Pembrolizumab-combination therapy for NSCLC- effectiveness and predictive factors in real-world practice.

Introduction: Pembrolizumab combined with chemotherapy has become the standard of care for patients with non-small-cell lung cancer (NSCLC) and the expression of programmed death ligand 1 (PD-L1) in <50% of tumour cells (TC). Methods: We evaluated the efficacy of the treatment in real-world practice, paying attention to the predictive factors, with a special focus on low level of PD-L1 expression. This study is a multicenter retrospective analysis of patients with stage IV NSCLC. Results: A group of 339 consecutive patients was analysed, among them 51% patients with low PD-L1 expression. In the overall population, the ORR was 40.6%, median PFS and OS were 13 months (95% CI 11.4-15) and 16.8 months (95% CI 13.3-20.3), respectively. In multivariate analysis for the entire study population, performance status - ECOG 1 vs. 0 (HR 2.2, 95%CI 1.1-4.6; p=0.02), neutrophil to lymphocyte ratio (NLR)>3 (HR 2.3, 95%CI 1.3-4.2; p=0.04), presence of liver (HR 2.0, 95%CI 1-3.7; p=0. 03) and bone metastases (HR 1.3, 95%CI 1-3; p=0.04), weight loss (HR 1.8, 95%CI 1.1-2.8; p=0.01) and sum of measurable lesions diameters >110 mm (HR 1.7, 95%CI 1-2.9, p=0.049) had a negative impact on OS. Conclusions: In the real world, patients can clinically benefit from immunochemotherapy, regardless of the expression of PD-L1 and the histological type. Other clinicopathological factors such as performance status, extent, and location of secondary lesions have prognostic significance.

Influencing Factors on the Quality of Lymph Node Dissection for Stage IA Non-Small Cell Lung Cancer: A Retrospective Nationwide Cohort Study.

Lymphadenectomy is an essential part of complete surgical operation for non-small cell lung cancer (NSCLC). This retrospective, multicenter cohort study aimed to identify factors that influence the lymphadenectomy quality. Data were obtained from the Polish Lung Cancer Study Group Database. The primary endpoint was lobe-specific mediastinal lymph node dissection (L-SMLND). The study included 4271 patients who underwent VATS lobectomy for stage IA NSCLC, operated between 2007 and 2022. L-SMLND was performed in 1190 patients (27.9%). The remaining 3081 patients (72.1%) did not meet the L-SMLND criteria. Multivariate logistic regression analysis showed that patients with PET-CT (OR 3.238, 95% CI: 2.315 to 4.529; p < 0.001), with larger tumors (pT1a vs. pT1b vs. pT1c) (OR 1.292; 95% CI: 1.009 to 1.653; p = 0.042), and those operated on by experienced surgeons (OR 1.959, 95% CI: 1.432 to 2.679; p < 0.001) had a higher probability of undergoing L-SMLND. The quality of lymphadenectomy decreased over time (OR 0.647, 95% CI: 0.474 to 0.884; p = 0.006). An analysis of propensity-matched groups showed that more extensive lymph node dissection was not related to in-hospital mortality, complication rates, and hospitalization duration. Actions are needed to improve the quality of lymphadenectomy for NSCLC.

SKYSCRAPER-02: Tiragolumab in Combination With Atezolizumab Plus Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer.

PURPOSE: The phase III SKYSCRAPER-02 study determined whether the benefits of atezolizumab plus carboplatin and etoposide (CE) could be enhanced by the addition of tiragolumab in untreated extensive-stage small-cell lung cancer (ES-SCLC). We report final progression-free survival (PFS) and overall survival (OS) analyses. METHODS: Patients received tiragolumab 600 mg/placebo, plus atezolizumab 1,200 mg and CE (four cycles), then maintenance tiragolumab/placebo plus atezolizumab. Primary end points were investigator-assessed PFS and OS in patients without history/presence of brain metastases (primary analysis set [PAS]). Additional end points included PFS and OS in all patients regardless of brain metastases status (full analysis set [FAS]), response, and safety. RESULTS: Four hundred ninety patients were randomly assigned (FAS): 243 to tiragolumab arm and 247 to control arm. At the cutoff date (February 6, 2022; median duration of follow-up, 14.3 months [PAS] and 13.9 months [FAS]), final analysis of PFS in the PAS (n = 397) did not reach statistical significance (stratified hazard ratio [HR], 1.11; P = .3504; median, 5.4 months tiragolumab v 5.6 months control). At the cutoff date (September 6, 2022; median duration of follow-up, 21.2 months [FAS]), median OS in the PAS at final OS analysis was 13.1 months in both arms (stratified HR, 1.14; P = .2859). Median PFS and OS in the FAS were consistent with the PAS. The proportion of patients with immune-mediated adverse events (AEs) in the tiragolumab and control arms was 54.4% and 49.2%, respectively (grade 3/4: 7.9% and 7.7%). AEs leading to treatment withdrawal occurred in 8.4% and 9.3% of tiragolumab- and control-treated patients, respectively. CONCLUSION: Tiragolumab did not provide additional benefit over atezolizumab and CE in untreated ES-SCLC. The combination was well tolerated with no new safety signals.

