Physical performance and plasma metabolic profile as potential prognostic factors in metastatic lung cancer patients.

BACKGROUND: Low physical performance is associated with higher mortality rate in multiple pathological conditions. Here, we aimed to determine whether body composition and physical performance could be prognostic factors in non-small cell lung cancer (NSCLC) patients. Moreover, we performed an exploratory approach to determine whether plasma samples from NSCLC patients could directly affect metabolic and structural phenotypes in primary muscle cells. METHODS: This prospective cohort study included 55 metastatic NSCLC patients and seven age-matched control subjects. Assessments included physical performance, body composition, quality of life and overall survival rate. Plasma samples from a sub cohort of 18 patients were collected for exploratory studies in cell culture and metabolomic analysis. RESULTS: We observed a higher survival rate in NSCLC patients with high performance in the timed up-and-go (+320%; p = .007), sit-to-stand (+256%; p = .01) and six-minute walking (+323%; p = .002) tests when compared to NSCLC patients with low physical performance. There was no significant association for similar analysis with body composition measurements (p > .05). Primary human myotubes incubated with plasma from NSCLC patients with low physical performance had impaired oxygen consumption rate (-54.2%; p < .0001) and cell proliferation (-44.9%; p = .007). An unbiased metabolomic analysis revealed a list of specific metabolites differentially expressed in the plasma of NSCLC patients with low physical performance. CONCLUSION: These novel findings indicate that physical performance is a prognostic factor for overall survival in NSCLC patients and provide novel insights into circulating factors that could impair skeletal muscle metabolism.

Diagnostic potential of protein serum biomarkers for distinguishing small and non-small cell lung cancer in patients with suspicious lung lesions.

BACKGROUND: Biomarkers play a role in identifying, managing, and predicting cancer outcomes. In lung cancer, they are used at various time points. Doubts remain regarding their accuracy for differential diagnosis and histological subtyping. A diagnostic test study was conducted. It included malignant lesions and controls with benign lesions. Before lung biopsy, all patients had the following biomarkers measured in serum (Pro-GRP,NSE,CYFRA21-1,SCC-Ag,CEA). METHODS: The predictive capacity of serum biomarkers was evaluated to discriminate between lung cancer and benign pathology. The accuracy was also assessed for distinguishing between SCLC and NSCLC and explored their ability to perform histological subtyping. RESULTS: 93 patients were included, 60 with lung cancer, 33 with benign pathology. Pro-GRP and NSE were elevated in SCLC compared with NSCLC or nonmalignant disease. The most accurate for differentiating between malignant and benign pathology were CEA and CYFRA21-1. Pro-GRP had a poor predictive capacity for distinguishing NSCLC from SCLC. However, combined with CEA and CYFRA21-1, performance improved. For SCLC, the diagnostic capacity of Pro-GRP increased by combining with biomarkers, such as NSE/CYFRA21-1. CONCLUSIONS: Biomarkers lacked the sensitivity and specificity for independent differential diagnosis or histological subtyping. However, the observed patterns in biomarker levels associated with specific histological subtypes suggest potential utility in a multi-biomarker approach or in conjunction with other diagnostic tools. This insight could guide future research to improve diagnostic accuracy and personalized treatment strategies in lung cancer.

Biomarkers are crucial for identifying, managing, and predicting outcomes in lung cancer, though they lack accuracy in differentiating histological subtypes.CEA and CYFRA21-1 were the most accurate biomarkers for distinguishing between malignant and benign pathology.Pro-GRP and NSE levels were elevated in SCLC compared to NSCLC. Pro-GRP alone had poor predictive capacity for differentiating NSCLC from SCLC, but combining it with CEA and CYFRA21-1 improved diagnostic performance.Patterns in biomarker levels suggest that a multi-biomarker approach, especially when combined with other diagnostic tools, could improve diagnostic accuracy.

