Synergizing the interaction of single nucleotide polymorphisms with dosiomics features to build a dual-omics model for the prediction of radiation pneumonitis.

OBJECTIVE: Radiation pneumonitis (RP) is the major dose-limiting toxicity of thoracic radiotherapy. This study aimed to developed a dual-omics (single nucleotide polymorphisms, SNP and dosiomics) prediction model for symptomatic RP. MATERIALS AND METHODS: The potential SNPs, which are of significant difference between the RP grade ≥ 3 group and the RP grade ≤ 1 group, were selected from the whole exome sequencing SNPs using the Fisher's exact test. Patients with lung cancer who received thoracic radiotherapy at our institution from 2009 to 2016 were enrolled for SNP selection and model construction. The factorization machine (FM) method was used to model the SNP epistasis effect, and to construct the RP prediction model (SNP-FM). The dosiomics features were extracted, and further selected using the minimum redundancy maximum relevance (mRMR) method. The selected dosiomics features were added to the SNP-FM model to construct the dual-omics model. RESULTS: For SNP screening, peripheral blood samples of 28 patients with RP grade ≥ 3 and the matched 28 patients with RP grade ≤ 1 were sequenced. 81 SNPs were of significant difference (P < 0.015) and considered as potential SNPs. In addition, 21 radiation toxicity related SNPs were also included. For model construction, 400 eligible patients (including 108 RP grade ≥ 2) were enrolled. Single SNP showed no strong correlation with RP. On the other hand, the SNP-SNP interaction (epistasis effect) of 19 SNPs were modeled by the FM method, and achieved an area under the curve (AUC) of 0.76 in the testing group. In addition, 4 dosiomics features were selected and added to the model, and increased the AUC to 0.81. CONCLUSIONS: A novel dual-omics model by synergizing the SNP epistasis effect with dosiomics features was developed. The enhanced the RP prediction suggested its promising clinical utility in identifying the patients with severe RP during thoracic radiotherapy.

Impact of different genetic mutations on granulocyte development and G-CSF responsiveness in congenital neutropenia.

ABSTRACT: Congenital neutropenia (CN) is a genetic disorder characterized by persistent or intermittent low peripheral neutrophil counts, thus increasing susceptibility to bacterial and fungal infections. Various forms of CN, caused by distinct genetic mutations, exhibit differential responses to granulocyte colony-stimulating factor (G-CSF) therapy, with the underlying mechanisms not fully understood. This study presents an in-depth comparative analysis of clinical and immunological features in 5 CN patient groups (severe congenital neutropenia [SCN]1, SCN3, cyclic neutropenia [CyN], warts, hypogammaglobulinaemia, infections and myelokathexis [WHIM], and Shwachman-Bodian-Diamond Syndrome [SBDS]) associated with mutations in ELANE, HAX1, CXCR4, and SBDS genes. Our analysis led to the identification of 11 novel mutations in ELANE and 1 each in HAX1, CXCR4, and G6PC3 genes. Investigating bone marrow (BM) granulopoiesis and blood absolute neutrophil count after G-CSF treatment, we found that SCN1 and SCN3 presented with severe early-stage disruption between the promyelocyte and myelocyte, leading to a poor response to G-CSF. In contrast, CyN, affected at the late polymorphonuclear stage of neutrophil development, showed a strong G-CSF response. WHIM, displaying normal neutrophil development, responded robustly to G-CSF, whereas SBDS, with moderate disruption from the early myeloblast stage, exhibited a moderate response. Notably, SCN1 uniquely impeded neutrophil development, whereas SCN3, CyN, WHIM, and SBDS also affected eosinophils and basophils. In addition, SCN1, SCN3, and CyN presented with elevated serum immunoglobulins, increased BM plasma cells, and higher A Proliferation-Inducing Ligand levels. Our study reveals a strong correlation between the stage and severity of granulocyte development disruption and the efficacy of G-CSF therapy.

Impact of age on long-term relative survival benefit of radiotherapy for early-stage grade I-II follicular lymphoma from the SEER database (2000-2015).

The aim of this study was to investigate the effect of age on long-term mortality and net survival benefit of radiotherapy (RT) for early-stage grade I-II FL. Five thousand three hundred and five patients with early-stage grade I-II FL in the SEER database (2000-2015) were identified. Primary therapy included RT alone (RT, 20.7%), chemotherapy alone (CT, 27.6%), combined modality therapy (CMT, 5.9%), and observation (45.8%). Inverse probability of treatment weighting (IPTW) was conducted to balance the treatment arms. Relative survival (RS), the standardized mortality ratio (SMR), and transformed Cox regression were used to compare survival differences between treatments. RT with or without CT had significantly higher 10-year OS (approximately 78%) and RS (>95%), but lower SMR (1.47-1.76), compared with CT (67.8%; 86.3%; 2.35; ps < .001), observation (70.2%; 91.2%; 1.82; ps < .05). RT was an independent predictor of better OS and RS in multivariate analyses (p < .001). No significant interaction between age and RT was identified for RS (Pinteraction = .509) or OS (Pinteraction = .769), indicating similar survival benefits across all-ages patients. RT was associated with long-term OS and net survival benefits in patients with early-stage grade I-II FL, irrespective of age.HighlightsThe pattern and incidence of mortality varied by age-group as elderly patients often die of other diseases other than FL beyond 5 years.Radiotherapy was associated with higher long-term OS/RS and better SMR compared with other approaches, regardless of age.