Molecular alterations of driver genes in non-small cell lung cancer: from diagnostics to targeted therapy.

Lung cancer is the leading cause of cancer death all over the world. The majority (80-85 %) of lung cancer cases are classified as non-small cell lung cancer (NSCLC). Within NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the most often recognized. The histological and immunohistochemical examination of NSCLC is a basic diagnostic tool, but insufficient for comprehensive therapeutic decisions. In some NSCLC patients, mainly adenocarcinoma, molecular alterations in driver genes, like EGFR, KRAS, HER2, ALK, MET, BRAF, RET, ROS1, and NTRK are recognized. The frequency of some of those changes is different depending on race, and between smokers and non-smokers. The molecular diagnostics of NSCLC using modern methods, like next-generation sequencing, is essential in estimating targeted, personalized therapy. In recent years, a breakthrough in understanding the importance of molecular studies for the precise treatment of NSCLC has been observed. Many new drugs were approved, including tyrosine kinase and immune checkpoint inhibitors. Clinical trials testing novel molecules like miRNAs and trials with CAR-T cells (chimeric antigen receptor - T cells) dedicated to NSCLC patients are ongoing.

Treatment Patterns, Testing Practices, and Outcomes in Patients with EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer in Poland: A Descriptive Analysis of National, Multicenter, Real-World Data from the REFLECT Study.

Non-small-cell lung cancer (NSCLC) represents 85% of new cases of lung cancer. Over the past two decades, treatment of patients with NSCLC has evolved from the empiric use of chemotherapy to more advanced targeted therapy dedicated to patients with an epidermal growth factor receptor (EGFR) mutation. The multinational REFLECT study analyzed treatment patterns, outcomes, and testing practices among patients with EGFR-mutated advanced NSCLC receiving first-line EGFR tyrosine kinase inhibitor (TKI) therapy across Europe and Israel. The aim of this study is to describe the Polish population of patients from the REFLECT study, focusing on treatment patterns and T790M mutation testing practice. A descriptive, retrospective, non-interventional, medical record-based analysis was performed on the Polish population of patients with locally advanced or metastatic NSCLC with EGFR mutations from the REFLECT study (NCT04031898). A medical chart review with data collection was conducted from May to December 2019.The study involved 110 patients. Afatinib was used as the first-line EGFR-TKI therapy in 45 (40.9%) patients, erlotinib in 41 (37.3%), and gefitinib in 24 (21.8%) patients. The first-line EGFR-TKI therapy was discontinued in 90 (81.8%) patients. The median progression-free survival (PFS) on first-line EGFR-TKI therapy was 12.9 months (95% CI 10.3-15.4). A total of 54 patients started second-line therapy, of whom osimertinib was administered to 31 (57.4%). Among 85 patients progressing on first-line EGFR-TKI therapy, 58 (68.2%) were tested for the T790M mutation. Positive results for the T790M mutation were obtained from 31 (53.4%) tested patients, all of whom received osimertinib in the next lines of therapy. The median overall survival (OS) from the start of first-line EGFR-TKI therapy was 26.2 months (95% CI 18.0-29.7). Among patients with brain metastases, the median OS from the first diagnosis of brain metastases was 15.5 months (95% CI 9.9-18.0). The results of the Polish population from the REFLECT study highlight the need for effective treatment of patients with advanced EGFR-mutated NSCLC. Nearly one-third of patients with disease progression after first-line EGFR-TKI therapy were not tested for the T790M mutation and did not have the opportunity to receive effective treatment. The presence of brain metastases was a negative prognostic factor.

Low on-treatment levels of serum soluble CD8 (sCD8) predict better outcomes in advanced non-small cell lung cancer patients treated with atezolizumab.

