Case report: A rare immune-related adverse effect: hepatic cavernous hemangioma induced by camrelizumab.

Background: Camrelizumab, a programmed death 1 (PD-1) inhibiting antibody, has demonstrated efficacy in various malignancies and received approval in multiple countries. Despite its therapeutic benefits, camrelizumab is associated with a unique spectrum of immune-related adverse effects (irAEs), predominantly reactive cutaneous capillary endothelial proliferation (RCCEP). However, visceral manifestations of such endothelial proliferations, particularly hepatic cavernous hemangiomas, have not been extensively documented. Methods: This case series retrospectively reviews six patients who developed hepatic hemangiomas following treatment with camrelizumab in combination with other chemotherapeutic agents. The series highlights the clinical course, imaging findings, management strategies, and outcomes associated with this complication. A detailed analysis was conducted to discern the potential causal relationship between camrelizumab therapy and the development of hepatic hemangiomas. Results: All six patients, after varying cycles of camrelizumab-based therapy, presented with hepatic lesions identified as cavernous hemangiomas on imaging. These findings were atypical for metastatic disease and were further complicated by significant clinical events, including massive intra-abdominal bleeding post-biopsy. Discontinuation of camrelizumab led to a reduction in the size of the hemangiomas in two cases, suggesting a potential link between the drug and the development of these vascular lesions. The incidence of RCCEP remained high, and the use of other agents such as bevacizumab did not mitigate the occurrence of hepatic hemangiomas, indicating a possible unique pathogenic mechanism associated with camrelizumab. Conclusion: Hepatic cavernous hemangioma may represent a rare but clinically significant irAE associated with camrelizumab therapy. This series underscores the importance of vigilant monitoring and a high index of suspicion for atypical hepatic lesions in patients undergoing treatment with PD-1 inhibitors. Further studies are warranted to elucidate the pathophysiology of this complication and to establish guidelines for the management and surveillance of patients receiving camrelizumab.

Changes in T lymphocyte subsets predict the efficacy of atezolizumab in advanced non-small cell lung cancer: a retrospective study.

Background: It has remained unclear how programmed cell death ligand 1 (PD-L1) inhibitors affect peripheral blood lymphocyte (PBL) subsets in patients with advanced non-small cell lung cancer (NSCLC). This study assessed the predictive and prognostic value of PBL subsets in patients with advanced NSCLC who were treated with atezolizumab. Methods: A total of 30 patients with advanced NSCLC treated with atezolizumab were selected as the observation group, and 30 healthy individuals were chosen as the control group during same period. Flow cytometry was used to detect lymphocyte subsets before and after treatment. The relationship between the changes of lymphocyte subsets and atezolizumab in the treatment of NSCLC was analyzed and calculated. Results: Before treatment, compared with the control group, the number of CD3+, CD4+ T, and CD4+/CD8+ indexes in the observation group were significantly decreased, whereas the level of CD8+ was significantly increased. The number of CD3+, CD4+ T, and CD4+/CD8+ indexes gradually increased with the process of atezolizumab treatment, whereas the number of CD8+ T gradually decreased. After the 4 cycles, the number of CD3+, CD4+ T, and CD4+/CD8+ indexes were significantly increased, and the number of CD8+ was significantly decreased. In the observation group, 22 patients achieved partial response (PR)/stable disease (SD) and 8 patients achieved progressive disease (PD) after 4 cycles of atezolizumab treatment. Before treatment, there were no significant differences in the level of lymphocyte subsets between those who achieved PR/SD or PD. However, a significant difference in the level of lymphocyte subsets appeared after 4 cycles of atezolizumab treatment. Among the 22 patients who achieved PR/SD, the number of CD3+, CD4+ T, and CD4+/CD8+ indexes were significantly increased, whereas the number of CD8+ T lymphocytes was significantly decreased. Meanwhile, the 8 patients who achieved PD displayed different results. In addition, ROC curve combined detection of CD3+, CD4+, and CD8+ T [area under the curve (AUC) =0.9018, P<0.0001] showed good predictive ability for the efficacy of atezolizumab in advanced NSCLC. Conclusions: Atezolizumab may alter the level of lymphocyte subsets in patients with advanced NSCLC, and the changes in lymphocyte subsets may predict the efficacy of atezolizumab for these patients.