Surgery vs. radiotherapy in a population-based cohort of elderly patients with early-stage small-cell lung cancer: an IPTW propensity-score analysis.

Background: Due to the lack of treatment outcome data comparing surgical and non-surgical treatment modalities in the era of contemporary staging and treatments, the management of elderly patients with early-stage small cell lung cancer (SCLC) continues to be debated. This study sought to compare surgery and radiotherapy in elderly patients (aged ≥70 years) with early-stage SCLC using data from the Surveillance, Epidemiology, and End Results (SEER) database. Methods: The inverse probability of treatment weighting (IPTW) method was used to address the selection bias between the surgery and radiotherapy groups. The Kaplan-Meier method and multivariate Cox proportional hazards regression were used to compare the overall survival (OS) of the treatment cohorts before and after the IPTW adjustment. The competing risk survival analyses used Fine and Gray's method to compare the cancer-specific survival between the groups. Results: Between 2004 and 2018, 685 elderly patients received local treatment for early-stage SCLC. Of these patients, 193 patients (26.6%) received surgery and 492 patients (73.4%) received radiotherapy. Surgery was associated with a longer OS time than radiotherapy (median OS time: 32 vs. 20 months; 5-year OS time: 30.6% vs. 17.6%; P=0.002). The survival advantage of surgery was consistent in the IPTW-adjusted cohort (median OS time: 32 vs. 20 months; 5-year OS time: 30.6% vs. 17.6%; P<0.002). In the multivariate analysis, an increased age (P=0.001), stage T2 (P=0.047), radiotherapy (P<0.001), and no chemotherapy (P=0.034) were associated with unfavorable OS. In the IPTW-adjusted cohort, the multivariate analysis showed a decreased age (P<0.001), stage T1 (P=0.038), and surgery (P<0.001) were associated with superior OS. The competing risk analyses demonstrated that surgery produced a consistent decrease in the cancer-specific mortality rate compared to radiotherapy among the patients aged 70-80 years (53.6% vs. 61.0%, P=0.01), but no difference was observed in the 5-year cumulative incidence rate of cancer-related death between the surgery and radiotherapy groups (66.3% vs. 64.9%; P=0.66) in patients aged ≥80 years. Conclusions: In this population-based study of the optimal local treatment for elderly early-stage SCLC, patients who underwent surgery had superior OS compared to those who underwent radiotherapy.

Epigenetic activation of the TUSC3 gene as a potential therapy for XMEN disease.

BACKGROUND: X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus infection and N-linked glycosylation defect (XMEN) disease is a rare combined immunodeficiency caused by loss-of-function mutations in the magnesium transporter 1 (MAGT1) gene. MAGT1 deficiency impairs magnesium transport and the N-linked glycosylation of a panel of proteins, which subsequently abolishes the expression of key immune receptors such as natural killer group 2, member D (aka NKG2D). These effects induce immune system abnormalities, chronic Epstein-Barr virus infection, and neoplasia. Recent research shows that MAGT1 and tumor candidate suppressor 3 (TUSC3) share high sequence and functional similarity. OBJECTIVE: We sought to investigate the feasibility of activating TUSC3 expression to provide a potential therapeutic strategy for XMEN disease. METHODS: The expression profiles of MAGT1 and TUSC3 were analyzed using multiple databases, real-time quantitative PCR, and Western blot. The effects of decitabine and panobinostat on the regulation of TUSC3 expression were explored in both MAGT1 knockout (KO)/patient-derived lymphocytes and MAGT1 KO hepatocytes. RESULTS: Although TUSC3 is widely expressed, it is undetectable specifically in the immune system and liver, consistent with the main diseased tissues in patients with XMEN disease. CRISPR/Cas9-mediated KO of MAGT1 in the NKL cell line successfully mimicked the phenotypes of XMEN patient-derived lymphocytes, and exogenous expression of TUSC3 rescued the deficiencies in KO NKL cells. Using this in vitro model, we identified 2 epigenetic drugs, decitabine and panobinostat, by screening. Combination treatment using these 2 drugs significantly upregulated TUSC3 expression and rescued the immune and liver abnormalities. CONCLUSIONS: Epigenetic activation of TUSC3 expression constitutes an effective therapeutic strategy for XMEN disease.