Variation of peripheral blood-based biomarkers for response of anti-PD-1 immunotherapy in non-small-cell lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) for non-small-cell lung cancer (NSCLC) are on the rise, but unfortunately, only a small percentage of patients benefit from them in the long term. Thus, it is crucial to identify biomarkers that can forecast the efficacy of immunotherapy. METHODS: We retrospectively studied 224 patients with NSCLC who underwent anti-PD-1 therapy. The role of biomarkers and clinical characteristics were assessed in a prognostic model. RESULTS: Only 14.3% of patients had both programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB) outcomes, highlighting the need to investigate more available biomarkers. Our analysis found a correlation between histological PD-L1 TPS and hematological PD-1 expression. Analysis of hematological biomarkers revealed that elevated expression of CD4/CD8 and LYM% are positively associated with effective immunotherapy, while PD-1+ on T cells, NLR, and MLR have a negative impact. Moreover, high level of ΔCEA%, CYFRA21-1 and LDH may suggest ineffective ICIs. We also observed that disparate immunotherapy drugs didn't significantly impact prognosis. Lastly, by comparing squamous carcinoma and adenocarcinoma cohorts, ΔCEA%, CD3+PD-1+, CD4+PD-1+, and CD4/CD8 are more important in predicting the prognosis of adenocarcinoma patients, while age is more significant for squamous carcinoma patients. CONCLUSION: Our research has yielded encouraging results in identifying a correlation between immunotherapy's response and clinical characteristics, peripheral immune cell subsets, and biochemical and immunological biomarkers. The screened hematological detection panel could be used to forecast an NSCLC patient's response to anti-PD-1 immunotherapy with an accuracy rate of 76.3%, which could help customize suitable therapeutic decision-making.

Circulating serum exosomes i-tRF-AspGTC and tRF-1-SerCGA as diagnostic indicators for non-small cell lung cancer.

BACKGROUND: tRF-RNA-a representative of non-coding RNA (ncRNA)-is a precursor or fragment of mature tRNA and plays a crucial regulatory role in the occurrence and development of cancer. There is currently little research on tRF-RNA as a diagnostic marker in cancer, especially for NSCLC from serum exosomes. METHOD: Serum exosomes were successfully extracted from serum; their physical morphology was captured by transmission electron microscopy (TEM); appropriate particle size detection was performed using qNano; surface labeling was verified through western blotting. Serum exosomes i-tRF-AspGTC and tRF-1-SerCGA were selected through gene microarray, and qPCR was used to validate their significance in 242 patients and 201 healthy individuals. The area under the curve (AUC) was used to evaluate the diagnostic indicators of non-small cell lung cancer (NSCLC). RESULT: Compared with 201 healthy individuals, i-tRF-AspGTC and tRF-1-SerCGA were significantly downregulated in 242 NSCLC patients and 95 early-stage patients. For tRF-AspGTC and tRF-1-SerCGA, the predictive diagnostic efficiency rates of AUC were 0.690 and 0.680, respectively, whereas the early diagnostic efficiency rates were 0.656 and 0.688, respectively. The result of combined diagnosis with CEA and CYFRA21-1 was 0.928, and the early diagnostic efficiency was 0.843, which is a very high biological predictive factor for NSCLC. CONCLUSION: The expression of serum exosomes i-tRF-AspGTC and tRF-1-SerCGA was significantly downregulated in NSCLC patients. These exosomes could be used as predictive indicators for diagnosis or early diagnosis of NSCLC.

Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy.

Although the majority of patients with metastatic non-small-cell lung cancer (mNSCLC) lacking a detectable targetable mutation will receive pembrolizumab-based therapy in the frontline setting, predicting which patients will experience a durable clinical benefit (DCB) remains challenging. MATERIALS AND METHODS: Patients with mNSCLC receiving pembrolizumab monotherapy or in combination with chemotherapy underwent a 74-gene next-generation sequencing panel on blood samples obtained at baseline and at 9 weeks. The change in circulating tumor DNA levels on-therapy (molecular response) was quantified using a ratio calculation with response defined by a > 50% decrease in mean variant allele fraction. Patient response was assessed using RECIST 1.1; DCB was defined as complete or partial response or stable disease that lasted > 6 months. Progression-free survival and overall survival were recorded. RESULTS: Among 67 patients, 51 (76.1%) had > 1 variant detected at a variant allele fraction > 0.3% and thus were eligible for calculation of molecular response from paired baseline and 9-week samples. Molecular response values were significantly lower in patients with an objective radiologic response (log mean 1.25% v 27.7%, P < .001). Patients achieving a DCB had significantly lower molecular response values compared to patients with no durable benefit (log mean 3.5% v 49.4%, P < .001). Molecular responders had significantly longer progression-free survival (hazard ratio, 0.25; 95% CI, 0.13 to 0.50) and overall survival (hazard ratio, 0.27; 95% CI, 0.12 to 0.64) compared with molecular nonresponders. CONCLUSION: Molecular response assessment using circulating tumor DNA may serve as a noninvasive, on-therapy predictor of response to pembrolizumab-based therapy in addition to standard of care imaging in mNSCLC. This strategy requires validation in independent prospective studies.