ARID1A deficiency associated with MMR deficiency and a high abundance of tumor-infiltrating lymphocytes predicts a good prognosis of endometrial carcinoma.

BACKGROUND: ARID1A alterations have been detected in 40% of endometrial carcinomas (ECs) and are associated with loss of its expression. The role of ARID1A in tumorigenesis and development is complex, and the prognostic role in EC remains controversial. Hence, it is of great significance to confirm the role of ARID1A in EC. METHODS: A total of 549 EC patients (cohort A) from TCGA were evaluated to explore the prognostic role of ARID1A. NGS was performed for 13 EC patients (cohort B), and expression of ARID1A, CD3, CD8 and mismatch repair (MMR) proteins in 52 patients (cohort C) from our center was determined by immunohistochemistry (IHC). The Kaplan-Meier method was used to perform survival analyses. RESULTS: ARID1A alterations were detected in 32% of EC patients and correlated with good disease-free survival (DFS, P = 0.004) and overall survival (OS, P = 0.0353). ARID1A alterations were found to co-occur with MMR-related gene mutations and correlated with higher PD-L1 expression. Patients concomitantly harboring ARID1A alterations and MMR-related gene mutations had the best prognosis (DFS: P = 0.0488; OS: P = 0.0024). A cohort from our center showed that ARID1A deficiency was an independent prognostic factor and predicted longer recurrence-free survival (P = 0.0476). ARID1A loss was associated with a tendency toward MSI-H (P = 0.0060). ARID1A alterations and expression loss were associated with a higher abundance of CD3+ (P = 0.0406) and CD8+ (P = 0.0387) T cells. CONCLUSION: ARID1A alterations and expression loss are tightly associated with MMR deficiency and a high abundance of tumor-infiltrating lymphocytes, which might contribute to the good prognosis of EC.

Comprehensive characterization of ferroptosis in hepatocellular carcinoma revealing the association with prognosis and tumor immune microenvironment.

Background: Ferroptosis is a type of regulatory cell death (RCD) mode that depends on iron-mediated oxidative damage. It has the potential to improve the efficacy of tumor immunotherapy by modulating the tumor microenvironment (TME). Currently, immunotherapy has significantly improved the overall treatment strategy for advanced hepatocellular carcinoma (HCC), but the distinct immune microenvironment and high tolerance to the immune make massive differences in the immunotherapy effect of HCC patients. As a result, it is imperative to classify HCC patients who may benefit from immune checkpoint therapy. Simultaneously, the predictive value of ferroptosis in HCC and its potential role in TME immune cell infiltration also need to be further clarified. Methods: Three ferroptosis molecular models were built on the basis of mRNA expression profiles of ferroptosis-related genes (FRGs), with notable variations in immunocyte infiltration, biological function, and survival prediction. In order to further investigate the predictive impact of immunotherapy response in HCC patients, the ferroptosis score was constructed using the principal component analysis (PCA) algorithm to quantify the ferroptosis molecular models of individual tumors. Results: In HCC, there were three totally different ferroptosis molecular models. The ferroptosis score can be used to assess genetic variation, immunotherapy response, TME characteristics, and prognosis. Notably, tumors with low ferroptosis scores have extensive tumor mutations and immune exhaustion, which are associated with a poor prognosis and enhanced immunotherapy response. Conclusions: Our study indicates that ferroptosis plays an indispensable role in the regulation of the tumor immune microenvironment. For HCC, the ferroptosis score is an independent prognostic indicator. Assessing the molecular model of ferroptosis in individual tumors will assist us in better understanding the characteristics of TME, predicting the effect of immunotherapy in HCC patients, and thus guiding a more reasonable immunotherapy program.

[Retracted] Long noncoding RNA UCID sponges miR­152­3p to promote colorectal cancer cell migration and invasion via the Wnt/ß­catenin signaling pathway.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that there appeared to be matching data panels comparing between the Transwell invasion and migration assays shown in Figs. 2C and 5C; moreover, one of the data panels shown in Fig. 2D had previously appeared in a paper written largely by different authors (the author 'T­D Shan' was held in common) at different research institutes in the journal Oncotarget in 2016 [Shan T­D, Xu, J­H, Yu T, Li J­Y, Zhao L­N, Ouyang H, Luo S, Lu X­J, Huang C­Z, Lan Q­S et al: Knockdown of linc­POU3F3 suppresses the proliferation, apoptosis, and migration resistance of colorectal cancer. Oncotarget 7: 961­975, 2016]. Finally, an independent investigation of these data in the Editorial Office revealed that, in addition to the data shared between Figs. 2 and 5, there were overlapping data panels both within Fig. 5C and within the wound healing assay data shown in Fig. 3B. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, and given the number of cases of overlapping data panels both within and between figures in the artce itself, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they did not agree with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 44: 1194­1295, 2020; DOI: 10.3892/or.2020.7670].