Rapid diagnosis of Talaromyces marneffei infection by metagenomic next-generation sequencing technology in a Chinese cohort of inborn errors of immunity.

Talaromyces marneffei (T. marneffei) is an opportunistic pathogen. Patients with inborn errors of immunity (IEI) have been increasingly diagnosed with T. marneffei in recent years. The disseminated infection of T. marneffei can be life-threatening without timely and effective antifungal therapy. Rapid and accurate pathogenic microbiological diagnosis is particularly critical for these patients. A total of 505 patients with IEI were admitted to our hospital between January 2019 and June 2022, among whom T. marneffei was detected in 6 patients by metagenomic next-generation sequencing (mNGS), and their clinical and immunological characteristics were summarized. We performed a systematic literature review on T. marneffei infections with published immunodeficiency-related gene mutations. All patients in our cohort were confirmed to have genetic mutations in IL12RB1, IFNGR1, STAT1, STAT3, and CD40LG. T. marneffei was detected in both the blood and lymph nodes of P1 with IL12RB1 mutations, and the clinical manifestations were serious and included recurrent fever, weight loss, severe anemia, splenomegaly and lymphadenopathy, all requiring long-term antifungal therapy. These six patients received antifungal treatment, which relieved symptoms and improved imaging findings. Five patients survived, while one patient died of sepsis after hematopoietic stem cell transplantation. The application of mNGS methods for pathogen detection in IEI patients and comparison with traditional diagnosis methods were investigated. Traditional diagnostic methods and mNGS tests were performed simultaneously in 232 patients with IEI. Compared to the traditional methods, the sensitivity and specificity of mNGS in diagnosing T. marneffei infection were 100% and 98.7%, respectively. The reporting time for T. marneffei detection was approximately 26 hours by mNGS, 3-14 days by culture, and 6-11 days by histopathology. T. marneffei infection was first reported in IEI patients with IL12RB1 gene mutation, which expanded the IEI lineage susceptible to T. marneffei. For IEI patients with T. marneffei infection, we highlight the application of mNGS in pathogenic detection. mNGS is recommended as a front-line diagnostic test for rapidly identifying pathogens in complex and severe infections.

MiR-323a-3p acts as a tumor suppressor by suppressing FMR1 and predicts better esophageal squamous cell carcinoma outcome.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has unfavorable outcomes with the highest incidence seen in China. Accordingly, exploring effective molecular biomarkers is of great value. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression and modulate numerous biological processes in tumors. Our study aimed to identify prognostic miRNAs and investigate their role in ESCC. METHODS: Prognosis-related plasma miRNAs were detected by miRNA microarray and qRT-PCR. Functional assays and molecular mechanism studies were used to investigate the role of miRNA in ESCC. RESULTS: Over-expression of miR-323a-3p was associated with a favorable prognosis. MiR-323a-3p negatively regulated proliferation, migration, and invasion. Through biological predictions, the fragile X mental retardation 1 (FMR1) was found to be a potential target of miR-323a-3p. Further investigation revealed that miR-323a-3p directly targeted and suppressed FMR1. MiR-323a-3p and FMR1 mRNA, as well as miR-323a-3p and the FMR1-encoded protein FMRP, showed negative correlations. Luciferase activity of FMR1-3'-UTR, but not mutant counterparts, was decreased by mimic compared with that of the control. The compromised cell proliferation, migration, and invasion induced by transfection with miR-323a-3p mimic were rescued by transfection with a FMR1 expression plasmid. Tumors induced by miR-323a-3p overexpressed ESCC cells grew significantly slower in vivo and resulted in smaller tumor masses. Metastatic lung colonization was also inhibited by miR-323a-3p overexpression. CONCLUSIONS: MiR-323a-3p was significantly associated with survival and acted as a tumor suppressor by inhibiting proliferation, migration, and invasion via the regulation of FMR1. MiR-323a-3p is a promising biomarker and may be a potential therapeutic target.

Model to predict cause-specific mortality in patients with olfactory neuroblastoma: a competing risk analysis.

PURPOSE: The main objective of this study was to evaluate the cumulative incidence of cause-specific mortality and other causes of mortality for patients with olfactory neuroblastoma (ONB). The secondary aim was to model the probability of cause-specific death and build a competing risk nomogram to predict cause-specific mortality for this disease. METHODS: Patients with ONB from 1975 to 2016 were identified from the Surveillance, Epidemiology, and End Results database. We estimated the cumulative incidence function (CIF) for cause-specific mortality and other causes of mortality, and constructed the Fine and Gray's proportional subdistribution hazard model, as well as a competing-risk nomogram based on Fine and Gray's model, to predict the probability of cause-specific mortality for patients with ONB. RESULTS: After data selection, 826 cases were included for analysis. Five-year cumulative incidence of cause-specific mortality was 19.5% and cumulative incidence of other causes of mortality was 11.3%. Predictors of cause-specific mortality for ONB included tumor stage, surgery and chemotherapy. Age was most strongly predictive of other causes of mortality: patients aged > 60 years exhibited subdistribution hazard ratios of 1.063 (95 % confidence interval [CI] 1.05-1.08; p = 0.001). The competing risk nomogram for cause-specific mortality was well-calibrated, and had good discriminative ability (concordance index = 0.79). CONCLUSIONS: We calculated the CIF of cause-specific mortality and other causes of mortality in patients with the rare malignancy ONB. We also built the first competing risk nomogram to provide useful individualized predictive information for patients with ONB.