BACKGROUND: Immunotherapy has changed the paradigm of treating non-small cell lung cancer (NSCLC). But, selecting patients who will achieve long-term benefits from treatment remains unsatisfactory. Here, we investigated the possible use of the soluble form of CD8 antigen (sCD8) in predicting durable disease control after PD-1/PD-L1 blockade. CD8 is a marker of the cytotoxic T lymphocytes. Its soluble form (sCD8) is secreted under activation of the immune system but also has immunosuppressive properties. The data about serum sCD8 in patients dosed with anti-PD-1/PD-L1 drugs are lacking. METHODS AND RESULTS: We included 42 NSCLC patients and collected samples at baseline and for the first 3 months of atezolizumab immunotherapy. The serum sCD8 concentrations were measured with the ELISA kit and correlated with treatment outcomes. Patients with durable (≥ 12 months) disease control presented lower serum sCD8 than those without long-term benefits. The sCD8 levels measured at the end of cycle 2 (sCD8.2) were the earliest time point that successfully differentiated patients (3.76 vs. 9.68 ng/mL, respectively, p < 0.001). Individuals with low sCD8.2 (≤ 4.09 ng/mL) presented longer progression-free survival (HR = 0.061, p < 0.001) and overall survival (HR = 0.104, p < 0.05) compared to individuals with high sCD8.2 (median values unreached vs. 4.4 months and 14.4 months for PFS and OS, respectively). CONCLUSIONS: Serum sCD8 could be an early biomarker of durable disease control after anti-PD-L1 treatment. Higher sCD8 in patients with worse outcomes could suggest the inhibitory effect of sCD8 on cytotoxic T-cells activation.

NEPTUNE: Phase 3 Study of First-Line Durvalumab Plus Tremelimumab in Patients With Metastatic NSCLC.

INTRODUCTION: NEPTUNE, a phase 3, open-label study, evaluated first-line durvalumab plus tremelimumab versus chemotherapy in metastatic NSCLC (mNSCLC). METHODS: Eligible patients with EGFR and ALK wild-type mNSCLC were randomized (1:1) to first-line durvalumab (20 mg/kg every 4 weeks until progression) plus tremelimumab (1 mg/kg every 4 weeks for up to four doses) or standard chemotherapy. Randomization was stratified by tumor programmed death-ligand 1 expression (≥25% versus <25%), tumor histologic type, and smoking history. The amended primary end point was overall survival (OS) in patients with blood tumor mutational burden (bTMB) greater than or equal to 20 mutations per megabase (mut/Mb). Secondary end points included progression-free survival (PFS) in patients with bTMB greater than or equal to 20 mut/Mb and safety and tolerability in all treated patients. RESULTS: As of June 24, 2019, 823 patients were randomized (intention-to-treat [ITT]); 512 (62%) were bTMB-evaluable, with 129 of 512 (25%) having bTMB greater than or equal to 20 mut/Mb (durvalumab plus tremelimumab [n = 69]; chemotherapy [n = 60]). Baseline characteristics were balanced in the intention-to-treat. Among patients with bTMB greater than or equal to 20 mut/Mb, OS improvement with durvalumab plus tremelimumab versus chemotherapy did not reach statistical significance (hazard ratio 0.71 [95% confidence interval: 0.49-1.05; p = 0.081]; median OS, 11.7 versus 9.1 months); the hazard ratio for PFS was 0.77 (95% confidence interval, 0.51-1.15; median PFS, 4.2 versus 5.1 months). In the overall safety population, incidence of grade 3 or 4 treatment-related adverse events was 20.7% (durvalumab plus tremelimumab) and 33.6% (chemotherapy). CONCLUSIONS: NEPTUNE did not meet its primary end point of improved OS with durvalumab plus tremelimumab versus chemotherapy in patients with mNSCLC and bTMB greater than or equal to 20 mut/Mb. Despite the amended study design, with a resultant small primary analysis population, therapeutic activity was aligned with expectations based on mechanistic biology and previous studies.

Normal Lung Tissue CT Density Changes after Volumetric-Arc Radiotherapy (VMAT) for Lung Cancer.

