyroptotic risk score. Patients with the high-risk score showed shorter overall survival (OS) compared to those with the low-risk score in the training set (P

Abstract Background Thymic epithelial tumors (TETs) are rare malignancies and the treatment options are limited. We aimed to evaluate the efficacy and safety of apatinib, an angiogenesis inhibitor, in advanced TETs. Methods This was an open-label, single-arm, phase II trial at three centers in China. Patients with TET who had progressed after failure of at least one line of platinum-based chemotherapy were enrolled. Patients received apatinib 500 mg orally per day. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results From June 29, 2017, to April 18, 2019, 25 patients were enrolled. At data cut off (September 30, 2021), one patient achieved complete response, nine achieved partial response, and 11 achieved stable disease, with an ORR of 40% (95% CI 21–61%) and DCR of 84% (95% CI 64–95%). The median PFS was 9.0 (95% CI 5.4–12.6) months. The median OS was 24.0 (95% CI 8.2–39.8) months. All patients reported treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred 26 times in 15 patients. No grade 4 or 5 toxicities occurred. Conclusions This is the first trial of apatinib for the treatment of TETs. Apatinib showed promising antitumor activity and the toxicities were tolerable and manageable.

Abstract This retrospective study investigated the association between the pattern of disease progression and molecular mechanism of acquired resistance in a large cohort of 49 patients with ROS1-rearranged advanced non-small-cell lung cancer treated with first-line crizotinib. We found that treatment-emergent ROS1 point mutations were the major molecular mechanism of crizotinib resistance, particularly for patients who developed extracranial-only disease progression. Our findings highlight the importance of rebiopsy and gene testing for subsequent-line therapeutic management.

Abstract Background There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations. Methods In this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored. Results Seventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2–60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2–30.0), with median PFS of 5.6 months (95% CI, 2.8–8.4), and median OS of 10.5 months (95% CI, 8.7–12.3). The median duration of response was 9.9 months (95% CI, 6.2–13.6). All treatment-related adverse events (TRAEs) were grade 1–3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression. Conclusions Pyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation. Trial registration Chinese Clinical Trial Registry Identifier: ChiCTR1800020262

The outcomes of patients with diffuse large B-cell lymphoma (DLBCL) vary widely, and about 40% of them could not be cured by the standard first-line treatment, R-CHOP, which could be due to the high heterogeneity of DLBCL. Here, we aim to construct a prognostic model based on the genetic signature of metabolic heterogeneity of DLBCL to explore therapeutic strategies for DLBCL patients. Clinical and transcriptomic data of one training and four validation cohorts of DLBCL were obtained from the GEO database. Metabolic subtypes were identified by PAM clustering of 1,916 metabolic genes in the 7 major metabolic pathways in the training cohort. DEGs among the metabolic clusters were then analyzed. In total, 108 prognosis-related DEGs were identified. Through univariable Cox and LASSO regression analyses, 15 DEGs were used to construct a risk score model. The overall survival (OS) and progression-free survival (PFS) of patients with high risk were significantly worse than those with low risk (OS: HR 2.86, 95%CI 2.04–4.01, p < 0.001; PFS: HR 2.42, 95% CI 1.77–3.31, p < 0.001). This model was also associated with OS in the four independent validation datasets (GSE10846: HR 1.65, p = 0.002; GSE53786: HR 2.05, p = 0.02; GSE87371: HR 1.85, p = 0.027; GSE23051: HR 6.16, p = 0.007) and PFS in the two validation datasets (GSE87371: HR 1.67, p = 0.033; GSE23051: HR 2.74, p = 0.049). Multivariable Cox analysis showed that in all datasets, the risk model could predict OS independent of clinical prognosis factors (p < 0.05). Compared with the high-risk group, patients in the low-risk group predictively respond to R-CHOP (p = 0.0042), PI3K inhibitor (p < 0.05), and proteasome inhibitor (p < 0.05). Therefore, in this study, we developed a signature model of 15 DEGs among 3 metabolic subtypes, which could predict survival and drug sensitivity in DLBCL patients.

