Comprehensive Analysis and Experimental Validation of FOXD2 as a Novel Potential Prognostic Biomarker Associated with Immune Infiltration in Head and Neck Squamous Cell Carcinoma.

BACKGROUND: The role of Forkhead Box D2 (FOXD2) in head and neck squamous cell carcinoma (HNSC) has never been studied. OBJECT: Our object was to explore the role of FOXD2 in HNSC. METHODS: Clinical data for patients with HNSC was obtained from TCGA. Our study examined the atypical expression of FOXD2 in both HNSC and pan-cancer, along with its diagnostic and prognostic implications, as well as the association between FOXD2 expression and clinical characteristics, immune infiltration, immune checkpoint genes, and MSI. Gene set enrichment analysis (GESA) was used to investigate the potential regulation network of FOXD2 in HNSC. We analyze the genomic alterations of FOXD2 in HNSC. GSE13397 and qRT-PCR were used for the validation of FOXD2 expression. RESULTS: FOXD2 was aberrantly expressed in 24 tumors. FOXD2 was significantly up-regulated in HNSC compared to normal head and neck tissue (p < 0.001). High FOXD2 expression was associated with the histologic grade of the patient with HNSC (p < 0.001), lymphovascular infiltration (p = 0.002) and lymph node neck dissection (p = 0.002). In HNSC, an autonomous correlation between FOXD2 expression and OS was observed (HR: 1.36; 95% CI: 1.04-1.78; p = 0.026). FOXD2 was associated with the neuronal system, neuroactive ligand-receptor interaction, and retinoblastoma gene in cancer. FOXD2 was associated with immune infiltration, immune checkpoints, and MSI. The somatic mutation rate of FOXD2 in HNSC was 0.2%. FOXD2 was significantly up-regulated in HNSC cell lines. CONCLUSION: Our findings suggest that FOXD2 has the potential to serve as a prognostic biomarker and immunotherapeutic target for individuals with HNSC.

Identification of PANoptosis-related predictors for prognosis and tumor microenvironment by multiomics analysis in glioma.

PANoptosis is a newly described inflammatory programmed cell death, that highlights coordination between pyroptosis, apoptosis and necroptosis. However, the functions of PANoptosis-related genes in glioma progression still remain to be explored. This study aims to identify PANoptosis-related predictors that may be utilized for prognosis prediction and development of new therapeutic targets. Firstly, bulk and single-cell RNA-seq (scRNA-seq) data of glioma patients were extracted from TCGA, CGGA and GEO database. Genetic analysis indicates a considerably high mutation frequency of PANoptosis-related genes (PANRGs) in glioma. Consensus clustering was applied to reveal different subtypes of glioma based on PANRGs. Two PANoptosis subtypes with distinct prognostic and TME characteristics were identified. Then, with LASSO-Cox regression analysis, four PANoptosis-related predictors (MYBL2, TUBA1C, C21orf62 and KCNIP2) were determined from bulk and scRNA-seq analysis. Predictive PANRG score model was established with these predictors and its correlation with tumor microenvironment (TME) was investigated. The results showed that patients with low PANRG score, had higher infiltration of anti-tumor immune cells, higher MSI score and lower TIDE score, which are more likely to benefit from immunotherapy. Further analysis identified 16 potential drugs associated with PANoptosis-related predictors. Moreover, the expression levels of four PANoptosis-related predictors were examined in clinical samples and the results were consistent with those analyzed in the database. Besides, we also confirmed the biological functions of two oncogenic predictors (MYBL2 and TUBA1C) by cell experiments, which revealed that knockdown of MYBL2 or TUBA1C could significantly inhibit the proliferation and migration of glioma cells. These findings highlight the prognostic value and biological functions of PANRGs in glioma, which may provide valuable insights for individualized treatment.

Geriatric nutritional risk index as a predictor of prognosis in hematologic malignancies: a systematic review and meta-analysis.