Radiation-induced lung injury remains a significant toxicity in thoracic radiotherapy. Because a precise diagnosis is difficult and commonly used assessment scales are unclear and subjective, there is a need to establish quantitative and sensitive grading methods. The lung tissue density change expressed in Hounsfield units (HUs) derived from CT scans seems a useful numeric surrogate. The study aimed to confirm a dose-response effect on HU value changes (ΔHU), their evolution in time, and the impact of selected clinical and demographic factors. We used dedicated, self-developed software to register and analyze 120 pairs of initial and follow-up CT scans of 47 lung cancer patients treated with dynamic arc radiotherapy. The differences in HU values between CT scans were calculated within discretized dose-bins limited by isodose lines. We have proved the dose-effect relationship, which is well described with a sigmoid model. We found the time evolution of HU changes to suit a typical clinical presentation of radiation-induced toxicity. Some clinical factors were found to correlate with ΔHU degree: planning target volume (PTV), V35 in the lung, patient's age and a history of arterial hypertension, and initial lung ventilation intensity. Lung density change assessment turned out to be a sensitive and valuable method of grading post-RT lung toxicity.

Validation of the Elderly Traumatic Brain Injury Score: Observational Case Control Study.

BACKGROUND: Traumatic brain injury (TBI) poses a particular health risk for the elderly. The recently developed elderly TBI (eTBI) score combines the prognostic information of the risk factors characteristic of the geriatric population. We aimed to determine its validity and reliability on an independent sample. METHODS: We present a retrospective analysis of 506 consecutive patients after TBI aged ≥65 years. The previously described nomogram and the eTBI score were used. The primary outcome measure was mortality or vegetative state at 30 days after hospital admission. RESULTS: Mortality or vegetative state rate was 21.3%. The nomogram and eTBI Score showed similar predictive performance with accuracy of 83.8% (95% confidence interval 80.2%-87%) and 84.4% (95% confidence interval 80.8%-87.6%), respectively. On the basis of the Youden index and C4.5 algorithm, we divided patients according to the 3-tier pattern into low-, high-, and medium-risk groups. The outcome prediction in the first 2 groups was correct in 93.1% (survival in the low-risk group) and 94.4% (mortality in the high-risk group). Patients included in the medium-risk group usually required surgical treatment (85.3%) and were characterized by increased mortality or vegetative state (55%). Among patients with eTBI ≥5 (n = 221), there was no difference in outcome between those treated conservatively and surgically. CONCLUSIONS: This is the first study confirming the validity of the eTBI Score and its close association with outcome of geriatric population after TBI. The novel 3-tier risk stratification scheme was applicable to both conservatively and surgically treated patients.

Serum sCD25 Protein as a Predictor of Lack of Long-Term Benefits from Immunotherapy in Non-Small Cell Lung Cancer: A Pilot Study.

Prognosis of advanced non-small cell lung carcinoma (NSCLC) is poor. Even though it can improve with anti-PD-1/PD-L1 agents, most patients do not respond to treatment. We hypothesized that the serum soluble form of the unit α of the interleukin-2 receptor (sCD25) could be used as a biomarker of successful immunotherapy in NSCLC. We recruited patients dosed with atezolizumab (n = 42) or pembrolizumab (n = 20) and collected samples at baseline and during the treatment. Levels of sCD25 were quantified with the ELISA kits. Patients with a high sCD25 at baseline (sCD25.0 ≥ 5.99 ng/mL) or/and at the end of the fourth treatment cycle (sCD25.4 ≥ 7.73 ng/mL) progressed faster and lived shorter without the disease progression and serious toxicity. None of the patients with high sCD25 at both time points continued therapy longer than 9.3 months, while almost 40% of patients with low sCD25 were treated for ≥12.3 months. There was a 6.3-times higher incidence of treatment failure (HR = 6.33, 95% CI: 2.10-19.06, p = 0.001) and a 6.5-times higher incidence of progression (HR = 6.50, 95% CI: 2.04-20.73, p = 0.002) in patients with high compared with low sCD25.0 and sCD25.4. Serum levels of sCD25 may serve as a non-invasive biomarker of long-term benefits from the anti-PD-1/PD-L1s in NSCLC.

Differences between TNM classification and 2-[18F]FDG PET parameters of primary tumor in NSCLC patients.