Impact of detecting plasma EGFR mutations with ultrasensitive liquid biopsy in outcomes of NSCLC patients treated with first- or second-generation EGFR-TKIs.

BACKGROUND: Few trials have evaluated the utility of liquid biopsies to detect epidermal growth factor receptor mutations (EGFRm) at the time of response evaluation and its association with the clinical characteristics and outcomes of non-small-cell lung cancer (NSCLC) patients. OBJECTIVE: This study aimed to evaluate, in a real-world clinical setting, the prevalence of plasma EGFRm and its association with the clinical characteristics, response and survival outcomes of NSCLC patients under treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). METHODS: This observational study enrolled advanced or metastatic NSCLC patients, with confirmed tumor EGFRm, receiving treatment with first- or second-generation EGFR-TKIs. Blood samples for the detection of plasma EGFRm were collected at the time of response evaluation and processed using the Target Selector™ assay. The main outcomes were the detection rate of plasma EGFRm, median Progression-Free Survival (PFS) and Overall Survival (OS) according to plasma EGFR mutational status. RESULTS: Of 84 patients, 50 (59.5%) had an EGFRm detected in plasma. After a median follow-up of 21.1 months, 63 patients (75%) had disease progression. The detection rate of plasma EGFRm was significantly higher in patients with disease progression than in patients with partial response or stable disease (68.3% versus 33.3%; P< 0.01). PFS and OS were significantly longer in patients without plasma EGFRm than among patients with plasma EGFRm (14.3 months [95% CI, 9.25-19.39] vs 11.0 months [95% CI, 8.61-13.46]; P= 0.034) and (67.8 months [95% CI, 39.80-95.94] vs 32.0 months [95% CI, 17.12-46.93]; P= 0.006), respectively. A positive finding in LB was associated with the presence of ⩾ 3 more metastatic sites (P= 0.028), elevated serum carcinoembryonic (CEA) at disease progression (P= 0.015), and an increase in CEA with respect to baseline levels (P= 0.038). CONCLUSIONS: In NSCLC patients receiving EGFR-TKIs, the detection of plasma EGFRm at the time of tumor response evaluation is associated with poor clinical outcomes.

Comprehensive assessment of multiple tryptophan metabolites as potential biomarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer.

PURPOSE: Tryptophan metabolites have immunomodulatory functions, suggesting possible roles in cancer immunity. METHODS: Plasma tryptophan metabolites were measured using liquid chromatography/mass spectrometry before immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). RESULTS: The 19 patients with NSCLC had significantly lower levels of tryptophan (p = 0.002) and xanthurenic acid (p = 0.032), and a significantly higher level of 3-hydroxyanthranilic acid (3-HAA) (p = 0.028) compared with the 10 healthy volunteers. The patients achieving objective responses had significantly lower levels of 3-HAA than those who did not (p = 0.045). Receiver operating characteristic analyses determined that the cutoff value of 3-HAA for objective response was 35.4 pmol/mL (sensitivity: 87.5% and specificity: 83.3%). The patients with 3-HAA < 35.4 pmol/mL had significantly longer median progression-free survival (7.0 months) than those without (1.6 months, p = 0.022). CONCLUSIONS: Tryptophan metabolites may have a potential for predicting the efficacy of ICIs. REGISTRATION NUMBER: University Hospital Medical Information Network Clinical Trial Registry 000026140.

Next-generation sequencing of circulating tumor DNA for metastatic non-small cell lung cancer: a discussion on its implementation in the Brazilian clinical practice.