Objective: Recent studies have reported inconsistent results regarding the association between geriatric nutritional risk index (GNRI) and clinical outcomes in patients with hematologic malignancies (HMs). We performed a meta-analysis to evaluate the effect of low GNRI on the overall survival (OS) and progression-free survival (PFS) in patients with HMs. Research Methods and Procedures: We conducted the research via PubMed, Embase, and Cochrane Library databases to identify trials. Exploring the association between GNRI and prognosis in patients with HMs. A meta-analysis of OS and PFS was performed. Quality In Prognostic Studies instrument and Newcastle-Ottawa quality assessment Scale were used to assess the quality of included trials. Results: Fourteen studies enrolling 3,524 patients with HMs were included. Low GNRI was associated with shorter OS (Hazard ratio (HR) = 1.77; 95% CI = 1.44-2.18, p < 0.01) and PFS (HR = 1.63; 95% CI = 1.17-2.27, p < 0.01) in patients with HMs. In the subgroup analysis, GNRI was not significantly associated with prognosis in Chinese patients with HMs (OS, HR =1.33; 95% CI = 0.89-1.98, p = 0.16; PFS, HR = 1.70; 95% CI = 0.72-4.01, p = 0.23). For the subgroup with a GNRI cutoff value less than 98, there was no significant difference in PFS (HR = 1.34; 95% CI = 0.98-1.83, p = 0.06). Conclusion: Low GNRI negatively impacted on the prognosis in patients with HMs. Prospective studies to identify the best cut-off value for GNRI are required.

Circ_0087378 intensifies the malignant behavior of non-small cell lung cancer cells in vitro by facilitating DDR1 via sponging miR-199a-5p.

Background: Circular RNA hsa_circ_0087378 (circ_0087378) has been found to have different functions in different cancer types. However, its function in non-small cell lung cancer (NSCLC) remains unclear. This study revealed the effect of circ_0087378 on the malignant behavior of NSCLC cells in vitro to broaden the options for NSCLC treatment. Methods: This study detected the expression of circ_0087378 in NSCLC cells via real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The discoidin domain receptor 1 (DDR1) protein in NSCLC cells was investigated through western blot. The influence of circ_0087378 on the malignant behavior of NSCLC cells in vitro was investigated by cell counting kit-8 assay, colony formation assay, Transwell assay, and flow cytometry. Dual-luciferase reporter gene assay and RNA pull-down assay were performed to verify the binding between two genes. Results: Circ_0087378 was abundantly expressed in NSCLC cells. The loss of circ_0087378 repressed the proliferation, colony formation, migration, invasion, but enhanced the apoptosis in NSCLC cells in vitro. Circ_0087378 could repress microRNA-199a-5p (miR-199a-5p) by acting as a sponge. The loss of miR-199a-5p abrogated the inhibition of circ_0087378 loss on the malignant phenotype of NSCLC cells in vitro. DDR1 was directly repressed via miR-199a-5p. DDR1 counteracted the repressive role of miR-199a-5p on the malignant behavior of NSCLC cells in vitro. Conclusions: Circ_0087378 promotes the malignant behavior of NSCLC cells in vitro by facilitating DDR1 via sponging miR-199a-5p. It may be a promising target for treatment.

Predictive Impact of Prognostic Nutritional Index in Patients with Cancer Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

A few previous studies have investigated the prognostic value of the prognostic nutritional index (PNI) in patients treated with immune checkpoint inhibitors (ICIs); however, the results are inconsistent. Therefore, this study aimed to clarify the prognostic significance of PNI. The PubMed, Embase, and Cochrane Library databases were searched. A meta-analysis of the impact of PNI on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and rate of adverse events (AEs) in patients treated with ICIs was performed. Twenty-three studies involving 2,386 patients were included. Low PNI was associated with significantly poor OS (hazard ratio [HR] = 2.26, 95% confidence interval [CI]: 1.81-2.82, P < .001) and short PFS (HR = 1.75, 95% CI: 1.54-1.99, P < .001). Patients with low PNI tended to have a low ORR (odds ratio [OR] = 0.47, 95% CI: 0.34-0.65, P < .001) and DCR (OR = 0.43, 95% CI: 0.34-0.56, P < .001). However, the subgroup analysis demonstrated no significant association between PNI and survival time in patients receiving a programmed death ligand-1 inhibitor. PNI was significantly associated with survival time and treatment efficacy in patients treated with ICIs.

Long-Term Outcomes of Nasopharyngeal Carcinoma by Epstein-Barr Virus Status in the Chinese Population: A Multicenter Investigation.