Development of a competing risk nomogram for the prediction of cause-specific mortality in patients with thymoma: a population-based analysis.

BACKGROUND: This study was developed to assess the odds of cause-specific mortality and other types of mortality in thymoma patients. In addition, these analyses were leveraged to develop a comprehensive competing risk model-based nomogram capable of predicting cause-specific mortality as a result of thymoma. METHODS: Thymoma patients included within the Surveillance, Epidemiology, and End Results (SEER) database from 2004-2016 were identified, and the odds of cause-specific mortality due to thymoma and other forms of mortality for these patients were estimated. In addition, Fine and Gray's proportional subdistribution hazard model was constructed, and a competing risk nomogram was developed using this model that was capable of predicting the odds of 3-, 5-, and 10-year cause-specific mortality in thymoma patients. RESULTS: In total, 1,591 relevant cases in the SEER database were selected for analysis. In this patient cohort, the respective 5-year cumulative incidence rates for cause-specific mortality and mortality attributable to other causes were 12.4% and 8.2%. Variables significantly associated with cause-specific mortality included age, chemotherapy, surgery, and Masaoka stage. Additionally, the odds of other-cause-specific mortality rose with increasing patient age, and chemotherapy was correlated with other-cause-specific mortality. The competing risk nomogram that was developed exhibited good discriminative ability as a means of predicting cause-specific mortality, as evidenced by a concordance index (C-index) value of 0.84. Calibration curves further revealed excellent consistency between predicted and actual mortality when using this nomogram. CONCLUSIONS: In summary, we herein assessed the odds of cause-specific and other-cause-specific mortality among thymoma patients, and we designed a novel nomogram capable of predicting cause-specific mortality for thymoma, providing a promising tool that may be of value in the context of individualized patient prognostic evaluation.

The miR-4306/IGF2R axis modulates the lung adenocarcinoma response to irradiation in vitro and in vivo.

BACKGROUND: Lung adenocarcinoma accounts for more than 50% of non-small cell lung cancers. Dysregulated microRNAs (miRNAs) and coding genes play a critical role in lung adenocarcinoma irradiation resistance and might be promising therapeutic targets. In the present study, we demonstrate the effect of the miR-4306/IGF2R axis on malignant behaviors of lung adenocarcinoma cells and the response to irradiation. METHODS: Quantitative realtime-PCR and Western blot assays were applied for miR-4306 and IGF2R expression in tumors and cells. A CCK-8 assay kit was used to detect cell viability. Colony formation assay was implied to detect cell proliferation. Transwell assay was used to detect cell invasion. A subcutaneous tumor model was performed in nude mice to detect tumor formation in vivo. Hematoxylin & eosin (H&E) staining were used to observe pathological status of tumor in nude mice. To validate the miR-4306 binding IGF2R 3'-UTR, a dual-luciferase reporter assay was performed. RESULTS: The expression level of miR-4306 was dramatically upregulated in lung adenocarcinoma samples and cells, and could be induced by irradiation in a dose-dependent manner. In lung adenocarcinoma cells, miR-4306 overexpression significantly promoted cell viability and invasive abilities and attenuated the inhibitory effect of irradiation on malignant cancer cell behaviors. In a subcutaneous tumor model in nude mice, miR-4306 overexpression promoted tumor growth and attenuated the suppressive effect of irradiation on tumor growth. miR-4306 directly inhibited the expression of IGF2R. In lung adenocarcinoma cells without irradiation, IGF2R overexpression was inhibited, while IGF2R knockdown promoted cell viability and invasive abilities. The effects of miR-4306 overexpression were partially attenuated by IGF2R overexpression. In lung adenocarcinoma cells, suppressive role of irradiation on cancer cell viability and invasive abilities were enhanced by IGF2R overexpression, but attenuated by IGF2R knockdown. The effects of miR-4306 overexpression on cancer cell viability and invasive abilities were also partially attenuated by IGF2R overexpression in lung adenocarcinoma cells with irradiation. In tissue samples, expression of miR-4306 and IGF2R were negatively correlated. CONCLUSIONS: The miR-4306/IGF2R axis could significantly affect lung adenocarcinoma progression and response to radiotherapy, and further investigation of the clinical implications of this axis is strongly recommended.