BACKGROUND: The aim of the study was to compare the TNM classification with 2-[18F]FDG PE T biological parameters of primary tumor in patients with NSCLC. MATERIALS AND METHODS: Retrospective analysis was performed on a group of 79 newly diagnosed NSCLC patients. PET scans were acquired on Gemini TF PET/CT scanner 60-70 min after injection of 2-[18F]FDG with the mean activity of 364 ± 75 MBq, with the area being examined from the vertex to mid-thigh. The reconstructed PET images were evaluated using MIM 7.0 Software for SUVmax, MTV and TLG values. RESULTS: The analysis of the cancer stage according to TNM 8th edition showed stage IA2 in 8 patients, stage IA3 - 6 patients, stage IB - 4 patients, IIA - 3 patients, 15 patients with stage IIB, stage IIIA - 17 patients, IIIB - 5, IIIC - 5, IVA in 7 patients and stage IVB in 9 patients. The lowest TLG values of primary tumor were observed in stage IA2 (11.31 ± 15.27) and the highest in stage IIIC (1003.20 ± 953.59). The lowest value of primary tumor in SUVmax and MTV were found in stage IA2 (6.8 ± 3.8 and 1.37 ± 0.42, respectively), while the highest SUVmax of primary tumor was found in stage IIA (13.4 ± 11.4) and MTV in stage IIIC (108.15 ± 127.24). CONCLUSION: TNM stages are characterized by different primary tumor 2-[18F]FDG PET parameters, which might complement patient outcome.

Detection of EGFR mutations in liquid biopsy samples using allele-specific quantitative PCR: A comparative real-world evaluation of two popular diagnostic systems.

PURPOSE: The detection of epidermal growth factor receptor (EGFR) mutations in plasma cell-free DNA (cfDNA) is an auxiliary tool for the molecular diagnosis of non-small cell lung cancer (NSCLC), especially when an adequate tumor tissue specimen cannot be obtained. We compared the diagnostic accuracy of two commonly used in vitro diagnostic-certified allele-specific quantitative PCR assays for detecting plasma cfDNA EGFR mutations. METHODS: We analyzed EGFR mutations in plasma cfDNA from 90 NSCLC patients (stages I-IV) before treatment (n â€‹= â€‹60) and after clinical progression on EGFR tyrosine kinase inhibitors (n â€‹= â€‹30) using the cobas EGFR mutation test v2 (Roche Molecular Systems, Inc.) and therascreen EGFR Plasma RGQ PCR kit (Qiagen GmbH). RESULTS: There was higher concordance between plasma cfDNA and matched tumor tissue EGFR mutations with cobas (66.67%) compared with therascreen (55.93%). The concordance rate increased to 90.00% with cobas (Cohen's kappa coefficient, κ â€‹= â€‹0.80; p â€‹< â€‹0.0001) and 73.33% with therascreen (κ â€‹= â€‹0.49; p â€‹= â€‹0.0009) in advanced NSCLC patients. In treatment-naïve patients, cobas was superior to therascreen (sensitivity: 82.35% vs. 52.94%; specificity: 100% vs. 100%). In patients with clinical progression on EGFR tyrosine kinase inhibitors, EGFR exon 20 p.T790M was detected in 30% and 23% of cfDNA samples by cobas and therascreen, respectively. CONCLUSIONS: Cobas was superior to therascreen for detection of plasma EGFR mutations in advanced NSCLC. Plasma cfDNA EGFR mutation analysis is complex; therefore, the diagnostic accuracy of commercially available assays should be validated.

The quality of life after transnasal microsurgical and endoscopic resection of nonfunctioning pituitary adenoma.

BACKGROUND: A pituitary tumor can be reached by a transsphenoidal approach with the use of a microscope or an endoscope. The impact of the surgical technique on the patient's quality of life (QOL) is of great interest to us. Currently, the development of both surgical techniques, especially the endoscopic one, is very rapid. Treatment outcomes are extremely important, especially in terms of patients' QOL after pituitary tumor resection, irrespective of the technical aspects. OBJECTIVES: To compare the quality of life between patients who had undergone either transsphenoidal microscopic (MTS) or endoscopic (ETS) non-functioning pituitary adenoma resection. MATERIAL AND METHODS: The study population consisted of 32 consecutive patients (21 for the endoscopic and 11 for the microscopic method) who had undergone pituitary adenoma resection. Their QOL was evaluated using the World Health Organization's Quality of Life assessment tool (WHOQOL-BREF), the Sino-Nasal Outcome Test (SNOT-22) and the Visual Functioning Questionnaire (VFQ-25). Questionnaires were collected before and after surgery during the patients' hospital stay and 3 months after the surgery. RESULTS: The patients in the 2 groups did not differ significantly in terms of age, sex, tumor size, length of hospital stay, or QOL before the surgery. Vision-related QOL (VR-QOL) significantly improved in patients undergoing endoscopic surgery (p < 0.001). There were no statistically significant differences in QOL between the study groups at any stage of the trial (p > 0.05). Significantly more patients had improved QOL after endoscopic surgery according to the WHOQOL-BREF (p = 0.005) and the VFQ-25 (p = 0.002). CONCLUSIONS: The novel observation in this study is the significant improvement of VR-QOL in patients after endoscopic non-functioning pituitary adenoma resection in comparison to patients having microscopic resection. The microscopic method does not exacerbate rhinological symptoms more than the endoscopic one. Endoscopic surgery seems to be more beneficial for patients with pituitary adenoma, which deteriorates VR-QOL.