Neoadjuvant toripalimab plus platinum-paclitaxel chemotherapy in stage II-III non-small cell lung cancer: a single-center, single-arm, phase I study in China.

BACKGROUND: Neoadjuvant and adjuvant immune checkpoint inhibitor treatments for non-small cell lung cancer (NSCLC) patients with resectable disease have presented promising results. This is a phase I study to evaluate the safety and efficacy of neoadjuvant toripalimab in combination with chemotherapy for NSCLC. METHODS: Treatment-naive patients with resectable NSCLC (stage II-IIIB) received two to four cycles of toripalimab (240 mg, intravenously, q3w) combined with platinum-paclitaxel chemotherapy. Surgical operation was performed approximately 4 weeks after the last cycle. The primary end point was safety. The efficacy endpoints included radiographic and pathological response rates, expression of programmed death ligand 1 (PD-L1) and molecular targets. RESULTS: A total of 11 patients were enrolled, consisting of 2 patients (18%) with adenocarcinoma and 9 patients (82%) with squamous cell carcinoma. All patients received two to four cycles of toripalimab plus chemotherapy and underwent radical resection. Regarding safety, 5 of 11 patients (45%) had neoadjuvant treatment-related adverse events, and 1 patient (9%) experienced grade 3 or worse treatment-related adverse events. Radiographic partial response was achieved in 10 patients, with an objective response rate of 91%. Among 11 patients, 6 (55%) achieved pathological complete response, including 1 PD-L1-negative patient. CONCLUSION: Neoadjuvant toripalimab plus platinum-paclitaxel chemotherapy was tolerable and induced a pathological complete response in 55% of resectable NSCLC patients.

Optimal Treatments for NSCLC Patients Harboring Primary or Acquired MET Amplification.

Background: In non-small cell lung cancer (NSCLC) patients harboring MET mutations, MET-tyrosine kinase inhibitors (TKIs) have been proven to achieve a good response. However, the relative efficacy of different therapeutics in primary NSCLC patients with MET amplification and the treatment options for patients harboring acquired MET amplification after the failure of epidermal growth factor receptor (EGFR)-TKIs remain unclear. Methods: In total, 33 patients harboring primary MET amplification and 9 patients harboring acquired MET alterations identified by next-generation sequencing were enrolled. A retrospective analysis was conducted to compare the efficacy of different therapeutics. In addition, studies reporting various treatments for patients harboring MET alterations were included in the meta-analysis. Results: In our cohort of patients harboring primary MET amplification, crizotinib displayed better efficacy than immunotherapy and chemotherapy, as demonstrated both in first-line (P = .0378) and second-line treatment regimens (P = .0181). The disease control rates for crizotinib, immunotherapy, and chemotherapy were 81.8%, 72.7%, and 63.6%, respectively. In particular, the median progression-free survival (PFS) time after immunotherapy in patients harboring MET amplification and high programed death ligand 1 (PD-L1) expression (>50%) was only 77.5 days. The meta-analysis revealed that the median PFS times after crizotinib and immunotherapy were 4.57 and 2.94 months, respectively. In patients harboring acquired MET amplification, chemotherapy plus bevacizumab had superior efficacy (310.0 days vs 73.5 days, P = .0360) compared with MET-TKIs ± EGFR-TKIs. Conclusions: Immunotherapy showed a low response in patients harboring MET alterations, even those with concurrent high PD-L1 expression. MET-TKIs might be an optional treatment with worth-expecting efficacy. However, chemotherapy plus bevacizumab could benefit the subpopulation of patients harboring acquired MET amplification after the failure of EGFR-TKIs.

Next-generation sequencing identifies potential novel therapeutic targets in Chinese HGSOC patients.