Background: Because the vast majority of nasopharyngeal carcinoma (NPC) in Chinese patients is a direct result of Epstein-Barr virus (EBV) infection, there is a dearth of data for EBV-negative patients in this population. This multicenter study sought to examine the clinical characteristics of EBV-negative patients and compare long-term outcomes with a propensity-matched (1:1.5) EBV-positive cohort. Methods: NPC patients with known EBV status from four hospitals were collated (2013-2021). A logistic regression model was conducted to evaluate the relationship between patient characteristics and EBV status. The Kaplan-Meier method and Cox regression analysis were used to analyze survival data. Results: This study analyzed 48 (40%) EBV-negative and 72 (60%) EBV-positive patients. The median follow-up time was 63.5 months. Most EBV-negative NPC patients (77.1%) were diagnosed in advanced stages with a higher rate (87.5%) of positive lymph node disease, and no significant prognostic factors were discerned in this subpopulation. The EBV-negative disease was more associated with the keratinizing subtype (18.8% vs. 1.4%, p < 0.05). Compared to EBV-negative NPC patients, EBV-positive NPC patients were more likely to develop a local recurrence (9.7% vs. 0%, p = 0.026). There was no statistical difference in mortality (EBV-negative vs. EBV- positive, 8.3% vs. 4.2%, p = 0.34) during the follow-up period. Although the median PFS and median OS were not reached, the 3-year PFS rate was 68.8% vs. 70.8% (EBV-negative vs. EBV-positive, p = 0.06), the 3-year OS rate was 70.8% vs. 76.4% (EBV-negative vs. EBV-positive, p = 0.464), the 5-year PFS rate was 56.3% vs. 50% (EBV-negative vs. EBV-positive, p = 0.451), and the 5-year OS rate was 56.3% vs. 58.3% (EBV-negative vs. EBV-positive, p = 0.051), respectively. These data show that EBV-positive NPC patients seem to have a tendency to gain better survival compared with EBV-negative NPC patients. Conclusions: Most of the EBV-negative patients were in the middle and late stages at the time of diagnosis and were more associated with the keratinizing subtype. EBV status may be associated with prognosis in NPC. EBV positivity seems to be associated with better survival in NPC patients. Still, due to the small cohort of patients and the short observation period for a number of patients, further work is required to corroborate these conclusions.

FOXK1 regulates epithelial-mesenchymal transition and radiation sensitivity in nasopharyngeal carcinoma via the JAK/STAT3 signaling pathway.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is the most common head and neck tumor in China. Forkhead box (FOX) proteins have 19 subfamilies, which can maintain cell metabolism, regulate cell cycle and cell growth, etc. FOXK1 is a member of the FOX family, and studies have found that FOXK1 is closely related to tumors. OBJECTIVE: This experiment aims to study the effects of FOXK1 interference on proliferation, apoptosis, invasion, epithelial-mesenchymal transition (EMT), and radiosensitivity, by regulating the Janus kinas/signal translator and activator of the transfer 3 (JAK/STAT3) pathway. METHODS: The expression of FOXK1 was detected via immunohistochemistry using clinical nasopharyngeal carcinoma tissues and adjacent tissues. The relationship between FOXK1 expression and tumor stage was subsequently evaluated. The colony formation rate was calculated through the colony formation experiment. Cell apoptosis and cell cycle distribution were detected using flow cytometry, while cell invasion was detected using the Transwell method. The number of cells in the nucleus of each group after 30 min, 4 h, and 24 h of radiotherapy with the 2 Gy dose was counted using immunofluorescence under γ-H2AX focal points of a laser confocal microscope. RESULTS: FOXK1 is clearly expressed in the patients' cancer tissues. The expression of FOXK1 was significantly correlated with the patient's sex. FOXK1 interference or Peficitinib can upregulate the apoptosis rate of 5-8 F and CNE-2 cells; increase the G2 phase of cells; and inhibit the invasion, migration, and EMT of cells. At the same time, FOXK1 interference can downregulate the protein expression of p-JAK1, p-JAK2, and p-STAT3 in cells. Interference from FOXK1 or Peficitinib alone can reduce the rate of cell colony formation under different radiation doses, and enhance the green fluorescence intensity of γ-H2AX in the nucleus after 4 and 24 h of the 2 Gy dose of radiotherapy. These results are optimal when FOXK1 interference and Peficitinib are used together. CONCLUSION: FOXK1 interference in NPC cells can regulate EMT through the JAK/STAT3 signal pathway, enhance the radiosensitivity of cells, and thus inhibit tumor cell progression.