The objective of this review is to address the barriers limiting access to next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) for metastatic nonsquamous non-small cell lung cancer in Brazil and to propose its implementation in practice. A selected panel of lung cancer experts was provided with relevant prompts to address at a conference; a paper was then compiled on the topic. The authors propose specific and realistic recommendations for implementing access to ctDNA NGS. Further, the authors address all barriers and impediments mentioned within this review. There is a great need to increase ctDNA NGS for cancer care in Brazil. Adapting the current cancer testing framework is essential to expanding the use of this tool.

Identifying predictive biomarkers of CIMAvaxEGF success in non-small cell lung cancer patients.

BACKGROUND: Immunosenescence biomarkers and peripheral blood parameters are evaluated separately as possible predictive markers of immunotherapy. Here, we illustrate the use of a causal inference model to identify predictive biomarkers of CIMAvaxEGF success in the treatment of Non-Small Cell Lung Cancer Patients. METHODS: Data from a controlled clinical trial evaluating the effect of CIMAvax-EGF were analyzed retrospectively, following a causal inference approach. Pre-treatment potential predictive biomarkers included basal serum EGF concentration, peripheral blood parameters and immunosenescence biomarkers. The proportion of CD8 + CD28- T cells, CD4+ and CD8+ T cells, CD4/CD8 ratio and CD19+ B cells. The 33 patients with complete information were included. The predictive causal information (PCI) was calculated for all possible models. The model with a minimum number of predictors, but with high prediction accuracy (PCI > 0.7) was selected. Good, rare and poor responder patients were identified using the predictive probability of treatment success. RESULTS: The mean of PCI increased from 0.486, when only one predictor is considered, to 0.98 using the multivariate approach with all predictors. The model considering the proportion of CD4+ T cell, basal Epidermal Growth Factor (EGF) concentration, neutrophil to lymphocyte ratio, Monocytes, and Neutrophils as predictors were selected (PCI > 0.74). Patients predicted as good responders according to the pre-treatment biomarkers values treated with CIMAvax-EGF had a significant higher observed survival compared with the control group (p = 0.03). No difference was observed for bad responders. CONCLUSIONS: Peripheral blood parameters and immunosenescence biomarkers together with basal EGF concentration in serum resulted in good predictors of the CIMAvax-EGF success in advanced NSCLC. Future research should explore molecular and genetic profile as biomarkers for CIMAvax-EGF and it combination with immune-checkpoint inhibitors. The study illustrates the application of a new methodology, based on causal inference, to evaluate multivariate pre-treatment predictors. The multivariate approach allows realistic predictions of the clinical benefit of patients and should be introduced in daily clinical practice.

Dynamic evaluation of neutrophil-to-lymphocyte ratio as prognostic factor in stage III non-small cell lung cancer treated with chemoradiotherapy.

PURPOSE: Locally advanced non-small cell lung cancer (LA-NSCLC) is frequently treated with chemoradiotherapy (CRT). Despite the efforts, long-term outcomes are poor, and novel therapies have been introduced to improve results. Biomarkers are needed to detect early treatment failure and plan future follow-up and therapies. Our aim is to evaluate the role of dynamics of neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced NSCLC treated with CRT. METHODS: We retrospectively reviewed patients diagnosed with LA-NSCLC receiving definitive CRT at our center from 2010 to 2015. Baseline and post-treatment NLR were collected from our center database. NLR was dichotomized (threshold = 4) and patients were divided into two groups based on the variation from baseline to post-treatment NLR. The prognostic role and association with response were examined with logistic regression and multivariate Cox regression model, respectively. RESULTS: Ninety-two patients were included. Our analysis shows that NLR after treatment is associated with response to treatment [OR in the multivariate analysis 4.94 (1.01-24.48); p value = 0.048]. Furthermore, NLR and ECOG are independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Specifically, PFS was 25.79 months for the good prognosis group and 12.09 for the poor prognosis group [HR 2.98 (CI 95% = 1.74-5.10), p < 0.001]; and OS was 42.94 months and 18.86 months, respectively [HR 2.81 (CI 95% = 1.62-4.90), p < 0.001]. CONCLUSION: Dynamics of NLR have a prognostic value in stage III NSCLC treated with definitive CRT. Pre- and post-CRT NLR should be evaluated in prospective clinical trials involving consolidation treatment with immunotherapy.