BACKGROUND: Targeted therapy, especially the use of poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors (PARPis), has improved the outcome of patients with ovarian cancer. However, most high-grade serous ovarian cancer (HGSOC) patients have wild-type BRCA1/2, and it is necessary to disclose more potential novel targets for other available targeted drugs. So, detection of genetic alterations beyond BRCA1/2 is critical to screen HGSOC patients for personalized therapy. In this study, a broad, hybrid capture-based next-generation sequencing (NGS) assay was used to identify actionable genetic alterations from HGSOC cancer tissues. METHODS: Sixty-eight patients with HGSOC were enrolled, including 6 International Federation of Gynecology and Obstetrics (FIGO) stage I, 15 stage II, 37 stage III and 10 stage IV patients. All patients signed informed consent forms. Potentially actionable genetic alterations, including base substitutions, indels, copy number alterations, and gene fusions, were identified using targeted NGS. RESULTS: In our study, 14.7% (10/68) of the tumors harbored actionable genetic alterations in patients with BRCA1. A total of 25.0% (17/68) of patients without BRCA1 mutations harbored other actionable genetic alterations, such as homologous recombination repair (HRR) pathway-related genes (ATM, CDK12, FANCA, and FANCD2), PI3K/AKT/mTOR pathway genes (NF1, FBXW7, PIK3CA, PTEN, TSC1, and TSC2), and some other genes (ARID1A, FGFR1, KRAS, and NRAS). Furthermore, some patients harboring ARID1A or NF1 actionable genetic alterations showed good clinical efficacy to immune checkpoint inhibitors (ICIs) and everolimus, respectively. CONCLUSIONS: Our research indicates that 39.7% (27/68) of patients with HGSOC harbored at least one actionable genetic alteration. 25.0% (17/68) of patients had somatic mutations or copy number variations beyond BRCA1 mutations and might be treated with off-label therapy or to be allocated into clinical trial. NGS assays of HGSOC patients are necessary to screen actionable genetic alterations to guide personalized and precise treatment.

A Pilot Study: Favorable Effects of Clostridium butyricum on Intestinal Microbiota for Adjuvant Therapy of Lung Cancer.

Probiotics as medications have previously been shown to change intestinal microbial characteristics, potentially influencing cancer therapy efficacy. Patients with non-squamous non-small cell lung cancer (NS-NSCLC) treated by bevacizumab plus platinum-based chemotherapy were randomized to obtain Clostridium butyricum supplement (CBS) or receive a placebo as adjuvant therapy. Clinical efficacy and safety were assessed using progression-free survival (PFS), overall survival (OS), and adverse events (AE). Intestinal microbiota was longitudinally explored between CBS and placebo groups over time. Patients who took CBS had significantly decreased bacterial richness and abundance, as well as increased the total richness of the genus Clostridium, Bifidobacterium, and Lactobacillus compared to the placebo group (p < 0.05). Beta diversity and the interactional network of intestinal microbiota were distinctly different between CBS and placebo group. However, there were no significant variations between them in terms of microbial taxonomical taxa and alpha diversity. The potential opportunistic pathogen Shewanella was still detectable after treatment in the placebo group, while no distinguishing microbial markers were found in the CBS group. In terms of clinical efficacy, the CBS group had a significantly reduced AE compare to the placebo group (p < 0.05), although no significantly longer PFS and OS. Therefore, favorable modifications in intestinal microbiota and significant improvements in drug safety make probiotics be promising adjunctive therapeutic avenues for lung cancer treatment.

Anlotinib Combined with Toripalimab as Second-Line Therapy for Advanced, Relapsed Gastric or Gastroesophageal Junction Carcinoma.