Optimizing induction chemotherapy regimens for radiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: The optimal number of cycles of induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LANPC) remains unresolved. This study aimed to quantitatively assess the changes in gross tumor volumes (GTVs) and to select the most optimal number of IC cycles. METHODS: We analyzed 54 patients who received a three-cycle IC before commencing radiotherapy, with the tumor and nodal responses assessed by a CT scan before IC and after each IC cycle. The gross tumor volumes of the nasopharynx primary lesion (GTV_T), involved retropharyngeal lymph node (GTV_RP), and involved cervical lymph node (GTV_N) were contoured on each scan. The volume change following each IC cycle was evaluated with Wilcoxon signed-rank test. The three-dimensional vector displacements of target centers were also calculated and compared. RESULTS: The volume reductions of GTVs following IC varied across different patients and showed different trends for the three GTV types. GTV_T and GTV_RP did not display further volume reduction after two IC cycles, whereas GTV_N showed monotonic volume decreases. For GTV_T and GTV_RP following the three IC cycles, the total volume reduction relative to the initial volume before IC was 12.0%, 22.5%, and 20.1% and 26.0%, 44.1%, and 42.2%, respectively. In contrast, for GTV_N, continuing volume reduction was observed with a total reduction of 25.3%, 43.2%, and 54.7% following the three cycles, and the reductions were all significant. Average displacements of the GTVs were <1.5 mm in all directions; their average three-dimensional displacements were 2.6, 4.0, and 1.7 mm, respectively. Acceptable toxicity was observed in most patients. CONCLUSION: This study supports two cycles of IC before radiotherapy for patients with LANPC if the initial metastatic cervical lymph node volume is not dominating. Otherwise, three cycles of IC is recommended to further reduce the cervical node volume.

Exploration of prognostic biomarkers in head and neck squamous cell carcinoma microenvironment from TCGA database.

Background: Immune checkpoint blockade (ICB) therapies have redefined human cancer treatment, including for head and neck squamous cell carcinoma (HNSCC). However, clinical responses to various immune checkpoint inhibitors are often accompanied by immune-related adverse events (irAEs). Therefore, it is crucial to obtain a comprehensive understanding of the association between different immune tumor microenvironments (TMEs) and the immunotherapeutic response. Methods: The research data were obtained from The Cancer Genome Atlas (TCGA) database. We applied RNA-seq genomic data from tumor biopsies to assess the immune TME in HNSCC. As the TME is a heterogeneous system that is highly associated with HNSCC progression and clinical outcome, we relied on the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm to calculate immune and stromal scores that were evaluated based on the immune or stromal components in the TME. Then, the Tumor Immune Dysfunction and Exclusion algorithm (TIDE) was used to predict the benefits of ICB to each patient. Finally, we identified specific prognostic tumor-infiltrating immune cells (TIICs) by quantifying the cellular composition of the immune response in HNSCC and its association to survival outcome, using the CIBERSORT algorithm. Results: Utilizing the HNSCC cohort of the TCGA database and TIDE and ESTIMATE algorithm-derived immune scores, we obtained a list of microenvironment-associated lncRNAs that predicted different clinical outcomes in HNSCC patients. We validated these correlations in a different HNSCC cohort available from the TCGA database and provided insight into the prediction of response to ICB therapies in HNSCC. Conclusions: This study confirmed that CD8+ T cells were significantly associated with better survival in HNSCC and verified that the top five significantly mutated genes (SMGs) in the TCGA HNSCC cohort were TP53, TTN, FAT1, CDKN2A, and MUC16. A high level of CD8+ T cells and high immune and stroma scores corresponded to a better survival probability in HNSCC.