Effectiveness of osimertinib in patients with lung adenocarcinoma in clinical practice - the Expanded Drug Access Program in Poland.

INTRODUCTION: Osimertinib is a third-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated efficacy in the treatment of EGFR-mutant non-small-cell lung cancer (NSCLC) in prospective clinical trials. MATERIAL AND METHODS: This retrospective analysis evaluated the outcomes of 32 pretreated patients with EGFR T790M mutation who received osimertinib in clinical practice at seven centers in Poland within the Expanded Drug Access Program. Osimertinib was used in the second line in 59% of patients and in later lines in 41%. RESULTS: Objective response was attained in 16 patients (50%), and 12 subjects (38%) had stable disease. Median progression -free survival was 11.3 months in the overall population, 12.6 months in patients with EGFR exon 19 mutation and 7.5 months in patients with EGFR exon 21 mutation (p = 0.045). Median overall survival (OS) was 18.3 months. Overall, 58.4% and 45.6% of patients remained in follow-up after 12 and 24 months, respectively. Median OS appeared longer for patients without cerebral metastases than for those with cerebral metastases (27.4 vs 9.4 months, respectively; p = 0.078), and for patients with the Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 than those with ECOG PS 2 (27.4 vs 11.8 months, respectively; p = 0.189), although neither result reached statistical significance. Median OS of patients with partial response, stable disease and progressive disease was 27.4, 12.7 and 4.5 months, respectively (p < 0.001). Age, comorbidities, line of treatment with osimertinib, and type of activating EGFR mutation did not impact on OS. Adverse events of any grade or grade 3/4 were reported in 38% and 9% of patients, respectively. One person discontinued due to interstitial pneumonia. CONCLUSION: These results confirm the value of osimertinib in patients with previously treated EGFR T790M-mutant NSCLC. Clinical benefit was evident in patients with cerebral metastases and moderate performance status.

Inflammatory Myofibroblastic Tumor of Spinal Canal: Brief Case Report.

We describe a case of an intradural extramedullary inflammatory myofibroblastic tumor of the cervical spine. A 56-year-old woman presented with progressive neck pain, radiating to the right scapula, without any neurologic deficit. Magnetic resonance imaging showed an intradural extramedullary tumor with a dural tail sign, located at the C3-T1 segment with homogeneous contrast enhancement. The patient was operated on for a suspected meningioma. Pathologic examination showed fibrosis and inflammation with infiltration of B and T lymphocytes accompanied by plasmocytes, macrophages, and myofibroblast oocytes. We present the clinical course and review of the literature.

PF-06439535 (a Bevacizumab Biosimilar) Compared with Reference Bevacizumab (Avastin®), Both Plus Paclitaxel and Carboplatin, as First-Line Treatment for Advanced Non-Squamous Non-Small-Cell Lung Cancer: A Randomized, Double-Blind Study.