Our study aimed to explore the efficacy and safety of anlotinib-toripalimab combination therapy as a second-line treatment for advanced relapsed gastric or gastroesophageal junction carcinoma (GC/GEJC). In this single arm, single-center extension clinical trial, patients with advanced relapsed GC/GEJC received toripalimab (240 mg, intravenously over 60 minutes, once every 2 weeks) plus anlotinib (12 mg/day, orally, 2 weeks on and 1 week off, every 3 weeks) as second-line therapy. There were 29 patients who achieved partial response, and the ORR was 32.3% (95% CI, 26.6%-38.5%). Grade 3 treatment-related adverse events (TRAEs) were recorded in 7 participants (11.3%), all of which were manageable. The PFS and OS were 4.0 and 11.1 months, respectively. Patients with programmed death-ligand 1 (PD-L1) positive expression showed numerically longer OS than the negative ones although the difference was not significantly. The tumor mutational burden-high (TMB-H) group showed a significantly better OS (P = .05) than the TMB-Low (TMB-L) group. Next-generation sequencing (NGS) revealed that fibroblast growth factor receptor 2 (FGFR2) mutations positively correlated with target lesion reduction (odds ratio [OR] = 0.14; P = .02). The new regimen increased tumor-infiltration of CD8+ T and CD3+ T cells. Furthermore, a patient-derived organoid (PDO) study indicated that anlotinib could promote an immune-supportive tumor microenvironment. As conclusion, the anlotinib-toripalimab combination showed promising efficacy and favorable safety as a second-line treatment for advanced, relapsed GC/GEJC. The PD-L1 expression, TMB, and FGFR2 mutation are potential biomarkers for predicting the efficacy of this regimen (ClinicalTrials.gov registration number: NCT04713059).

Anlotinib combined with anti-PD-1 antibody, camrelizumab for advanced NSCLCs after multiple lines treatment: An open-label, dose escalation and expansion study.

OBJECTIVES: Combined therapy should be invested for those patients who are refractory to first-line therapy. Anti-angiogenic agents could enhance tumor immunity response. We designed a phase IB clinical trial and analyzed the effectiveness and safety of anlotinib combined with PD-1inhibitors Camrelizumab for multi-line pretreated and failed advanced NSCLC to explore the synergistic effect of anti-angiogenic agents and immunotherapy. METHODS: All enrolled patients should receive camrelizumab 200 mg every 3 weeks. Eligible patients were randomized successively to three dose cohorts of Anlotinib in a dose escalation clinical setting. Once maximal tolerable dose was established, the primary end point of this study was progression-free survival, overall survival and safety. Risk factor was an exploratory end point. RESULTS: The identified expansion dose for anlotinib was 12 mg. The median PFS of ITT patients was 8.2 months (95% CI, 4.3-12.1 months). And the mOS was 12.7 months (95% CI, 10.2-15.1 months). There was significant difference of mPFS between the 8 mg cohort and the 12 mg cohort (5.6 m vs.11.0 m, p = 0.04). Patients with brain metastasis had a significantly higher risk of death (HR 5.90; 95% CI 2.01-17.30; P = 0.001). Patients whose ECOG was 0 and 1 had a significantly lower risk of death (HR 0.36; 95% CI 0.14-0.91; P = 0.031). CONCLUSIONS: Anlotinib plus camrelizumab had shown promising efficacy and manageable toxicity as a second-line or later-line treatment for NSCLCs, especially in the 12 mg cohorts. Large-scale phase III clinical trials are needed to further explore the rational combination models and biomarkers.

The safety and efficacy of lenvatinib combined with immune checkpoint inhibitors therapy for advanced hepatocellular carcinoma.

China has one of the highest incidence rates of hepatocellular carcinoma (HCC) in the world. As most patients are diagnosed with advanced or unretractable HCC, systematic therapy is still the main treatment method for HCC. Currently, tyrosine kinase inhibitors (TKIs) and Immune checkpoint inhibitors (ICIs) are both the chief systematic therapy. And some studies have shown that the combination of TKIs and ICIs is more effective than monotherapy. The purpose of this review is to outline the rationale for the combination between lenvatinib and anti-PD-1(programmed cell death 1) and clinical trials to support this "golden combination". We also discuss the commonly treatment-emergent adverse events (AEs) and solutions for the patients with HCC who received the combination between lenvatinib and anti-PD-1 antibodies. Finally, we focus on the novel approaches, future perspectives and potential challenges about the combination of TKIs and ICIs.

Complete response to pembrolizumab in a patient with extensive-stage small-cell lung cancer: a case report.

Small cell lung cancer (SCLC) is an invasive lung cancer subtype. Despite its sensitivity to first-line chemotherapy, SCLC has a high recurrence rate and poor response to second-line therapy. Recently, immunotherapy has shown promise as a novel therapy for the treatment of SCLC. One immune-checkpoint inhibitor, pembrolizumab, has demonstrated antitumor activity in patients with SCLC. In June 2019, based on data from the KEYNOTE-28 and KEYNOTE-158 trial, the US Food and Drug Administration (FDA) approved pembrolizumab for treatment of metastatic SCLC patients who had made progress on a platinum-based chemotherapy and at least one other line of therapy. Herein, we reported an 86-year-old female patient with extensive-stage disease (ED-SCLC) who was treated with pembrolizumab after relapse following first-line therapy and achieved a complete response (CR) in only one month after initiation of treatment. This case highlights that patients with ED-SCLC may benefit from immunotherapy and identifies a clinically meaningful therapeutic option.