Notoginsenoside R1 induces oxidative stress and modulates LPS induced immune microenvironment of nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant tumor with high incidence. Notoginsenoside R1 (NGR1) is the main active compound of total Panax notoginseng saponin, and has multiple anti-tumor effects. This study aimed to investigate the effect and mechanism of NGR1 in NPC. MATERIALS: NPC cells were treated with different doses of NGR1. The NGR1 function in NPC was evaluated using Cell Counting Kit-8, Transwell, Western blot, flow cytometry, immunofluorescence assay, and quantitative real-time PCR. Meanwhile, the NGR1 mechanism in NPC was assessed by rescue experiments. Furthermore, the NGR1 function in vivo was determined by constructing an NPC xenotransplantation model, TUNEL, and immunohistochemistry assays. RESULTS: NGR1 repressed NPC cell growth and invasion but facilitated NPC cell apoptosis and oxidative stress. Also, NGR1 alleviated inflammation in NPC cells. Mechanistically, NGR1 restrained NPC cell growth and induced oxidative stress in NPC cells, while these effects were abolished after lipopolysaccharide (an activator of the TRAF6/NF-κB pathway) treatment, implying that NGR1 reduced NPC cell growth and induced oxidative stress in NPC cells by the inactivation of TRAF6/NF-κB axis. Moreover, in vivo studies further proved the palliative effect of NGR1 on NPC. CONCLUSION: NGR1 inhibited NPC cell growth and induced oxidative stress in NPC cells by inactivating TRAF6/NF-κB axis.

HIF­1α and MBP1 are associated with the progression of breast cancer cells by repressing ß­catenin transcription.

Breast cancer (BC) is a common type of tumor. Numerous patients are diagnosed and treated in the early stages of the disease; however, the recurrence rate remains high. Therefore, identifying sensitive and specific tumor markers to prevent and treat BC is essential. c­Myc promoter binding protein 1 (MBP1) is a regulatory molecule located in the cell nucleus. It targets and regulates the expression of various cell proliferation­, apoptosis­ and tumor­associated genes. MBP1 expression in BC tissues was detected using immunohistochemistry and further validated in BC and normal human cell lines using RT­qPCR and western blot analysis. Low MBP1 expression, in clinical samples of BC, was associated with a poor prognosis of BC (n=50). MBP1 overexpression effectively inhibited the growth and metastasis of xenograft tumors in vivo. Cell counting kit­8 assays confirmed that the proliferation of the BC cell lines was significantly increased following knockdown of MBP1 expression, while overexpression of MBP1 could significantly inhibit the proliferation of the BC cell lines. Mechanistically, a dual­luciferase assay was used to confirm that MBP1 was the key transcriptional regulator of ß­catenin. In addition, MBP1 transcription and hypoxia­inducible factor (HIF­1α) induction were associated. By regulating the hypoxic microenvironmental state in the MDA231 and MCF7 cell lines, it was demonstrated that MBP1 served as a hypoxia­responsive factor and could be a new target for tumor therapy. Taken together, these results suggested that MBP1, as a potential tumor marker associated with prognosis of BC and may serve as a therapeutic target for BC. Moreover, MBP1 plays a critical role in inhibiting the growth and progression of BC cell lines.

Lymph node metastasis as the initial symptom of a germ cell tumor in an adult: A case report.

RATIONALE: Germ cell tumors in the head and neck are very rare. In cases of germ cell tumors, it is uncommon for lymph node metastasis to be the only and initial symptom, and this can easily lead to a misdiagnosis. Herein, we report about a 28-year-old woman with lymph node metastasis, in whom a primary tumor appeared in the nasal cavity. PATIENT CONCERNS: A 28-year-old woman presented with enlarged left submandibular lymph nodes. No other mass was found on whole-body screening using positron emission tomography-computed tomography. DIAGNOSIS: After partial submandibular lymphadenectomy was performed, histopathological and immunohistochemical examinations revealed a metastatic germ cell tumor. However, it was difficult to further classify and affirm the origin. INTERVENTIONS: As the patient was receiving four cycles of bleomycin, etoposide, and cisplatin chemotherapy, a primary tumor emerged in the nasal cavity, which was finally confirmed as an immature teratoma of a high World Health Organization histological grade and Norris grade 3. This tumor was found to contain similar components to lymph nodes with respect to histopathological and immunohistochemical characteristics, especially the immature neural tubes or nervous tissue in the nasal cavity. Fortunately, the patient recovered well with no signs of relapse, and the size of residual lymph nodes remained unchanged after she received another four cycles of bleomycin, etoposide, and cisplatin chemotherapy and two cycles of doxorubicin and ifosfamide (AI) chemotherapy. OUTCOMES: Unfortunately, 11 months later, during the coronavirus disease pandemic, the patient died owing to respiratory failure and pulmonary infection. CONCLUSIONS: In cases of malignant tumor in the submandibular lymph nodes of adults, the metastasis of a germ cell tumor should be considered an important differential diagnosis even if a primary tumor does not emerge. In this case, adequate postoperative chemotherapy is necessary.