BACKGROUND: PF-06439535 is a bevacizumab biosimilar. We aimed to compare the efficacy and safety of PF-06439535 with that of reference bevacizumab (Avastin®) sourced from the EU (bevacizumab-EU), each with paclitaxel and carboplatin, in the first-line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: In this double-blind, parallel-group study, we recruited patients from 159 centers in 27 countries. Participants were randomized 1:1 to receive PF-06439535 plus paclitaxel and carboplatin or bevacizumab-EU plus paclitaxel and carboplatin on day 1 of each 21-day cycle for 4-6 cycles, followed by blinded monotherapy with PF-06439535 or bevacizumab-EU until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study. Randomization was stratified by region, sex, and smoking history. The primary endpoint was objective response rate (ORR) in accordance with RECIST 1.1, based on responses achieved by week 19 and confirmed by week 25. RESULTS: Between 21 May 2015 and 14 November 2016, 719 patients were randomized to the PF-06439535 group (n = 358) or the bevacizumab-EU group (n = 361). As of data cutoff for analysis of the primary endpoint (8 May 2017), 45.3% (95% confidence interval [CI] 40.01-50.57) of patients in the PF-06439535 group and 44.6% (95% CI 39.40-49.89) of patients in the bevacizumab-EU group achieved an objective response by week 19 that was confirmed by week 25. The unstratified ORR risk ratio was 1.015 (95% CI 0.863-1.193; 90% CI 0.886-1.163), and the unstratified ORR risk difference was 0.653% (95% CI - 6.608 to 7.908); all three CIs fell within pre-specified equivalence margins. Using final data after study completion (22 December 2017), no notable differences in progression-free survival or overall survival were observed between the groups. The most frequently reported grade 3 or higher treatment-emergent adverse events were hypertension, neutropenia, and anemia. There were no clinically meaningful differences in safety, pharmacokinetics, or immunogenicity across treatment groups. CONCLUSION: Among patients with advanced non-squamous NSCLC, PF-06439535 demonstrated similarity to bevacizumab-EU in terms of efficacy. Safety profiles for the two treatments were comparable. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02364999. FUNDING: Pfizer.

The expression of circulating miR-504 in plasma is associated with EGFR mutation status in non-small-cell lung carcinoma patients.

MicroRNAs (miRNAs), key regulators of gene expression at the post-transcriptional level, are grossly misregulated in some human cancers, including non-small-cell lung carcinoma (NSCLC). The aberrant expression of specific miRNAs results in the abnormal regulation of key components of signalling pathways in tumour cells. MiRNA levels and the activity of the gene targets, including oncogenes and tumour suppressors, produce feedback that changes miRNA expression levels and indicates the cell's genetic activity. In this study, we measured the expression of five circulating miRNAs (miR-195, miR-504, miR-122, miR-10b and miR-21) and evaluated their association with EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) mutation status in 66 NSCLC patients. Moreover, we examined the discriminative power of circulating miRNAs for EGFR mutant-positive and -negative NSCLC patients using two different data normalisation approaches. We extracted total RNA from the plasma of 66 non-squamous NSCLC patients (31 of whom had tumours with EGFR mutations) and measured circulating miRNA levels using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The miRNA expression levels were normalised using two endogenous controls: miR-191 and miR-16. We found significant associations between the expression of circulating miR-504 and EGFR-activating mutations in NSCLC patients regardless of the normalisation approach used (p = 0.0072 and 0.0236 for miR-16 and miR-191 normalisation, respectively). The greatest discriminative power of circulating miR-504 was observed in patients with EGFR exon 19 deletions versus wild-type EGFR normalised to miR-191 (area under the curve (AUC) = 0.81, p < 0.0001). Interestingly, circulating miR-504 levels were significantly reduced in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated subgroup compared to EGFR-mutated patients (p < 0.0030) and those with EGFR/KRAS wild-type tumours (p < 0.0359). Our study demonstrated the feasibility and potential diagnostic value of plasma miR-504 expression analysis to distinguish between EGFR-mutated and wild-type NSCLC patients. However, quality control and normalisation strategies are very important and have a major impact on the outcomes of circulating miRNA analyses.

Mortality After Traumatic Brain Injury in Elderly Patients: A New Scoring System.

BACKGROUND: Traumatic brain injury (TBI) remains a life-threatening condition characterized by growing incidence worldwide, particularly in the aging population, in which the primary goal of treatment appears to be avoidance of chronic institutionalization. METHODS: To identify independent predictors of 30-day mortality or vegetative state in a geriatric population and calculate an intuitive scoring system, we screened 480 patients after TBI treated at a single department of neurosurgery over a 2-year period. We analyzed data of 214 consecutive patients aged ≥65 years, including demographics, medical history, cause and time of injury, neurologic state, radiologic reports, and laboratory results. A predictive model was developed using logistic regression modeling with a backward stepwise feature selection. RESULTS: The median Glasgow Coma Scale (GCS) score on admission was 14 (interquartile range, 12-15), whereas the 30-day mortality or vegetative state rate amounted to 23.4%. Starting with 20 predefined features, the final prediction model highlighted the importance of GCS motor score (odds ratio [OR], 0.17; 95% confidence interval [CI], 0.09-0.32); presence of comorbid cardiac, pulmonary, or renal dysfunction or malignancy (OR, 2.86; 9 5% CI, 1.08-7.61); platelets ≤100 × 109 cells/L (OR, 13.60; 95% CI, 3.33-55.49); and red blood cell distribution width coefficient of variation ≥14.5% (OR, 2.91; 95% CI, 1.09-7.78). The discovered coefficients were used for nomogram development. It was further simplified to facilitate clinical use. The proposed scoring system, Elderly Traumatic Brain Injury Score (eTBI Score), yielded similar performance metrics. CONCLUSIONS: The eTBI Score is the first scoring system designed specifically for older adults. It could constitute a framework for clinical decision-making and serve as an outcome predictor. Its capability to stratify risk provides reliable criteria for assessing efficacy of TBI management.