Long noncoding RNA UCID sponges miR­152­3p to promote colorectal cancer cell migration and invasion via the Wnt/ß­catenin signaling pathway.

Research has shown that long noncoding RNAs (lncRNAs) play significant roles in colorectal cancer (CRC). However, the role of lnc­UCID (lncRNA upregulating CDK6 by interacting with DHX9) in CRC remains largely unknown. In the present study, analyses revealed that lnc­UCID was markedly upregulated in CRC compared with that in normal specimens. Functional experiments showed that the depletion of lnc­UCID inhibited CRC cell invasion and migration significantly, while overexpression of lnc­UCID had the opposite effect. A candidate target of lnc­UCID, microRNA miR­152­3p, was identified using bioinformatic analysis. Moreover, in CRC tissue, we noted an inverse correlation between miR­152­3p and lnc­UCID expression levels. Overexpression and knockdown experiments revealed opposing roles for miR­152­3p and lnc­UCID, suggesting that lnc­UCID negatively regulates miR­152­3p. Luciferase reporter assays demonstrated that miR­152­3p directly targets lnc­UCID. The results suggest that lnc­UCID acts as an endogenous miRNA sponge, competing for miR­152­3p binding and thereby regulating the miRNA's targets. Overall, we propose that the lnc­UCID/miR­152­3p/Wnt/ß­catenin signaling axis represents a novel mechanism that explains the migration and invasion of CRC.

Primary resistance to first-generation EGFR-TKIs induced by MDM2 amplification in NSCLC.

INTRODUCTION: Targeted therapy for NSCLC is rapidly evolving. EGFR-TKIs benefit NSCLC patients with sensitive EGFR mutations and significantly prolong survival. However, 20-30% of patients demonstrate primary resistance to EGFR-TKIs, which leads to the failure of EGFR-TKI treatment. The mechanisms of primary resistance to EGFR-TKIs require further study. METHODS: Targeted sequencing was used for the detection of genomic alterations among patients in our center. Regular cell culture and transfection with plasmids were used to establish NSCLC cell lines over-expressing MDM2 and vector control. We used the MTT assays to calculate the inhibition rate after exposure to erlotinib. Available datasets were used to determine the role of MDM2 in the prognosis of NSCLC. RESULTS: Four patients harboring concurrent sensitive EGFR mutations and MDM2 amplifications demonstrated insensitivity to EGFR-TKIs in our center. In vitro experiments suggested that MDM2 amplification induces primary resistance to erlotinib. Over-expressed MDM2 elevated the IC50 value of erlotinib in HCC2279 line and reduced the inhibition rate. In addition, MDM2 amplification predicted a poor prognosis in NSCLC patients and was associated with a short PFS in those treated with EGFR-TKIs. The ERBB2 pathway was identified as a potential pathway activated by MDM2 amplification could be the focus of further research. CONCLUSION: MDM2 amplification induces the primary resistance to EGFR-TKIs and predicts poor prognosis in NSCLC patients. MDM2 may serve as a novel biomarker and treatment target for NSCLC. Further studies are needed to confirm the mechanism by which amplified MDM2 leads to primary resistance to EGFR-TKIs.

Influence and mechanism of lung cavitation development on antiangiogenic therapy.