Pretreatment Body Mass Index (BMI) as an Independent Prognostic Factor in Nasopharyngeal Carcinoma Survival: A Systematic Review and Meta-Analysis.

We performed a meta-analysis to investigate the association between pretreatment body mass index (BMI) and prognosis of nasopharyngeal carcinoma (NPC). Case-control and cohort studies were searched from PubMed, Web of Science, EMBASE, and CNKI databases. Pooled hazard ratios (HR) with 95% confidence intervals (CI) for overall survival (OS) or distant metastasis-free survival (DMSF) were used to estimate the prognostic value. Bias in the included studies was evaluated using funnel plots. The results showed that compared with normal weight patients, the estimated HR of OS was 1.54 (95% CI: 1.25-1.90; P < 0.05) for underweight, 0.63 (95% CI: 0.48-0.83; P < 0.05) for overweight, and 0.67 (95% CI: 0.41-1.08; P = 0.102) obese patients. We also found that compared with normal-weight patients, the estimated HR of DMFS was 1.63 (95% CI: 1.38-1.92; P < 0.05) for underweight, 0.83 (95% CI: 0.61-1.13; P = 0.244) for overweight, and 0.60 (95% CI: 0.39-0.92; P < 0.05) for patients with obesity. BMI is an independent prognostic factor for NPC survival. Being underweight before treatment was associated with poorer OS and DMFS in patients with NPC. Neither overweight nor obesity before treatment has an unfavorable effect on NPC survival.

Corrigendum: The Regulators Associated With N6-Methyladenosine in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma Reveal New Clinical and Prognostic Markers.

[This corrects the article DOI: 10.3389/fcell.2021.741521.].

Efficacy and safety of apatinib combined with whole-brain radiation therapy with a simultaneous integrated boost for brain metastases from non-small cell lung cancer: a multicenter retrospective study.

Background: Brain metastases (BMs) develop in 20-65% of non-small cell lung cancer (NSCLC) patients and are associated with a poor prognosis. Apatinib, a tyrosine kinase inhibitor (TKI) that selectively inhibits the vascular endothelial growth factor receptor 2, is safe and significantly prolongs the survival of chemotherapy-refractory gastric cancer patients. This retrospective study evaluated the safety and efficacy of apatinib combined with concurrent brain radiotherapy in NSCLC patients with BMs. Methods: This trial enrolled patients with non-recurrent BM from histologically-confirmed NSCLC without any limits regarding the BM size/quantity. Eligibility criteria were patients 18-75 years old with measurable BM from histologically-confirmed NSCLC (including both newly-diagnosed and previously treated NSCLC) and expected survival time greater than 3 months. Oral apatinib (500 or 250 mg/day) was started within 1 week prior to commencing whole brain radiotherapy with simultaneous integrated boost (WBRT-SIB) and continued until one week after radiotherapy completion. In addition to toxicities, analyzed outcomes included intracranial overall response rate (iORR), intracranial disease control rate (iDCR), intracranial progression free survival (iPFS), and overall survival (OS). Results: From July 2016 to January 2020, 16 patients were enrolled in this retrospective study. After 3 months of brain radiotherapy, the iORR was 75%, the iDCR was 100%, and the brain edema index (EI) was significantly reduced compared to that before brain radiation therapy (4.2 vs. 1.9; P=0.02). The median iPFS was 16.5 months [95% confidence interval (CI): 15.1-37.4 months]. The median OS was 26 months (95% CI: 17.0-54.0 months). Most of the patients tolerated apatinib well, but 7 patients had side effects, most commonly grade 1 or 2. Only 2 patients experienced grade 3 adverse events (hypertension and oral mucositis), and no grade 4 or 5 toxicities were observed. Conclusions: Apatinib combined with WBRT-SIB appears to be safe and effective in treating BMs in NSCLC patients.