Isoprostanes as potential cerebral vasospasm biomarkers.

Despite enormous progress in medicine, symptomatic cerebral vasospasm (CVS), remains an unexplained clinical problem, which leaves both physicians and patients helpless and relying on chance, due to the lack of specific marker indicative of imminent danger as well as the lack of specific treatment. In our opinion CVS occurrence depends on dynamic disbalance between free radicals' formation (oxidative stress) and antioxidant activity. Isoprostanes are products of free-radical peroxidation of polyunsaturated fatty acids, and seem to mark a promising path for the research aiming to unravel its possible mechanism. Not only are they the biomarkers of oxidative stress in vivo and in vitro, but also have manifold biological effects (including vasoactive, inflammatory and mitogenic) via activation of the thromboxane A2 receptor (TBXA2R), both in physiological and pathophysiological processes. This review addresses the importance of isoprostanes in CVS in quest of appropriate biomarkers.

Discrepancies between ALK protein disruption and occurrence of ALK gene rearrangement in Polish NSCLC patients.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangement are predisposed to molecularly targeted therapies. Proper diagnostic is crucial for quick and correct patients qualification to optimal treatment method. Genetic tests to detect predictive factors could be performed sequentially. After excluding EGFR mutations, abnormal ALK protein expression should be tested using immunohistochemistry (IHC) method. In patients with disrupted ALK expression, the rearrangement of the ALK gene should be confirmed by FISH method. Despite few years of experience in analysis of these predictive factors, there are still problems in interpretation of diagnostic tests results. Especially, some recommendations for ALK IHC diagnosis are not precise. METHODS: Mutations in EGFR gene were examined using real-time PCR technique in 1,108 formalin-fixed paraffin-embedded (FFPE) tissues, 398 FFPE cell-blocks and 470 cytological specimens of NSCLC. The disrupted ALK protein expression was analysed in 1,100 samples including 782 histological and 306 cytological (cell-blocks) samples using IHC. Twelve materials (1.1%) were non-diagnostic in IHC. ALK gene rearrangement using FISH method was analysed in IHC positive cases. RESULTS: The frequency of EGFR mutations was 8.6%. EGFR mutations occurred significantly more often in females (P=0.00001, χ2=62.732) and in adenocarcinoma cases (P=0.0002, χ2=14.222). The exon 19 deletions (49%) and exon 21 Leu858Arg substitution (38%) were the most common, rare EGFR mutations occurred in 13% of patients. Any expression of abnormal ALK protein was detected in 202 cases (18.57%). ALK gene rearrangement was confirmed in 49 cases (4.5%). ALK gene rearrangement is significantly more common in female than in male (P=0.0105, χ2=6.541). In patients with ALK gene rearrangement, the median percentage of nuclei with ALK rearrangement was only 25.5%. The polysomy (≥4 gene copy number per nuclei) of ALK gene was observed in 39 cases (21.4% of patients with diagnostic result of FISH examination). Median number of ALK gene copy per nuclei was 2.9±0.77. Significant positive correlation between percentage of cells with abnormal ALK expression in IHC test and percentage of nuclei with ALK rearrangement in FISH method was detected (R=0.617, P<0.00001). Significant negative correlation between the number of copies of ALK gene and the percentage of cells with expression of abnormal ALK was observed (R=-0.2004, P<0.05). ALK gene rearrangement was significantly more frequently observed in the material with coarse-grained cytoplasmic and membranous IHC staining than in materials with light cytoplasmic stippling. The occurrence of cytoplasmic stippling correlated with the increase of ALK gene copy number. CONCLUSIONS: We indicated that diagnosis of ALK disruption in NSCLC patients should be notably careful using IHC and FISH methods. Recommendations for ALK diagnosis should include the way of interpretation of cases with low percentage of cells with abnormal ALK protein expression in IHC test, character of IHC reaction, and cases with ALK gene polysomy in FISH method.