Development and Application of Rapid Clinical Visualization Molecular Diagnostic Technology for Cryptococcus neoformans/C. gattii Based on Recombinase Polymerase Amplification Combined With a Lateral Flow Strip.

Cryptococcus neoformans (C. neoformans)/C. gattii can easily invade the human central nervous system and cause cryptococcal meningitis (CM). The clinical fatality rate of these fungi is extremely high and causes more than 180,000 deaths worldwide every year. At present, the common clinical identification methods of these fungi are traditional culture methods and Indian ink staining. In addition, enzyme-linked immunosorbent assay (ELISAs), polymerase chain reaction (PCR), real-time quantitative PCR detecting system (qPCR), mass spectrometry, and metagenomic next-generation sequencing (mNGS) have also been applied to detect these fungus. Due to the rapid progress of meningitis caused by C. neoformans/C. gattii infection, there is a desperate need for fast, sensitive, and on-site detection methods to meet the clinical diagnosis. Recombinase polymerase amplification (RPA) is a promising isothermal amplification technique that can compensate for the shortcomings of the above techniques, featuring short reaction time, high specificity, and high sensitivity, thus meeting the demand for in-field detection of C.neoformans/C. gattii. In our study, RPA- lateral flow strip (LFS) was used to amplify the capsule-associated gene, CAP64, of C. neoformans/C. gattii, and the primer-probe design was optimized by introducing base mismatches to obtain a specific and sensitive primer-probe combination for clinical testing, and specificity of the detection system was determined for 26 common clinical pathogens. This system was developed to obtain results in 20 min at an isothermal temperature of 37°C with a lower limit of detection as low as 10 CFU/µL or 1 fg/µL. A total of 487 clinical samples collected from multicenter multiplexes were tested to evaluate the detection performance of the RPA-LFS system, which revealed that the system could specifically detect C. neoformans/C. gattii, meeting the need for rapid, specific, and sensitive detection.

Case Report: Clinical and Immunological Features of a Chinese Cohort With Mycoplasma-Induced Rash and Mucositis.

Dermatological disorders are the most common extrapulmonary complications of Mycoplasma pneumoniae, of which Mycoplasma-induced rash and mucositis (MIRM) has recently been proposed to be a separate diagnostic entity. MIRM could easily be misdiagnosed as atypical Stevens-Johnson syndrome by clinicians due to the unawareness of this rare disease. We retrospectively reviewed the inpatient database from Jan. 2016 to Dec. 2019 of the Children's Hospital of Fudan University. In total, five patients (mean age 5.5 years, three male) matched the diagnostic criteria of MIRM. All patients had scattered lesions and more than two sites of mucosal involvement. The serum IgA level of three patients was higher than normal. Two patients had a significant decrease in peripheral blood CD3+ T and CD4+ T cells that improved with recovery. The percentage of TCRαß+ CD4-CD8-T cells of Patient five was higher than normal. All patients received treatments with antibiotics and corticosteroids, 3 patients received intravenous immunoglobulin. Among five patients, three patients complained of dyspigmentation, and two patients had an uneventful recovery. MIRM is a separate entity with predominant mucosal involvement and excellent prognosis that more often affects younger patients. Excessive inflammatory reactions may lead to immune disorders, including lymphopenia and a redistribution of CD4+ T cells. We recommend that pneumonia accompanied by mucocutaneous eruptions, especially in young patients, should raise clinical suspicion of MIRM.

Efficacy and safety of concurrent chemoradiotherapy in ECOG 2 patients with locally advanced non-small-cell lung cancer: a subgroup analysis of a randomized phase III trial.

BACKGROUND: There is no consensus on the therapeutic approach to ECOG 2 patients with locally advanced non-small-cell lung cancer (LA-NSCLC), despite the sizable percentage of these patients in clinical practice. This study focused on the efficacy, toxicity and the optimal chemotherapy regimen of CCRT in ECOG 2 patients in a phase III trial. METHODS: Patients capable of all self-care with bed rest for less than 50% of daytime were classified as ECOG 2 subgroup. A subgroup analysis was performed for ECOG 2 patients recruited in the phase III trial receiving concurrent EP (etoposide + cisplatin)/PC (paclitaxel + carboplatin) chemotherapy with intensity-modulated radiation therapy (IMRT) or three-dimensional conformal external beam radiation therapy (3D-CRT). RESULTS: A total of 71 ECOG 2 patients were enrolled into the study. Forty-six (64.8%) patients were treated with IMRT technique. The median overall survival (OS) and progression free survival (PFS) for ECOG 2 patients were 16.4 months and 9 months, respectively. No difference was observed in treatment compliance and toxicities between ECOG 2 patients and ECOG 0-1 patients. Within the ECOG 2 group (31 in the EP arm and 40 in the PC arm), median OS and 3-year OS were 15.7 months and 37.5% for the EP arm, and 16.8 months and 7.5% for the PC arm, respectively (p = 0.243). The incidence of grade ≥ 3 radiation pneumonitis was higher in the PC arm (17.5% vs. 0.0%, p = 0.014) with 5 radiation pneumonitis related deaths, while the incidence of grade 3 esophagitis was numerically higher in the EP arm (25.8% vs. 10.0%, p = 0.078). CONCLUSIONS: CCRT provided ECOG 2 patients promising outcome with acceptable toxicities. EP might be superior to PC in terms of safety profile in the setting of CCRT for ECOG 2 patients. Prospective randomized studies based on IMRT technique are warranted to validate our findings. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT01494558. (Registered 19 December 2011).