BackgroundThe aim of this study was to establish and validate a nomogram model for accurate prediction of patients’ survival with T1aN0M0 none small cell lung cancer (NSCLC).MethodsThe patients, diagnosed with the stage IA NSCLC from 2004–2015, were identified from the Surveillance, Epidemiology and End Results (SEER) database. The variables with a P-value < 0.05 in a multivariate Cox regression were selected to establish the nomogram. The discriminative ability of the model was evaluated by the concordance index (C-index). The proximity of the nomogram prediction to the actual risk was depicted by a calibration plot. The clinical usefulness was estimated by the decision curve analysis (DCA). Survival curves were made with Kaplan–Meier method and compared by Log–Rank test.ResultsEight variables, including treatment, age, sex, race, marriage, tumor size, histology, and grade were selected to develop the nomogram model by univariate and multivariate cox regression. The C-index was 0.704 (95% CI, 0.694–0.714) in the training set and 0.713 (95% CI, 0.697–0.728) in the test set, which performed significantly better than 8th edition AJCC TNM stage system (0.550, 95% CI, 0.408–0.683, P < 0.001). The calibration curve showed that the prediction ability of 3-years and 5-years survival rate demonstrated a high degree of agreement between the nomogram model and the actual observation. The DCA curves also proved that the nomogram-assisted decisions could improve patient outcomes.ConclusionWe established and validated a prognostic nomogram to predict 3-years and 5-years overall survival in stage IA NSCLC.

Abstract Background ROS1-rearranged lung cancers benefit from first-line crizotinib therapy; however, clinical and molecular factors that could affect crizotinib efficacy in ROS1-rearranged lung cancers are not yet well-elucidated. Our retrospective study aimed to compare the efficacy of chemotherapy and crizotinib in the first-line treatment of ROS1-rearranged advanced lung cancer and evaluate various clinical and molecular factors that might impact crizotinib efficacy in real-world practice. Methods Treatment responses, survival outcomes, and patterns of disease progression were analyzed for 235 patients with locally advanced to advanced disease who received first-line chemotherapy (n = 67) or crizotinib (n = 168). Results The overall response rate was 85.7% (144/168) for first-line crizotinib and 41.8% (28/67) for chemotherapy. Patients treated with first-line crizotinib (n = 168) had significantly longer median progression-free survival (PFS) than chemotherapy (n = 67) (18.0 months vs. 7.0 months, p

BackgroundOvarian cancer is one of the most common cause of cancer death in women due to its late diagnosis and susceptibility to drug resistance. Adenosine (ADO) signaling plays a key role in immune activity and tumor progression. In this study, we constructed a signature of ADO metabolism related genes expression in patients with ovarian cancer.MethodsA total of 372 ovarian cancer patients from TCGA was used as training set and 1,137 patients from six GEO datasets were as validation set. The gene expression and drug response inhibitory concentration values for ovarian cancer cell line from GDSC were used for drug sensitivity analysis. The non-negative matrix factorization algorithm and ssGSVA were used to construct the ADO score.ResultsPatients with high ADO score had shorter overall survival (OS) than those with low ADO score in both training set (HR = 1.42, 95% CI, 1.06-1.88) and validation sets (pooled HR = 1.24, 95% CI = 1.02-1.51). In GSEA analysis, genes in ATP synthesis related pathways were enriched in the low ADO score group (adjusted P value = 0.02). Further, we observed that the high ADO score group had significantly higher levels of most cancer hallmark signatures (all adjusted P values < 0.01) and T cell dysfunction and exclusion signatures than the low ADO score group (all adjusted P values < 0.001). Patients with lower ADO score tended to be sensitive to common drugs including Olaparib and Paclitaxel (adjusted P values = 0.05 and 0.04, respectively).ConclusionsIn conclusion, the established ADO signature could be used as a prognostic biomarker to stratify ovarian cancer patients and had the potential to guide the drug exploitation and personalized therapy selection.