Pretreatment plasma fibrinogen level as a prognostic biomarker for patients with lung cancer.

Many researchers have shown that pretreatment plasma fibrinogen levels are closely correlated with the prognosis of patients with lung cancer (LC). In this study, we thus performed a meta-analysis to systematically assess the prognostic value of pretreatment plasma fibrinogen levels in LC patients. A computerized systematic search in PubMed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) was performed up to March 15, 2018. Studies with available data on the prognostic value of plasma fibrinogen in LC patients were eligible for inclusion. The pooled hazard ratios (HRs) and odd ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the correlation between pretreatment plasma fibrinogen levels and prognosis as well as clinicopathological characteristics. A total of 17 studies with 6,460 LC patients were included in this meta-analysis. A higher pretreatment plasma fibrinogen level was significantly associated with worse overall survival (OS) (HR: 1.57; 95% CI: 1.39-1.77; p=0.001), disease-free survival (DFS) (HR: 1.53; 95% CI: 1.33-1.76; p=0.003), and progression-free survival (PFS) (HR: 3.14; 95% CI: 2.15-4.59; p<0.001). Furthermore, our subgroup and sensitivity analyses demonstrated that the pooled HR for OS was robust and reliable. In addition, we also found that a higher fibrinogen level predicted advanced TNM stage (III-IV) (OR=2.18, 95% CI: 1.79-2.66; p<0.001) and a higher incidence of lymph node metastasis (OR=1.74, 95% CI: 1.44-2.10; p=0.02). Our study suggested that higher pretreatment plasma fibrinogen levels predict worse prognoses in LC patients.

Resistin is associated with overall survival in non-small cell lung cancer patients during nivolumab treatment.

PURPOSE: Since the role of resistin was evaluated only in patients with non-small cell lung cancer (NSCLC) not treated with immunotherapy, we aimed to evaluate levels of resistin during immunotherapy (nivolumab) and its prognostic role with regard to OS. METHODS/PATIENTS: From a cohort of 78 patients with advanced NSCLC enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 43 patients have been considered for this sub-analysis because of the availability of samples. Before and during nivolumab administration, clinical information and blood samples were collected and resistin, matrix metalloproteinase (MMP)-8, MMP-9, and myeloperoxidase were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Median age was 71 with a prevalence of males and former smokers. Median resistin levels presented a peak at cycle 2 and then dropped down until the last cycle. Resistin correlated with all neutrophil degranulation products at cycle 1 (except for MMP-9) and at cycle 2 as well as with white blood cells and neutrophils. By a ROC curve analysis, a resistin value at cycle 2 of 19 ng/mL was tested as the best cut-off point for OS. Kaplan-Meier analysis demonstrated that patients above the resistin cut-off experienced a reduced OS (median OS 242.5 vs. 470 days, p = 0.0073), as confirmed by Cox proportional hazards regression analysis. CONCLUSIONS: Resistin levels > 19 ng/mL at the time of the second cycle of nivolumab treatment independently predict a reduced OS in patients with advanced NSCLC.

Paradoxical prognostic phenomenon of plasma T-cell-derived circulating DNA level in advanced non-small cell lung cancer.