BACKGROUND: Antiangiogenic agent-treated patients usually develop cavitation in their lung lesions. The clinical significance of lung cavitation development during antiangiogenic therapy has not been determined yet. Herein, we evaluated the clinical outcomes of patients who developed tumor cavitation following apatinib treatment and explored the mechanisms. METHODS: In this study (Clinical Trial No. NCT03629691), 187 patients (77 lung cancer and 110 gastric adenocarcinoma patients) who had progressed or relapsed after undergoing at least two lines of systemic therapy in accordance with the NCCN guidelines for primary or metastatic lung tumors were treated with apatinib at a dosage of 250 mg per day between February 1, 2015 and May 19, 2017. The effect of lung cavitation development on locoregional control (LRC), progression-free survival (PFS), and overall survival (OS) was analyzed with Kaplan-Meier estimates and compared with the log-rank test. Zebrafish experiments were used to study the anticancer mechanism of apatinib in different tumors. Western-blotting was used to analyze the expression of Cyclin D1, p53, HIF-α, and VEGFR before and after apatinib treatment in both normoxia and hypoxia. RESULTS: Cavitation development was beneficial in patients receiving apatinib therapy regardless of whether they had primary or metastatic lung cancer. Zebrafish experiments showed that apatinib inhibited tumor growth by both suppressing vascular growth and inhibiting cell proliferation. Vascular proliferation induced by the H1299 cell lines showed higher sensitivity to apatinib than that induced by the SCG-7901 cell line. However, apatinib showed weak tumor type selectivity on cell proliferation inhibition in vivo. Under hypoxic conditions, apatinib could not inhibit the protein expression of VEGFR and HIF-α in both cell lines; however, apatinib decreased the expression of cyclin D1 and P53 significantly. CONCLUSIONS: Lung cavitation development is common with apatinib therapy and is a potential prognostic marker. Apatinib inhibits tumor growth by both vessel growth inhibition and proliferation inhibition.

Concurrent TP53 mutations predict poor outcomes of EGFR-TKI treatments in Chinese patients with advanced NSCLC.

Purpose: The study investigated the impact of TP53 mutations on the clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors (TKIs) in Chinese patients with advanced or recurrent non-small-cell lung cancer (NSCLC). Patients and methods: Tissues from 163 NSCLC patients at the Affiliated Hospital of Qingdao University were analyzed by next-generation sequencing (NGS) to determine the mutational status of EGFR and concurrent genetic alterations. TP53 mutations were evaluated in relation to baseline patient characteristics and treatment outcomes (progression-free survival [PFS], overall survival [OS], objective response rate [ORR] and disease control rate [DCR]). Results: Among 163 patients with advanced NSCLC, 77 were identified as EGFR-mutant (47.2%). Six patients who did not receive TKI treatment were excluded. Among the remaining 71 patients with EGFR genetic alterations, the frequency of pathogenic TP53 mutations was 60.6% (43/71), while other concurrent mutations were rare events. Markedly shorter median PFS (mPFS) (6.5 versus 14.0 months, P=0.025) and median OS (mOS) (28.0 versus 52.0 months, P=0.023) were observed in TP53-mut patients than in TP53-wt controls. The overall DCR and ORR of TP53-mutant patients were both lower than those of the TP53-wt cases (DCR: 76.7% versus 89.3%, P=0.160; ORR: 25% versus 28%, P=0.374). Differences in prognosis were significant, especially in the subgroup of patients with TP53 non-missense mutations, non-disruptive mutations, mutations in exon 6, mutations in exon 7 and mutations in the non-DBD region among all TP53 mutations. Conclusion: TP53 mutations reduce responsiveness to TKIs and worsen the prognosis of EGFR-mutant NSCLC patients, especially for those with non-missense mutations and non-disruptive mutations, as well as mutations in exon 6, exon 7 and non-DBD region, thus acting as an independent predictor of poor outcome in advanced NSCLC patients treated with first-generation TKI therapy. Our study also suggests that TP53 mutation might be involved in primary resistance to EGFR-TKIs in Chinese NSCLC patients.

The safety and serious adverse events of approved ALK inhibitors in malignancies: a meta-analysis.

Background: A total of 2%-7% of non-small cell lung cancer (NSCLC) patients have anaplastic lymphoma kinase (ALK) mutations. At present, three or more generations of ALK inhibitors have been used for ALK-positive NSCLC treatment, including crizotinib, alectinib, ceritinib, and brigatinib. Although most adverse events (AEs) of ALK inhibitors are grades 1 to 2 and generally can be well tolerated, serious adverse events (SAEs) of ALK inhibitors lack data analysis, and the lung toxicity of ALK inhibitors needs attention. Thus, we performed this meta-analysis to evaluate the safety of ALK inhibitors, especially in terms of drug-related SAEs. Methods: A total of 19 studies from 4 databases (PubMed, Science Direct, ClinicalTrials.gov and Cochrane Library) were included in this meta-analysis. All statistical analyses in this meta-analysis were performed with the STATA 14.0 software. We analyzed the incidences of total AEs, total SAEs and SAEs for different ALK inhibitors. Results: AEs of the ALK inhibitors occurred in almost all participants, and SAEs occurred in more than 20% of the participants. For ceritinib and brigatinib, SAEs occurred in more than 40% of the participants. Alectinib is most likely the safest of the two generations of ALK inhibitors. Generally, the ALK inhibitors showed significant lung toxicity. Conclusion: In conclusion, attention should be focused on ALK inhibitor-related SAEs, especially lung toxicity. According to this meta-analysis, alxectinib seems to be the safest ALK inhibitor. Physicians should focus on the related SAEs when prescribing ALK inhibitors.