BackgroundEpidermal growth factor receptor (EGFR) exon 20 insertion mutations are uncommon EGFR mutations and generally resistant to first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs). In precision oncology, treatment regimens are tested for improving the clinical outcomes. Zebrafish embryo tumor transplant models are used in cancer research.MethodsWe report two Chinese females who were diagnosed with stage IV lung adenocarcinoma and shown to harbor EGFR exon 20 insertion mutations by next-generation sequencing (NGS). Then, we established lung cancer patient-derived xenografts using a zebrafish model. The tumor cells were isolated from the patient. For case one, tumor cells were collected from lymph node biopsy, while the tumor cells were obtained from the pleural effusion. Zebrafish were inoculated with tumor cells and placed in the culture medium containing the third-generation EGFR-TKI, osimertinib. Fluorescence microscope photographs were used to record the red fluorescence area, which represented the proliferation and migration of tumor cells in the zebrafish.ResultsCase one was diagnosed with lung adenocarcinoma (cT4N3M1b, stage IVB) and had an EGFR exon 20 mutation (p. N771delinsHH [abundance 14.08%]). Tumor cell proliferation and migration were significantly reduced in the osimertinib group compared with the control group. The patient received first-line osimertinib (160 mg). According to RECIST v1.1, she achieved a partial response. Case two had stage IVA lung adenocarcinoma with a pleural effusion. The pleural effusion sample was selected to obtain tumor cells for injection, and the zebrafish lung cancer model was established. The proliferation of tumor cells in the osimertinib group was significantly reduced compared to the control group. The migration of tumor cells was not significantly reduced compared to the control group. The patient also received first-line osimertinib (160 mg). The lung lesions were stable, but the pleural effusion was poorly controlled.ConclusionOur study demonstrates the applicability of a zebrafish embryos model as an innovative platform to targeted drug testing. More precise methods are needed to select treatment options in the future.

DNA damage response (DDR) pathways play a crucial role in lung cancer. In this retrospective analysis, we aimed to develop a prognostic model and molecular subtype based on the expression profiles of DDR-related genes in early-stage lung adenocarcinoma (LUAD). A total of 1,785 lung adenocarcinoma samples from one RNA-seq dataset of The Cancer Genome Atlas (TCGA) and six microarray datasets of Gene Expression Omnibus (GEO) were included in the analysis. In the TCGA dataset, a DNA damage response gene (DRG)–based signature consisting of 16 genes was constructed to predict the clinical outcomes of LUAD patients. Patients in the low-DRG score group had better outcomes and lower genomic instability. Then, the same 16 genes were used to develop DRG-based molecular subtypes in the TCGA dataset to stratify early-stage LUAD into two subtypes (DRG1 and DRG2) which had significant differences in clinical outcomes. The Kappa test showed good consistency between molecular subtype and DRG (K = 0.61, p < 0.001). The DRG subtypes were significantly associated with prognosis in the six GEO datasets (pooled estimates of hazard ratio, OS: 0.48 (0.41–0.57), p < 0.01; DFS: 0.50 (0.41–0.62), p < 0.01). Furthermore, patients in the DRG2 group benefited more from adjuvant therapy than standard-of-care, which was not observed in the DRG1 group. In summary, we constructed a DRG-based molecular subtype that had the potential to predict the prognosis of early-stage LUAD and guide the selection of adjuvant therapy for early-stage LUAD patients.

Microbial degradation is considered as an attractive method to eliminate exposure to aflatoxin B1 (AFB1), the most toxic mycotoxin that causes great economic losses and brings a serious threat to human and animal health, in food and feed. In this study, Bacillus amyloliquefaciens WF2020, isolated from naturally fermented pickles, could effectively degrade AFB1 ranging from 1 to 8 μg/ml, and the optimum temperature and pH value were 37–45°C and 8.0, respectively. Moreover, B. amyloliquefaciens WF2020 was considered to be a potential probiotic due to the synthesis of active compounds, absence of virulence genes, susceptibility to various antibiotics, and enhanced lifespan of Caenorhabditis elegans. Extracellular enzymes or proteins played a major role in AFB1 degradation mediated by B. amyloliquefaciens WF2020 into metabolites with low or no mutagenicity and toxicity to C. elegans. AFB1 degradation by the cell-free supernatant was stable up to 70°C, with an optimal pH of 8.0, and the cell-free supernatant could still degrade AFB1 by 37.16% after boiling for 20 min. Furthermore, B. amyloliquefaciens WF2020 caused a slight defect in fungal growth and completely inhibited AFB1 production when co-incubated with Aspergillus flavus. Additionally, B. amyloliquefaciens WF2020 suppressed the expression of 10 aflatoxin pathway genes and 2 transcription factors (alfR and alfS), suggesting that B. amyloliquefaciens WF2020 might inhibit AFB1 synthesis in A. flavus. These results indicate that B. amyloliquefaciens WF2020 and/or its extracellular enzymes or proteins have a promising potential to be applied in protecting food and feed from AFB1 contamination.