The Role of Prophylactic Cranial Irradiation in Patients With Non-small Cell Lung Cancer: An Updated Systematic Review and Meta-Analysis.

Background: The purpose of this study was to reevaluate the efficacy of prophylactic cranial irradiation (PCI) in non-small cell lung cancer (NSCLC) with the most recent published data and to identify subgroups who may be more likely to gain benefit from PCI. Methods: We searched PubMed, Embase, and Cochrane databases for randomized trials comparing PCI with non-PCI in NSCLC patients. We pooled the data of randomized controlled trials and compared brain metastasis (BM) and overall survival (OS) between PCI group and non-PCI group. Results: Seven studies including 1,462 patients were eligible for the current meta-analysis. Compared to non-PCI group, PCI group achieved decreased BM (RR = 0.37, 95% CI: 0.26-0.52) but similar OS (HR = 1.01, 95% CI: 0.87-1.22). In subgroup analyses of BM, PCI decreased BM for subgroups by pathology (squamous cell carcinoma or non-squamous cell carcinoma) and local treatment modality (surgery or no surgery). However, PCI failed to reduce BM for patients with poor performance status (WHO 2-3). The incidence of PCI related toxicities was low and PCI was well-tolerated by the majority of NSCLC. Low grade neurocognitive function (NCF) decline was reported in NAVLT study and greater deterioration in immediate and delayed recall was reported in RTOG 0214. No significant difference in quality of life (QOL) after PCI was reported. Conclusion: PCI reduces the incidence of BM except for patients with poor performance status. However, PCI fails to prolong OS significantly for NSCLC. An individual patient data meta-analysis may identify patients that could achieve OS prolongation with PCI.

Effect of Concurrent Chemoradiation With Celecoxib vs Concurrent Chemoradiation Alone on Survival Among Patients With Non-Small Cell Lung Cancer With and Without Cyclooxygenase 2 Genetic Variants: A Phase 2 Randomized Clinical Trial.

Importance: Treatment of locally advanced non-small cell lung cancer (NSCLC) remains challenging. The rationale of combining a cyclooxygenase 2 (COX-2) inhibitor with concurrent chemoradiation (CCRT) was based on results of preclinical research and prospective clinical studies; however, no randomized clinical trial has provided evidence of a direct comparison with CCRT alone. Objective: To determine the effect of combined selective COX-2 inhibition with standard CCRT on survival among patients with unresectable stage III NSCLC. Design, Setting, and Participants: A single-center, open-label, randomized phase 2 clinical trial was performed among 96 patients who had histologically and cytologically confirmed unresectable stage III NSCLC. Participants were enrolled from November 2011 to August 2015. Data were analyzed from February to October 2018. Intervention: Patients were randomized to receive thoracic radiation, 60 Gy, for 6 weeks concurrent with etoposide and cisplatin or the same regimen of CCRT combined with 200 mg of celecoxib, taken twice daily. Main Outcomes and Measures: The primary end point was overall survival. The secondary end points were the proportion of patients with treatment-related toxic effects, progression-free survival, and overall survival in subgroups with and without the COX-2 genotype. Results: A total of 100 patients were randomized. Following the exclusion of 4 outliers, 96 participants (96.0%) were analyzed (51 randomized to CCRT alone and 45 randomized to CCRT with celecoxib; mean [SD] age, 60.0 [8.3] years; 73.0 [76.0%] male). The median overall survival time was 32.8 (95% CI, 17.0-48.5) months in the group that received CCRT with celecoxib and 35.5 (95% CI, 25.8-45.2) months in the group that received CCRT alone (P = .88). Celecoxib with CCRT was well tolerated; the incidence of symptomatic radiation pneumonitis was 6.6% (95% CI, 1.4%-18.0%) in the group that received CCRT with celecoxib and 11.8% (95% CI, 4.4%-23.9%) in the group that received CCRT alone (P = .49). Among patients with the high-risk genotype, celecoxib plus CCRT was not associated with higher progression-free survival (hazard ratio, 0.36; 95% CI, 0.13-1.04; P = .05) or overall survival (hazard ratio, 0.50; 95% CI, 0.15-1.72; P = .26) compared with CCRT alone. Conclusions and Relevance: In unresectable stage III NSCLC, adding celecoxib to concurrent chemoradiation did not improve survival. A smaller, not statistically significant proportion of patients in the CCRT with celecoxib group compared with the CCRT alone group developed symptomatic radiation pneumonitis. Among patients with the high-risk genotype, adding celecoxib to CCRT did not improve overall or progression-free survival. Trial Registration: ClinicalTrials.gov identifier: NCT01503385.

