MicroRNA-126 selected with broad-spectrum analysis of microRNAs - a new predictive factor for the effectiveness of immunotherapy or chemoimmunotherapy in advanced NSCLC patients?

Introduction: Expression of PD-L1 on cancer cells is the only validated predictive factor for immunotherapy in NSCLC (Non-Small Cell Lung Cancer) patients. However, on this basis, it is difficult to predict the occurrence of resistance to immune checkpoint inhibitors (ICIs). MicroRNAs are widely studied as biomarkers of cancers. Our study was designed to determine whether microRNAs can be sensitive predictive factors in the qualification of NSCLC patients to first-line immunotherapy or chemoimmunotherapy. Material and methods: The two-stage research on validation group (n=20) and study group (n=35) of patients with advanced NSCLC was conducted. Analysis of microRNAs expression by qPCR in plasma collected prior to the start of immunotherapy (pembrolizumab) or chemoimmunotherapy (combination of pembrolizumab with chemotherapy) was made. Broad-spectrum analysis of microRNAs expression was used in the studied group. Three microRNAs selected in that group as important for the effectiveness of ICIs were then examined in the validation group. Results: In the studied group, significantly higher expression of miRNA-126-3p, miR-144-3p and miR-146-5p was observed in patients with long PFS compared to those with short PFS. In the validation group, low miRNA-126 expression indicated lower median progression-free survival and overall survival (2.3 vs. 5.0 months and 5.2 vs 11.2, respectively). These patients had a significantly higher risk of progression (HR= 2.92, 95% CI: 1.01 to 8.40, p=0.04) and death (HR=3.64, 95% CI: 1.22 to 10.84, p=0.02). Conclusion: Our study showed that the expression of miR-126 in blood plasma may be a predictive factor for the effectiveness of first-line immunotherapy or chemoimmunotherapy in advanced NSCLC patients.

The influence of plasma sPD-L1 concentration on the effectiveness of immunotherapy in advanced NSCLC patients.

INTRODUCTION: PD-L1 (Programmed Cell Death Ligand 1) is currently the only recognised marker of response to immunotherapy with anti-PD-1 or anti-PD-L1 antibodies in patients with advanced non-small cell lung cancer (NSCLC). However, this marker is not perfect. Soluble PD-L1 (sPD-L1) may be a novel predictor of immunotherapy efficacy in NSCLC patients. MATERIAL AND METHODS: We enrolled 120 patients (median age 68 ± 6.81 years, 70 males and 50 females) with locally advanced (stage IIIB; 10 patients) or advanced (stage IV; 110 patients) NSCLC. PD-L1 expression in tumour cells was assessed by immunohistochemistry (IHC) in 117 (97.5%) patients. The soluble PD-L1 concentration in plasma samples was measured using enzyme-linked immunosorbent assay (ELISA). The response to immunotherapy, progression-free survival (PFS), and overall survival (OS), calculated from the start of immunotherapy, were assessed in 119 patients. RESULTS: Patients with disease control had significantly lower (p = 0.0006) concentrations of sPD-L1 in blood plasma than patients with progression during the first months of immunotherapy or chemoimmunotherapy Patients with ≥ 6 month progression-free survival had a significantly higher (p = 0.013) percentage of tumor cells with PD-L1 expression than patients with shorter PFS. Patients with ≥ 6 months OS had significantly lower (p = 0.0142) plasma sPD-L1 concentrations than those with shorter overall survival. The median PFS was significantly higher in patients with low sPD-L1 concentrations than in those with high concentrations of this protein (5.8 vs. 2.5 months, HR = 0.6021, p = 0.0156). Similarly, patients with low sPD-L1 levels had a significantly higher median overall survival than those with sPD-L1 levels above the median (16.5 vs. 7 months, HR = 0.5354, p = 0.0071). There was no significant correlation between the percentage of tumour cells expressing PD-L1 and the concentration of sPD-L1 in the blood plasma. CONCLUSION: High sPD-L1 concentration is a negative predictor of immunotherapy efficacy in patients with NSCLC. It is worthwhile to determine sPD-L1 concentration to predict the risk of resistance to anti-PD-1 or anti-PD-L1 antibodies with greater certainty.

Breaking the 'Undruggable' Barrier: Anti-PD-1/PD-L1 Immunotherapy for Non-Small Cell Lung Cancer Patients with KRAS Mutations-A Comprehensive Review and Description of Single Site Experience.

Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mutations are among the most commonly found oncogenic alterations in non-small cell lung cancer (NSCLC) patients. Unfortunately, KRAS mutations have been considered "undruggable" for many years, making treatment options very limited. Immunotherapy targeting programmed death-ligand 1 (PD-L1), programmed death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) has emerged as a promising therapeutic option for NSCLC patients. However, some studies have suggested a lower response rate to immunotherapy in KRAS-mutated NSCLC patients with the coexistence of mutations in the STK11 (Serine/Threonine Kinase 11) gene. However, recent clinical trials have shown promising results with the combination of immunotherapy and chemotherapy or immunotherapy and KRAS inhibitors (sotorasib, adagrasib) in such patients. In other studies, the high efficacy of immunotherapy has been demonstrated in NSCLC patients with mutations in the KRAS gene that do not coexist with other mutations or coexist with the TP53 gene mutations. In this paper, we review the available literature on the efficacy of immunotherapy in KRAS-mutated NSCLC patients. In addition, we presented single-site experience on the efficacy of immunotherapy in NSCLC patients with KRAS mutations. The effectiveness of chemoimmunotherapy or immunotherapy as well as KRAS inhibitors extends the overall survival of advanced NSCLC patients with the G12C mutation in the KRAS gene to 2-3 years. This type of management has become the new standard in the treatment of NSCLC patients. Further studies are needed to clarify the potential benefits of immunotherapy in KRAS-mutated NSCLC patients and to identify potential biomarkers that may help predict response to therapy.

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.

Attempting to Identify Bacterial Allies in Immunotherapy of NSCLC Patients.

Introduction: Factors other than PD-L1 (Programmed Death Ligand 1) are being sought as predictors for cancer immuno- or chemoimmunotherapy in ongoing studies and long-term observations. Despite high PD-L1 expression on tumor cells, some patients do not benefit from immunotherapy, while others, without the expression of this molecule, respond to immunotherapy. Attention has been paid to the composition of the gut microbiome as a potential predictive factor for immunotherapy effectiveness. Materials and Methods: Our study enrolled 47 Caucasian patients with stage IIIB or IV non-small cell lung cancer (NSCLC). They were eligible for treatment with first- or second-line immunotherapy or chemoimmunotherapy. We collected stool samples before the administration of immunotherapy. We performed next-generation sequencing (NGS) on DNA isolated from the stool sample and analyzed bacterial V3 and V4 of the 16S rRNA gene. Results: We found that bacteria from the families Barnesiellaceae, Ruminococcaceae, Tannerellaceae, and Clostridiaceae could modulate immunotherapy effectiveness. A high abundance of Bacteroidaaceae, Barnesiellaceae, and Tannerellaceae could extend progression-free survival (PFS). Moreover, the risk of death was significantly higher in patients with a high content of Ruminococcaceae family (HR = 6.3, 95% CI: 2.6 to 15.3, p < 0.0001) and in patients with a low abundance of Clostridia UCG-014 (HR = 3.8, 95% CI: 1.5 to 9.8, p = 0.005) regardless of the immunotherapy line. Conclusions: The Clostridia class in gut microbiota could affect the effectiveness of immunotherapy, as well as the length of survival of NSCLC patients who received this method of treatment.

Presence of Akkermansiaceae in gut microbiome and immunotherapy effectiveness in patients with advanced non-small cell lung cancer.

The significance of Akkermansia bacteria presence in gut micobiome, mainly Akkermansia mucinifila, is currently being investigated in the context of supporting therapy and marker for response to immunotherapy in cancer patients. It is indicated that patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) respond better to treatment if this bacterium is present in the intestine.We performed next-generation sequencing of the gut microbiome from patients treated in the first or second line therapy with anti-PD-1 (anti-programmed death 1) or anti-PD-L1 (anti-programmed death ligand 1) monoclonal antibodies. In our study group of 47 NSCLC patients, the percentage of Akkermansiaceae was higher in patients with disease stabilization and with partial response to immunotherapy compared to patients with disease progression. Moreover, we found that a higher percentage of Akkermansiaceae was present in patients with squamous cell carcinoma compared to adenocarcinoma. Our study showed that Akkermansiaceae could be supporting marker for response to immunotherapies in NSCLC patients, nonetheless further in-depth studies should be conducted in the role of Akkermansiaceae in cancer immunotherapy.

Small Cell Lung Cancer in the Course of Idiopathic Pulmonary Fibrosis-Case Report and Literature Review.