A pilot study of function-based radiation therapy planning for lung cancer using hyperpolarized xenon-129 ventilation MRI.

PURPOSE: Radiation-induced lung injury (RILI) is a common side effect in patients with non-small cell lung cancer (NSCLC) treated with radiotherapy. Minimizing irradiation into highly functional areas of the lung may reduce the occurrence of RILI. The aim of this study is to evaluate the feasibility and utility of hyperpolarized xenon-129 magnetic resonance imaging (MRI), an imaging tool for evaluation of the pulmonary function, to guide radiotherapy planning. METHODS: Ten locally advanced NSCLC patients were recruited. Each patient underwent a simulation computed tomography (CT) scan and hyperpolarized xenon-129 MRI, then received 64 Gyin 32 fractions for radiotherapy. Clinical contours were drawn on CT. Lung regions with good ventilation were contoured based on the MRI. Two intensity-modulated radiation therapy plans were made for each patient: an anatomic plan (Plan-A) based on CT alone and a function-based plan (Plan-F) based on CT and MRI results. Compared to Plan-A, Plan-F was generated with two additional steps: (1) beam angles were carefully chosen to minimize direct radiation entering well-ventilated areas, and (2) additional optimization criteria were applied to well-ventilated areas to minimize dose exposure. V20Gy , V10Gy , V5Gy , and the mean dose in the lung were compared between the two plans. RESULTS: Plan-A and Plan-F were both clinically acceptable and met similar target coverage and organ-at-risk constraints (p > 0.05) except for the ventilated lungs. Compared with Plan-A, V5Gy (Plan-A: 30.7 ± 11.0%, Plan-F: 27.2 ± 9.3%), V10Gy (Plan-A: 22.0 ± 8.6%, Plan-F: 19.3 ± 7.0%), and V20Gy (Plan-A: 12.5 ± 5.6%, Plan-F: 11.0 ± 4.1%) for well-ventilated lung areas were significantly reduced in Plan-F (p < 0.05). CONCLUSION: In this pilot study, function-based radiotherapy planning using hyperpolarized xenon-129 MRI is demonstrated to be feasible in 10 patients with NSCLC with the potential to reduce radiation exposure in well-ventilated areas of the lung defined by hyperpolarized xenon-129 MRI.

Chinese expert consensus on intestinal microecology and management of digestive tract complications related to tumor treatment (version 2022).

The human gut microbiota represents a complex ecosystem that is composed of bacteria, fungi, viruses, and archaea. It affects many physiological functions including metabolism, inflammation, and the immune response. The gut microbiota also plays a role in preventing infection. Chemotherapy disrupts an organism's microbiome, increasing the risk of microbial invasive infection; therefore, restoring the gut microbiota composition is one potential strategy to reduce this risk. The gut microbiome can develop colonization resistance, in which pathogenic bacteria and other competing microorganisms are destroyed through attacks on bacterial cell walls by bacteriocins, antimicrobial peptides, and other proteins produced by symbiotic bacteria. There is also a direct way. For example, Escherichia coli colonized in the human body competes with pathogenic Escherichia coli 0157 for proline, which shows that symbiotic bacteria compete with pathogens for resources and niches, thus improving the host's ability to resist pathogenic bacteria. Increased attention has been given to the impact of microecological changes in the digestive tract on tumor treatment. After 2019, the global pandemic of novel coronavirus disease 2019 (COVID-19), the development of novel tumor-targeting drugs, immune checkpoint inhibitors, and the increased prevalence of antimicrobial resistance have posed serious challenges and threats to public health. Currently, it is becoming increasingly important to manage the adverse effects and complications after chemotherapy. Gastrointestinal reactions are a common clinical presentation in patients with solid and hematologic tumors after chemotherapy, which increases the treatment risks of patients and affects treatment efficacy and prognosis. Gastrointestinal symptoms after chemotherapy range from nausea, vomiting, and anorexia to severe oral and intestinal mucositis, abdominal pain, diarrhea, and constipation, which are often closely associated with the dose and toxicity of chemotherapeutic drugs. It is particularly important to profile the gastrointestinal microecological flora and monitor the impact of antibiotics in older patients, low immune function, neutropenia, and bone marrow suppression, especially in complex clinical situations involving special pathogenic microbial infections (such as clostridioides difficile, multidrug-resistant Escherichia coli, carbapenem-resistant bacteria, and norovirus).