Increased CYFRA 21-1, CEA and NSE are Prognostic of Poor Outcome for Locally Advanced Squamous Cell Carcinoma in Lung: A Nomogram and Recursive Partitioning Risk Stratification Analysis.

OBJECTIVES: This study aimed to: (1) assess the prognostic significance of serum tumor markers in locally advanced squamous cell carcinoma in lung (LA-SCCL); (2) generate a nomogram to predict the overall survival (OS) and (3) identify a prognostic stratification to assist the therapeutic decision-making. METHODS: LA-SCCL patients receiving definitive radiotherapy and baseline tumor marker measurement were eligible for this retrospective study. Cox proportional hazards regression was used to determine independent factors associated with various survival indexes and a nomogram was created to estimate the 5-year OS probability for individual patient. The identified prognostic factors were recruited into a recursive partitioning analysis (RPA) for OS to stratify patients with distinct outcome. RESULTS: A total of 224 patients were eligible for analysis. Increased cytokeratin-19 fragment (CYFRA 21-1) was independently associated with inferior OS, progression free survival (PFS) and a borderline decreased local-regional progression free survival (LRPFS). Elevated carcino-embryonic antigen (CEA) served as an unfavorable determinant for OS and increased neuron-specific enolase (NSE) was predictive of poor distant metastasis free survival (DMFS). A nomogram integrating KPS, TNM stage, CEA and CYFRA 21-1 was created, resulting in a c-index of 0.62. RPA identified 4 prognostic classifications, with median OS of 27.6, 19.9, 17.3 and 10.9 months for low, intermediate, high and very-high risk groups, respectively. CONCLUSIONS: Baseline tumor marker panel including CYFRA 21-1, CEA and NSE can be prognostic of outcome for LA-SCCL receiving definitive radiotherapy. The RPA identified four prognostic subgroups, which could assist personalized therapy and clinical trial design in LA-SCCL.

MicroRNA-29c functions as a tumor suppressor by targeting VEGFA in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LAD) is considered to be a highly aggressive disease with heterogeneous prognosis and the molecular mechanisms underlying tumor progression remain elusive. Growing evidence demonstrates that the dysregulation of microRNAs (miRNAs) plays an important role in various tumor processes. The aim of this study is to discover prognostic miRNA and investigate its role involved in progression of LAD. METHODS: Prognosis related miRNA was detected by miRNA microarray using formalin-fixed paraffin-embedded (FFPE) specimens from 87 patients with IIIA-N2 LAD. The cell proliferation was evaluated by Cell Titer 96 AQueous One Solution Cell Proliferation Assay (MTS), and the migration/invasion was evaluated by transwell assay. The bioinformatics methods and luciferase reporter assay were applied to detect the relationship between miRNA and its target. The mRNA and protein levels of miRNA target were determined by quantitative real time polymerase chain reaction (qRT-PCR) analysis, western blot and enzyme-linked immunosorbent assay (ELISA). Changes of angiogenesis induced by miRNA was evaluated by human umbilical vein endothelial cell (HUVEC) tube formation assay. Immunohistochemistry (IHC) analysis was performed in FFPE specimens of patients to evaluate the correlation between miR-29c with microvessel density (MVD) and vascular endothelial growth factor A (VEGFA) expression. RESULTS: MiR-29c expression downregulation was significantly associated with unfavorable prognosis in IIIA-N2 LAD. MiR-29c inhibited cell proliferation, migration and invasion in cell lines. Integrated analysis revealed that VEGFA was a direct target of miR-29c. MiR-29c reduced the capability of tumor cells to promote HUVEC tube formation. The compromised cell proliferation, migration/invasion and angiogenesis induced by miR-29c mimic transfection were reversed by transfection of VEGFA expression plasmid. Furthermore, the correlation of miR-29c with MVD and VEGFA was confirmed in patients' samples. CONCLUSIONS: MiR-29c acts as a tumor suppressor by targeting VEGFA and may represent a promising prognostic biomarker as well as a potential therapeutic target for LAD.

MicroRNA-Related Polymorphisms in PI3K/Akt/mTOR Pathway Genes Are Predictive of Limited-Disease Small Cell Lung Cancer Treatment Outcomes.