Idiopathic pulmonary fibrosis is a poorly prognosed form of progressive interstitial pneumonia. Patients with IPF have a significantly increased risk of developing lung cancer, which further worsens the course of the disease. The most common histological types of LC among patients with IPF are squamous cell carcinoma and adenocarcinoma. Furthermore, all LC treatment modalities can lead to developing an acute IPF exacerbation. In this report, we present a rare case of coexistence of IPF and small cell lung cancer in a 76-year-old patient with chronic obstructive pulmonary disease, and a former smoker. For over 2 years, the patient was treated with an anti-fibrotic drug-pirfenidone, which slowed down the progression of IPF. Unfortunately, after being diagnosed with an active SCLC, the patient was excluded from further participation in the pirfenidone drug program. SCLC is characterized by high aggressiveness, rapid growth and high metastatic potential; therefore, it is necessary to apply antitumor treatment as soon as possible. The described patient was treated with carboplatin-etoposide chemotherapy. Early treatment tolerance was good and after two cycles of cytotoxic treatment, a partial response was present in CT. The presented case emphasizes the need for further research to determine the treatment regimens in patients with coexisting IPF and LC and the appropriateness of antifibrotic treatment in them. In addition, it can help to choose the treatment method for similar patients, indicating a combination of carboplatin and etoposide as an effective and, at the same time, relatively safes method in terms of the risk of IPF's exacerbation.

Implementing Silica Nanoparticles in the Study of the Airborne Transmission of SARS-CoV-2.

Aerosol transmission constitutes one of the major transmission routes of the SARS-CoV-2 pathogen. Due to the pathogen's properties, research on its airborne transmission has some limitations. This paper focuses on silica nanoparticles (SiO2) of 40 and 200 nm sizes as the physicochemical markers of a single SARS-CoV-2 particle enabling experiments on the transmission of bioaerosols in public spaces. Mixtures of a determined silica concentration were sprayed on as an aerosol, whose particles, sedimented on dedicated matrices, were examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Since it was not possible to quantitatively identify the markers based on the obtained images, the filters exposed with the AirSampler aspirator were analyzed based on inductively coupled plasma optical emission spectroscopy (ICP-OES). The ICP-OES method enabled us to determine the concentration of silica after extracting the marker from the filter, and consequently to estimate the number of markers. The developed procedure opens up the possibility of the quantitative estimation of the spread of the coronavirus, for example in studies on the aerosol transmission of the pathogen in an open environment where biological markers-surrogates included-cannot be used.

Lung Cancer: Spectral and Numerical Differentiation among Benign and Malignant Pleural Effusions Based on the Surface-Enhanced Raman Spectroscopy.

We present here that the surface-enhanced Raman spectroscopy (SERS) technique in conjunction with the partial least squares analysis is as a potential tool for the differentiation of pleural effusion in the course of the cancerous disease and a tool for faster diagnosis of lung cancer. Pleural effusion occurs mainly in cancer patients due to the spread of the tumor, usually caused by lung cancer. Furthermore, it can also be initiated by non-neoplastic diseases, such as chronic inflammatory infection (the most common reason for histopathological examination of the exudate). The correlation between pleural effusion induced by tumor and non-cancerous diseases were found using surface-enhanced Raman spectroscopy combined with principal component regression (PCR) and partial least squares (PLS) multivariate analysis method. The PCR predicts 96% variance for the division of neoplastic and non-neoplastic samples in 13 principal components while PLS 95% in only 10 factors. Similarly, when analyzing the SERS data to differentiate the type of tumor (squamous cell vs. adenocarcinoma), PLS gives more satisfactory results. This is evidenced by the calculated values of the root mean square errors of calibration and prediction but also the coefficients of calibration determination and prediction (R2C = 0.9570 and R2C = 0.7968), which are more robust and rugged compared to those calculated for PCR. In addition, the relationship between cancerous and non-cancerous samples in the dependence on the gender of the studied patients is presented.

In vitro preliminary study on different anti-PD-1 antibody concentrations on T cells activation.

Lung adenocarcinoma predominates among diagnosed nonsmall cell lung cancer subtypes in nonsmokers. The introduction of immune checkpoint inhibitors into clinical practice offered patients prolonged progression-free survival and overall survival times. However, the results demonstrate that the benefits do not apply to all patients. Nivolumab is a monoclonal antibody against the PD-1 protein expressed mainly on T lymphocytes and is widely used in cancer therapy in different settings. Tumor cells often express the PD-L1 molecule and can effectively block the action of PD-1-positive lymphocytes. A body of knowledge regarding the high expression of PD-L1 on tumor cells highlights that it does not always correlate with the effectiveness of anti-PD-1 therapy. The side effects of the therapy also constitute a significant issue. These side effects can occur at any time during anti-PD-1 treatment and lead to discontinuation and even the death of the patient. In these situations, it is possible to delay the dosage. Nevertheless, unfortunately, it is not possible to reduce the dose of anti-PD-1 antibody, which would undoubtedly minimize side effects, leaving the patient's immune system active. In our preliminary study, we analyzed the effect of different concentrations of nivolumab on the functioning of T lymphocytes. Activation and proliferation markers were investigated on T cells after being cultured with antigen-stimulated autologous dendritic cells. This process may indicate an appropriate concentration of nivolumab, which shows clinical activity with minimal side effects.