Chemotherapy Alters the Phylogenetic Molecular Ecological Networks of Intestinal Microbial Communities.

Intestinal microbiota is now widely known to play key roles in nutritional uptake, metabolism, and regulation of human immune responses. There are multiple studies assessing intestinal microbiota changes in response to chemotherapy. In this study, microbial phylogenetic molecular ecological networks (pMENs) were firstly used to study the effects of chemotherapy on the intestinal microbiota of colorectal cancer (CRC) patients. Based on the random network model, we demonstrated that overall network structures and properties were significantly changed by chemotherapy, especially in average path length, average clustering coefficient, average harmonic geodesic distance and modularity (P < 0.05). The taxa in the module tended to co-exclude rather than co-occur in CRC patient networks, indicating probably competition relationships. The co-exclude correlations were decreased by 37.3% from T0 to T5 in response to chemotherapy. Significantly negative correlations were observed in positive/negative OTU degree and tumor markers (P < 0.05). Furthermore, the topological roles of the OTUs (module hubs and connectors) were changed with the chemotherapy. For example, the OTU167, OTU8, and OTU9 from the genera Fusobacterium, Bacteroides, and Faecalibacterium, respectively, were identified as keystone taxa, which were defined as either "hubs" or OTUs with highest connectivity in the network. These OTUs were significantly correlated with tumor markers (P < 0.05), suggesting that they probably were influenced by chemotherapy. The pMENs constructed in this study predicted the potential effects of chemotherapy on intestinal microbial community co-occurrence interactions. The changes may have an effect on the therapeutic effects. However, larger clinical samples are required to identify the conclusion.

Concordance Study Between IBM Watson for Oncology and Clinical Practice for Patients with Cancer in China.

BACKGROUND: IBM Watson for Oncology (WFO), which can use natural language processing to evaluate data in structured and unstructured formats, has begun to be used in China. It provides physicians with evidence-based treatment options and ranks them in three categories for treatment decision support. This study was designed to examine the concordance between the treatment recommendation proposed by WFO and actual clinical decisions by oncologists in our cancer center, which would reflect the differences of cancer treatment between China and the U.S. PATIENTS AND METHODS: Retrospective data from 362 patients with cancer were ingested into WFO from April 2017 to October 2017. WFO recommendations were provided in three categories: recommended, for consideration, and not recommended. Concordance was analyzed by comparing the treatment decisions proposed by WFO with those of the multidisciplinary tumor board. Concordance was achieved when the oncologists' treatment decisions were in the recommended or for consideration categories in WFO. RESULTS: Ovarian cancer showed the highest concordance, which was 96%. Lung cancer and breast cancer obtained a concordance of slightly above 80%. The concordance of rectal cancer was 74%, whereas colon cancer and cervical cancer showed the same concordance of 64%. In particular, the concordance of gastric cancer was very low, only 12%, and 88% of cases were under physicians choice. CONCLUSION: Different cancer types showed different concordances, and only gastric cancers were significantly less likely to be concordant. Incidence and pharmaceuticals may be the major cause of discordance. To be comprehensively and rapidly applied in China, WFO needs to accelerate localization. ClinicalTrials.gov Identifier: NCT03400514. IMPLICATIONS FOR PRACTICE: IBM Watson for Oncology (WFO) has begun to be used in China. In this study, concordance was examined between the treatment recommendation proposed by WFO and clinical decisions for 362 patients in our cancer center, which could reflect the differences of cancer treatment between China and the U.S. Different cancer types showed different concordances, and only gastric cancers were significantly less likely to be concordant. Incidence and pharmaceuticals may be the major causes of discordance. To be comprehensively and rapidly applied in China, WFO needs to accelerate localization. This study may have a significant effect on application of artificial intelligence systems in China.