BACKGROUND: Non-tumor-derived circulating DNA (nt-cirDNA) of advanced non-small cell lung cancer (NSCLC), with unclear origination, is associated with prognosis. We hypothesized that a part of nt-cirDNA release from CD3 or CD8 tumor-infiltrating lymphocytes (TILs) could have clinical implications. METHOD: To investigate the feasibility of T-cell-derived circulating DNA (T-cirDNA) detection, real-time PCR with Taqman assay-specific rearranged TCRß CDR3 region was conducted in plasma of 103 advanced NSCLC. CD3 and CD8-specific immunohistochemistry from biopsy specimen, was reviewed by one blinded pathologist to the T-cirDNA results. Prognostic impact including demographic characteristics was integrated into the model. RESULTS: Circulating DNA was detectable in 100 patients with median of 4 ng ml-1, while median of plasma T-cirDNA was 1.71 pg ml-1. Median %ratio of T-cirDNA/cirDNA was 0.02%. T-cirDNA was categorized by %ratio of T-cirDNA/cirDNA as undetectable, low (≤ 1%) and high (> 1%). Paradoxical prognostic impact of T-cirDNA/cirDNA was observed. Undetectable and high T-cirDNA/cirDNA translated to independent favorable prognostic outcome, HR of 0.54 [95% CI 0.30-0.96] and 0.41 [95% CI 0.21-0.80], respectively. 43 patients were assessed for CD3/CD8 TILs and PD-L1. High intratumoral CD3/CD8 TILs but not stromal CD3 TILs was correlated with high T-cirDNA/cirDNA representing active T-lymphocyte activity to eliminate cancer cells. While the prognosis of undetectable T-cirDNA/cirDNA, represents inactivated naïve T-cell, was determined by the presence of EGFR mutation and had long durable response of EGFR inhibitors. CONCLUSION: T-cirDNA could be a novel biomarker representing adaptive immune resistance in NSCLC patients. Further exploration as a predictive biomarker for EGFR inhibitors in setting of EGFR mutation might be warranted.

Pretreatment plasma fibrinogen level as a prognostic biomarker for patients with lung cancer

Many researchers have shown that pretreatment plasma fibrinogen levels are closely correlated with the prognosis of patients with lung cancer (LC). In this study, we thus performed a meta-analysis to systematically assess the prognostic value of pretreatment plasma fibrinogen levels in LC patients. A computerized systematic search in PubMed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) was performed up to March 15, 2018. Studies with available data on the prognostic value of plasma fibrinogen in LC patients were eligible for inclusion. The pooled hazard ratios (HRs) and odd ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the correlation between pretreatment plasma fibrinogen levels and prognosis as well as clinicopathological characteristics. A total of 17 studies with 6,460 LC patients were included in this meta-analysis. A higher pretreatment plasma fibrinogen level was significantly associated with worse overall survival (OS) (HR: 1.57; 95% CI: 1.39-1.77; p=0.001), disease-free survival (DFS) (HR: 1.53; 95% CI: 1.33-1.76; p=0.003), and progression-free survival (PFS) (HR: 3.14; 95% CI: 2.15-4.59; p<0.001). Furthermore, our subgroup and sensitivity analyses demonstrated that the pooled HR for OS was robust and reliable. In addition, we also found that a higher fibrinogen level predicted advanced TNM stage (III-IV) (OR=2.18, 95% CI: 1.79-2.66; p<0.001) and a higher incidence of lymph node metastasis (OR=1.74, 95% CI: 1.44-2.10; p=0.02). Our study suggested that higher pretreatment plasma fibrinogen levels predict worse prognoses in LC patients.

HIF-1α Levels in patients receiving chemoradiotherapy for locally advanced non-small cell lung carcinoma.

AIM: To examine the relationship between treatment response and hypoxia-inducible factor-1 alpha (HIF-1α) levels in patients with locally advanced non-small cell lung cancer (NSCLC) who received chemoradiotherapy (CRT). METHODS: Eighty patients with NSCLC were included in the study and treated at Acibadem Mehmet Ali Aydinlar University Medical Faculty. HIF-1 α levels were measured before and after CRT by the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Patients' stages were as follows; stage IIIA (65%) and stage IIIB (35%). Squamous histology was 45%, adenocarcinoma was 44%, and others were 11%. Chemotherapy and radiotherapy were given concurrently to 80 patients. Forty-five (56%) patients received cisplatin-based chemotherapy, and 35 (44%) received carboplatin-based chemotherapy. Serum HIF-1α levels (42.90 ± 10.55 pg/mL) after CRT were significantly lower than the pretreatment levels (63.10 ± 10.22 pg/mL, p<0.001) in patients with locally advanced NSCLC. CONCLUSION: The results of this study revealed that serum HIF-1α levels decreased after CRT. Decrease of HIF-1α levels after the initiation of CRT may be useful for predicting the efficacy of CRT.