Abstract Background ROS1 rearrangements are validated drivers in lung cancer, which have been identified in a small subset (1–2%) of patients with non-small cell lung cancer (NSCLC). To date, 18 fusion genes of ROS1 have been identified in NSCLC. The ALK inhibitor (crizotinib) exhibits therapeutic effect against ROS1-rearranged NSCLC. Next-generation sequencing (NGS) technology represents a novel tool for ROS1 detection that covers many fusion genes. Case presentation A 55-year-old female with EGFR mutation (L858R) was diagnosed with lung adenocarcinoma, who was responsive to first-generation EGFR-tyrosine kinase inhibitor (TKI). Afterwards, she developed acquired resistance accompanied with a ROS1 rearrangement. A NGS assay showed that the tumor had a novel ROS1-ADGRG6 rearrangement generated by the fusion of exons of 1–33 of ROS1 on chr6: q22.1 to exons of 2–26 of ADGRG6 on chr6: q24.2. The patient was obviously responsive to crizotinib. Conclusion We firstly identified ROS1-ADGRG6 fusion variant in NSCLC by NGS, which should be considered in further ROS1 detecting assays.

Abstract Background MET amplification is associated with acquired resistance to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in treating non-small-cell lung cancer (NSCLC); however, the therapeutic strategy in these patients is undefined. Herein we report the clinical outcomes of patients with c-MET amplification resistance to EGFR-TKIs treated with crizotinib. Methods We retrospectively analyzed advanced NSCLC patients from five sites who were diagnosed with EGFR-mutant NSCLC and received EGFR-TKI treatment. After disease progression, these patients were confirmed to have a MET-to-centromere ratio (MET:CEN) ≥ 1.8 based on fluorescence in situ hybridization (FISH) examination and without a T790M mutation. We assessed the efficacy and safety of crizotinib to overcome EGFR-TKI resistance in EGFR-activating mutations NSCLC with acquired MET amplification. Results Amplification of the acquired MET gene was identified in 18 patients with EGFR-mutant NSCLC. Fourteen patients received crizotinib treatment after acquired resistance to EGFR-TKIs. Among the 14 patients, 6 (42.9%) received crizotinib plus EGFR-TKI and 8 (57.1%) received crizotinib monotherapy. The overall objective response rate (ORR) and disease control rate (DCR) were 50.0% (7/14) and 85.7% (12/14), respectively. The median PFS (mPFS) of patients receiving crizotinib monotherapy and crizotinib plus EGFR-TKI was 6.0 and 12.6 months, respectively (P = 0.315). Notably, treatment efficacy was more pronounced in patients with crizotinib than patients with chemotherapy (24.0 months vs. 12.0 months, P = 0.046). The mOS for 8 of 14 patients receiving crizotinib monotherapy and 6 of 14 patients receiving crizotinib plus EGFR-TKI was 17.2 and 24.0 months, respectively (P = 0.862). Among the 14 patients, 1 who received crizotinib monotherapy (grade 3 nausea) and 2 who received crizotinib plus EGFR-TKI (grade 3 elevated liver aminotransferase levels) received reduced doses of crizotinib (200 mg twice daily) to better tolerate the dose. Conclusions We observed the clinical evidence of efficacy generated by combination of crizotinib and previous EGFR-TKIs after the resistance to first-generation EGFR-TKIs. These results might increase evidence of more effective therapeutic strategies for NSCLC treatment. Combination therapy did not increase the frequency of adverse reactions.