The Regulators Associated With N6-Methyladenosine in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma Reveal New Clinical and Prognostic Markers.

N6-methyladenosine (m6A) methylation is of significant importance in the initiation and progression of tumors, but how specific genes take effect in different lung cancers still needs to be explored. The aim of this study is to analyze the correlation between the m6A RNA methylation regulators and the occurrence and development of lung cancer. The data of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were obtained through the TCGA database. We systematically analyzed the related pathological characteristics and prognostic factors by applying univariate and multivariate Cox regression, as well as LASSO Cox regression. Some of 23 m6A regulators are identified as having high expression in lung cancer. In addition, risk score has been shown to be an independent prognostic factor in lung cancer. Our research not only fully reveals that m6A regulators and clinical pathological characteristics are potentially useful with respect to survival and prognosis in different lung tumors but also can lay a theoretical root for the treatment for lung cancer-notably, to point out a new direction for the development of treatment.

Meta-analysis and indirect treatment comparison of modified FOLFIRINOX and gemcitabine plus nab-paclitaxel as first-line chemotherapy in advanced pancreatic cancer.

BACKGROUND: Modified FOLFIRINOX and gemcitabine plus nab-paclitaxel (GEM-NAB) have been recommended as first-line therapies for advanced pancreatic cancer (PC). Due to the lack of evidence to directly compare them, we conducted this network meta-analysis to indirectly compare the effectiveness and toxicity of modified FOLFIRINOX and GEM-NAB. METHODS: The eligible retrospective studies on treatments related to modified FOLFIRINOX and GEM-NAB up to 4 April 2020 were searched and assessed. We used the frequentist model to analyze the survival and toxicity data between different treatments. Pooled analysis for overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and events of toxicity were analyzed in this study. RESULTS: Twenty-two studies were involved in this network meta-analysis. The comparisons on OS and PFS showed that modified FOLFIRINOX and GEM-NAB had similar treatment efficacy (OS: 1.13; 95% CI: 0.78-1.63; PFS: HR: 1.19; 95% CI: 0.85-1.67). GEM-NAB was more effective than modified FOLFIRINOX based on the result of ORR (RR: 1.43; 95% CI: 1.04-1.96). Moreover, our analysis showed a similar toxicity profile between modified FOLFIRINOX and GEM-NAB. CONCLUSIONS: The current evidence showed that modified FOLFIRINOX and GEM-NAB were similar in survival and toxicity. Many factors should be considered for in the formulation of optimal treatment, and our meta-analysis could provide some guidance to treatment selection in the first-line setting for advanced PC.

MET Amplification Attenuates Lung Tumor Response to Immunotherapy by Inhibiting STING.

Immune checkpoint blockade (ICB) has revolutionized cancer therapy. However, the response of patients to ICB is difficult to predict. Here, we examined 81 patients with lung cancer under ICB treatment and found that patients with MET amplification were resistant to ICB and had a poor progression-free survival. Tumors with MET amplifications had significantly decreased STING levels and antitumor T-cell infiltration. Furthermore, we performed deep single-cell RNA sequencing on more than 20,000 single immune cells and identified an immunosuppressive signature with increased subsets of XIST- and CD96-positive exhausted natural killer (NK) cells and decreased CD8+ T-cell and NK-cell populations in patients with MET amplification. Mechanistically, we found that oncogenic MET signaling induces phosphorylation of UPF1 and downregulates tumor cell STING expression via modulation of the 3'-UTR length of STING by UPF1. Decreased efficiency of ICB by MET amplification can be overcome by inhibiting MET. SIGNIFICANCE: We suggest that the combination of MET inhibitor together with ICB will overcome ICB resistance induced by MET amplification. Our report reveals much-needed information that will benefit the treatment of patients with primary MET amplification or EGFR-tyrosine kinase inhibitor resistant-related MET amplification.This article is highlighted in the In This Issue feature, p. 2659.