HIF-1α Levels in patients receiving chemoradiotherapy for locally advanced non-small cell lung carcinoma

SUMMARY AIM To examine the relationship between treatment response and hypoxia-inducible factor-1 alpha (HIF-1α) levels in patients with locally advanced non-small cell lung cancer (NSCLC) who received chemoradiotherapy (CRT). METHODS Eighty patients with NSCLC were included in the study and treated at Acibadem Mehmet Ali Aydınlar University Medical Faculty. HIF-1 α levels were measured before and after CRT by the enzyme-linked immunosorbent assay (ELISA) method. RESULTS Patients' stages were as follows; stage IIIA (65%) and stage IIIB (35%). Squamous histology was 45%, adenocarcinoma was 44%, and others were 11%. Chemotherapy and radiotherapy were given concurrently to 80 patients. Forty-five (56%) patients received cisplatin-based chemotherapy, and 35 (44%) received carboplatin-based chemotherapy. Serum HIF-1α levels (42.90 ± 10.55 pg/mL) after CRT were significantly lower than the pretreatment levels (63.10 ± 10.22 pg/mL, p<0.001) in patients with locally advanced NSCLC. CONCLUSION The results of this study revealed that serum HIF-1α levels decreased after CRT. Decrease of HIF-1α levels after the initiation of CRT may be useful for predicting the efficacy of CRT.

RESUMO OBJETIVO Examinar a relação entre a resposta ao tratamento e os níveis de fator 1 induzida por hipóxia (HIF-1α) em pacientes com câncer de pulmão de células não pequenas localmente avançado (NSCLC) que receberam quimiorradioterapia (CRT). MÉTODO Oitenta pacientes com NSCLC foram incluídos no estudo e foram tratados na Faculdade de Medicina da Acibadem Mehmet Ali Aydınlar University. O nível de HIF-1α foi medido antes e depois da TRC pelo método de ensaio imunoenzimático (ELISA). RESULTADOS Os estágios dos pacientes foram os seguintes; estágio IIIA (65%) e estágio IIIB (35%). A histologia escamosa foi de 45%, o adenocarcinoma de 44% e o outro de 11%. Quimioterapia e radioterapia foram dadas simultaneamente a 80 pacientes. Quarenta e cinco (56%) pacientes receberam quimioterapia à base de cisplatina e 35 (44%) receberam quimioterapia à base de carboplatina. Os níveis séricos de HIF-1α (42,90 ± 10,55 pg / mL) após a TRC foram significativamente menores do que os níveis pré-tratamento (63,10 ± 10,22 pg / mL, p <0,001) em pacientes com NSCLC localmente avançado. CONCLUSÃO Os resultados deste estudo revelaram que os níveis séricos de HIF-1α diminuíram após a TRC. A diminuição dos níveis de HIF-1α após o início da TRC pode ser útil para prever a eficácia da TRC.

ADA activity is decreased in lymphocytes from patients with advanced stage of lung cancer.

Cigarette smoking is directly associated with lung cancer. Non-small cell lung carcinoma (NSCLC) represents approximately 80% from all types of lung cancer. This latter is hard to diagnose and to treat due to the lack of symptoms in early stages of the disease. The aim of this study was to evaluate ADA activity and the expression of P2X7, A1, and A2A receptors and in lymphocytes. In addition, the profile of pro-inflammatory and anti-inflammatory cytokines serum levels of patients with lung cancer in advanced stage was evaluated. Patients (n = 13) previously treated for lung cancer at stage IV (UICC) with chemotherapy had their blood collected. Cancer patients showed a decrease in ADA activity and an increase in A1 receptor expression in lymphocytes when compared to the control group. Moreover, patients exhibited an increase in IL-6 and TNF-α, while IL-17 and INF-ϒ serum levels were lower in patients with lung cancer. The decreased ADA activity and the increase in A1 receptor expression may contribute to adenosine pro-tumor effects by increasing IL-6 and TNF-α and decreasing IL-17 and INF-γ serum levels. Our data show an indirect evidence that purinergic signaling may have a role in promoting a profile of cytokines levels that favors tumor progression.

Association of neurologic manifestations and CEA levels with the diagnosis of brain metastases in lung cancer patients.