TP53 has been proved to be associated with cytotoxic T-cell induced apoptosis, however, the association between TP53 and the benefit of immunotherapy in melanoma has not been studied. In the present study, we examined the relationship between TP53 mutation and response to CTLA-4 blockade in metastatic melanoma by analyzing the data from one public cohort consisting of 110 patients with metastatic melanoma. The sequencing, mRNA and survival data of 368 patients with skin melanoma from The Cancer Genome Atlas (TCGA) was used to explore the underlying mechanism. TP53 mutation was associated with significant poorer progression-free survival (HR, 2.25; 95% CI, 1.15–4.37; P = 0.014), poorer overall survival (HR, 2.05; 95% CI, 1.02–4.13; P = 0.040) and trend of poorer response (OR, 0.20; 95% CI, 0.02–1.62; P = 0.131). The correlations were significant in multivariate analysis including lactate dehydrogenase, tumor mutational burden and tumor stage (P

PURPOSE: The incidence of anaplastic lymphoma kinase (ALK) rearrangement in pulmonary sarcomatoid carcinoma (PSC) is controversial. In this study, we aimed to reveal the reliable frequency and the clinical-pathologic characteristics of pulmonary sarcomatoid carcinoma (PSC) with ALK rearrangement in Chinese population, and to provide insight into the translatability of anti-ALK treatment in this treatment-refractory disease. METHODS: Immunohistochemistry (IHC) using a Ventana anti-ALK (D5F3) rabbit monoclonal antibody was performed in 141 PSC specimens collected from multiple medical centers. IHC-positive cases were then confirmed using ALK fluorescent in situ hybridization (FISH). The incidence rates and clinical-pathologic characteristics of ALK-rearranged PSC were then analyzed. Response to ALK inhibitor crizotinib in a patient with ALK-rearranged PSC was evaluated according to the response evaluation criteria for solid tumors (RECIST) version 1.1. RESULTS: Five of 141 (3.5%) of PSCs showed ALK rearrangement-positive by IHC and then were confirmed by FISH. Two were carcinosarcomas and the other three were pulmonary pleomorphic carcinoma (PPC). Strong positive ALK rearrangement was observed in both the epithelioid and sarcomatoid components. The median age of ALK-positive patients was younger than that of ALK-negative patients. PSCs in never-smokers were more likely to harbor ALK rearrangement than those in former or current smokers (P

Burkitt lymphoma (BL) is a highly aggressive neoplasm, which arising from the germinal center or post germinal center B-cell. Primary breast lymphomas are extremely rare, and the most common histologic type is diffuse large B-cell lymphoma. Primary BL of the breast is much less common than the other types of lymphoma. Here, we report an extremely rare case of a 37-year-old Chinese female with localized bilateral breast, who was referred to our institution for bilateral breast swelling. The left breast tissue ultrasonography showed the short axis measuring 20.3 mm × 18.8 mm and the long axis measuring 22.1 mm × 20.8 mm soft tissue mass. The right breast tissue ultrasonography showed the short axis measuring 30.2 mm × 26.9 mm and the long axis measuring 33.5 mm × 2.18 mm. Coarse needle biopsy of breast masses demonstrated a non-Hodgkin's B-cell lymphoma. The patient underwent a bilateral mastectomy. Histological examination of the tumor showed a characteristic "starry sky" pattern, the medium-sized tumor cells were a monotonous pattern of growth, and there were many abnormal mitotic figures. The neoplastic cells strongly expressed CD20, CD79-μ, MUM-1, PAX-5, CD43 and Bcl-6, Ki-67 were nearly 100% positive, but negative for CD10, Bcl-2 and TdT. By fluorescence in situ hybridization an IGH-MYC gene fusion was detected in the tumor tissue which indicating the presence of a typical BL translocation t(8;14)(q24;q32). The final histopathological diagnosis was primary BL of the breast.