The phosphoinositide-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays an important role in cancer progression and treatment, including that of small cell lung cancer (SCLC), a disease with traditionally poor prognosis. Given the regulatory role of microRNA (miRNA) in gene expression, we examined the association of single nucleotide polymorphisms (SNPs) at miRNA-binding sites of genes in the mTOR pathway with the prognosis of patients with limited-disease SCLC. A retrospective study was conducted of 146 patients with limited-disease SCLC treated with chemoradiotherapy. Nine SNPs of six mTOR pathway genes were genotyped using blood samples. Cox proportional hazard regression modeling and recursive partitioning analysis were performed to identify SNPs significantly associated with overall survival. Three SNPs, MTOR: rs2536 (T>C), PIK3R1: rs3756668 (A>G), and PIK3R1: rs12755 (A>C), were associated with longer overall survival. Recursive partitioning analysis based on unfavorable genotype combinations of the rs2536 and rs3756668 SNPs classified patients into three risk subgroups and was internally validated with 1000 bootstrap samples. These findings suggest that miRNA-related polymorphisms in the PI3K/Akt/mTOR pathway may be valuable biomarkers to complement clinicopathological variables in predicting prognosis of limited-disease SCLC and to facilitate selection of patients likely to benefit from chemoradiotherapy.

Flectobacillus pallidus sp. nov., isolated from a freshwater spring.

A novel bacterial strain, MVW-6T, was isolated from a freshwater spring in Taiwan and characterized using a polyphasic taxonomy approach. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain MVW-6T belonged to the genus Flectobacillus and showed the highest levels of sequence similarity to Flectobacillus lacus CL-GP79T (98.2 % 16S rRNA gene sequence similarity) and Flectobacillus fontis MIB-4T (97.4 %). Cells of strain MVW-6T were Gram-stain-negative, aerobic, non-motile rods that were covered by large capsules and formed light pink colonies. Growth occurred at 15-37 °C (optimum 15-25 °C), at pH 5-9 (optimum pH 7) and with 0-0.5 % (w/v) NaCl (optimum 0 %). Strain MVW-6T contained iso-C15 : 0, summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c), C16 : 1ω5c and C16 : 0 as the predominant fatty acids. The polar lipid profile consisted of phosphatidylethanolamine, five unidentified aminophospholipids, one unidentified glycolipid, one unidentified phospholipid, one unidentified aminolipid and two unidentified lipids. The major isoprenoid quinone was MK-7. The G+C content of the genomic DNA was 39.5 mol%. DNA-DNA hybridization values for strain MVW-6T with Flectobacillus lacus CL-GP79T and Flectobacillus fontis MIB-4T were less than 50 %. On the basis of the phylogenetic inference and phenotypic data, strain MVW-6T a novel species of the genus Flectobacillus, for which the name Flectobacillus pallidus sp. nov. is proposed. The type strain is MVW-6T (=BCRC 80975T=LMG 29555T=KCTC 33800T).

Intensity-Modulated Radiation Therapy May Improve Local-Regional Tumor Control for Locally Advanced Non-Small Cell Lung Cancer Compared With Three-Dimensional Conformal Radiation Therapy.

BACKGROUND: Consistent results are lacking as regards the comparative effectiveness of intensity-modulated radiotherapy (IMRT) versus three-dimensional conformal radiotherapy (3DCRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). PATIENTS AND METHODS: Patients treated with definitive radiotherapy (RT) between 2002 and 2010 were retrospectively reviewed. Overall survival (OS), local-regional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) were compared among patients irradiated with different techniques. The association between RT technique and survival indexes was assessed in a Cox proportional hazard regression model. Propensity score matching (PSM) was used to balance known confounding factors. RESULTS: A total of 652 patients were eligible for analysis, including 206 with 3DCRT and 446 with IMRT. The median OS of the 3DCRT and IMRT groups were 19.4 and 23.3 months, with the 5-year rate of 13% and 19%, respectively (p = .043). Multivariate analysis identified IMRT as an independent favorable factor associated with LRPFS and DMFS. PSM analysis further verified the beneficial effect of IMRT on LRPFS. No difference in OS or PFS was observed between the two techniques. Subgroup analysis revealed that IMRT might be differentially more effective in both OS and LRPFS among patients who were female, nonsmokers, with adenocarcinoma, or without weight loss. There was a significant reduction of lung toxicity and similar esophagus toxicity in the IMRT group when compared with the 3DCRT group. CONCLUSION: IMRT may confer superior LRPFS and comparable OS than can be achieved with 3DCRT in LA-NSCLC, along with the reduction of pulmonary toxicity. IMPLICATIONS FOR PRACTICE: Based on the largest number of patients from a single institution, the present study demonstrated that intensity-modulated radiotherapy (IMRT) could provide superior local-regional progression-free survival and similar overall survival compared with the traditional three-dimensional conformal radiotherapy (3DCRT) for stage III non-small cell lung cancer (NSCLC). IMRT was also found to be associated with the significantly decreased incidence of pulmonary toxicity. These results suggest that IMRT should be considered a surrogate for 3DCRT in locally advanced NSCLC and might be the preferred option for a female nonsmoker with adenocarcinoma and a potentially high risk of pulmonary toxicity from radiotherapy.