PURPOSE: Lung cancer (LC) is the most common source of brain metastases (BM). Because of the difficulty in predicting LC patients who will develop BM, we aimed to identify the clinical and serologic markers that could predict the presence of BM in LC patients. METHODS: We analyzed a cohort of LC patients sent for neurooncological consultation for any neurologic symptom at a cancer center from June 2013 to July 2017. INCLUSION CRITERIA: histologically confirmed LC, age ≥ 18 years and complete clinical records. EXCLUSION CRITERIA: BM diagnosis before our consultation and absence of MRI. Oncologic history, clinical symptoms and comorbidities were analyzed. RESULTS: From 199 patients, most (70%) had > 1 neurological symptom. The most common was headache (n = 46, 21%), followed by seizures (17%), altered mental status (16%) and focal motor weakness (13%). BM was found in 74% of the patients during follow-up. Multivariate logistic regression analysis showed factors associated with a higher frequency of BM: age < 65 years [OR 3.15, 95% CI 1.3-7.5], headache (OR 3.8, 95% CI 1.2-11.8), seizures (OR 3.2, 95% CI 1.1-9.3) and CEA ≥ 15 ng/mL (OR 5.5, 95% CI 2.2-13.8). Focal sensory deficit was associated with a lower frequency of BM (OR 0.2, 95% CI 0.06-0.92). The presence of certain clinical neurologic symptoms, together with CEA level, was associated with a higher risk of BM in LC patients. CONCLUSION: The clinical manifestations of patients with LC should not be overlooked because some may have a substantial correlation with BM.

The detection and clinical significance of peripheral regulatory CD4+CD25hiCD127low T cells in patients with non-small cell lung cancer.

OBJECTIVE: In this study, we aimed to discuss the clinical significance of CD4+CD25hiCD127low regulatory T cells (Tregs) in the peripheral blood of patients with non-small cell lung cancer (NSCLC). METHODS: Sixty patients with NSCLC and 35 healthy controls were studied. Peripheral blood CD4+CD25hiCD127lowTregs, CD4+CD25hiT cells, and CD4+T cells were measured with flow cytometric analysis, and results were compared between the groups. RESULTS: Compared with healthy people, CD4+CD25hiCD127low Tregs and CD4+CD25hi T cells significantly increased in patients with NSCLC, while CD4+ T cell proportions decreased. CONCLUSIONS: CD4+CD25 hi CD127low Treg detection in the peripheral blood of NSCLC patients is highly significant, in that it provides additional knowledge to guide the selection of individualized treatment plans for patients with NSCLC.

Levels of peripheral blood polymorphonuclear myeloid-derived suppressor cells and selected cytokines are potentially prognostic of disease progression for patients with non-small cell lung cancer.

Polymorphonuclear-MDSC (PMN-MDSC) have emerged as an independent prognostic factor for survival in NSCLC. Similarly, cytokine profiles have been used to identify subgroups of NSCLC patients with different clinical outcomes. This prospective study investigated whether the percentage of circulating PMN-MDSC, in conjunction with the levels of plasma cytokines, was more informative of disease progression than the analysis of either factor alone. We analyzed the phenotypic and functional profile of peripheral blood T-cell subsets (CD3+, CD3+CD4+ and CD3+CD8+), neutrophils (CD66b+) and polymorphonuclear-MDSC (PMN-MDSC; CD66b+CD11b+CD15+CD14-) as well as the concentration of 14 plasma cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 p70, IL-17A, IL-27, IL-29, IL-31, and IL-33, TNF-α, IFN-γ) in 90 treatment-naïve NSCLC patients and 25 healthy donors (HD). In contrast to HD, NSCLC patients had a higher percentage of PMN-MDSC and neutrophils (P < 0.0001) but a lower percentage of CD3+, CD3+CD4+ and CD3+CD8+ cells. PMN-MDSC% negatively correlated with the levels of IL1-ß, IL-2, IL-27 and IL-29. Two groups of patients were identified according to the percentage of circulating PMN-MDSC. Patients with low PMN-MDSC (≤ 8%) had a better OS (22.1 months [95% CI 4.3-739.7]) than patients with high PMN-MDSC (9.3 months [95% CI 0-18.8]). OS was significantly different among groups of patients stratified by both PMN-MDSC% and cytokine levels. In sum, our findings provide evidence suggesting that PMN-MDSC% in conjunction with the levels IL-1ß, IL-27, and IL-29 could be a useful strategy to identify groups of patients with potentially unfavorable prognoses.