Efficacy of Osimertinib in Lung Squamous Cell Carcinoma Patients with EGFR Gene Mutation-Case Report and a Literature Review.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related mortality worldwide. It is responsible for 80-85% of lung cancer cases. NSCLC can be divided into several groups, led by adenocarcinoma (ADC)-40-50% and squamous cell carcinoma (SCC)-20-30%. The development of new molecular therapies targeting particular abnormalities such as mutations in the EGFR (Epidermal Growth Factor Receptor) gene or ROS1 or ALK genes rearrangements resolved in novel strategies in advanced NSCLC management. EGFR mutation occurs mostly in patients with ADC and those patients are mostly females with no or light smoking history. The hereby presented patient fitted the ADC characteristics, while they were diagnosed with SCC. The unusual diagnosis implied further genetic testing, which established the occurrence of L858R substitution in exon 21 in the EGFR gene. A 63-year-old female was admitted to the unit due to a dry cough, pain in the right chest area and dyspnoea. When diagnosed, the patient had a peripheral mass in the right lung superior lobe (55 × 40 mm), satellite nodules in the apex of the same lung and packets of disintegrating lymph nodes. Positron Emission Tomography (PET-CT) confirmed a diffuse neoplastic process qualified as stage IV on the TNM scale. Due to EGFR gene mutation, the woman was administered osimertinib, however, the treatment did not succeed, and other therapeutic solutions were undertaken. The patient died 10 months after diagnosis. Patients with advanced ADC harboring EGFR mutation can receive osimertinib, a third-generation tyrosine kinase inhibitor (TKI), however, the use of TKIs in SCC remains controversial. In some published cases, osimertinib treatment led to success, in others, the therapy did not result in the expected final effect. Small sample groups and diverse molecular backgrounds indicate the need for further research in this field. Thus, the treatment decision-making process in those patients overall remains extremely demanding and ambiguous.

The efficacy of T790M mutation testing in liquid biopsy-Real clinic data.

Osimertnib is still widely used in the treatment of NSCLC patients who have previously received erlotinib, gefitinib or afatinib and have developed resistance to these drugs mediated by the T790M mutation in exon 20 of EGFR gene. We assessed the results of T790M mutation testing in liquid biopsy by Entrogen test and real-time PCR technique in routine clinical practice. Analysis was conducted in 73 plasma samples from 41 patients with locally advanced or metastatic lung adenocarcinoma treated with first- or second-generation of EGFR TKIs. We detected T790M mutation in 18 patients (43.9% of patients, 24.6% positive tests in 73 samples). The incidence of T790M mutation in liquid biopsy was significantly higher in patients with T3-T4 tumors compared to patients with T0-T2 tumors (p = 0.0368, χ2 = 4.36). Median PFS at the time of progression according to RECIST was significantly (p = 0.0444) higher in patients with T790M mutation than in patients without this mutation (22.5 vs. 15 months). Our results confirmed that T790M mutation is more often detected in patients with a large tumor spreading in the chest and with the long duration of response to first- or second generation of EGFR TKIs. The low sensitivity of the real-time PCR technique in T790M mutation detection could be partially compensated by repeating the tests.

Residential Radon Exposure in Patients with Advanced Lung Cancer in Lublin Region, Poland.

Exposure to radon is the second most common factor causing lung cancer in smokers and the first among non-smokers. We aimed to measure the impact of the radon exposure on patients with different histological types of advanced lung cancer. The measurement of radon exposure was performed in 102 patients with lung cancer in stage 3B or higher (Poland). There were 78.4% of patients with non-small cell carcinoma and 21.6% of patients with small cell carcinoma. One month radon exposure measurement was performed with trace detectors in order to control whether high radon concentrations (>800 Bq/m3) were found in the homes of patients with cancer diagnosed. Results of the determinations were then compared with the representation of the most common types of lung cancer in the study population. In the analyzed group, the average concentration of radon during the exposure of the detector in the residential premises of the respondents accounted for 69.0 Bq/m3 [37.0−117.0] and had no statistically significant effect on the type of lung cancer developed in patients. The lack of statistical significance may result from the small study group and the accompanying exposure to other harmful components. As the incidence of lung adenocarcinoma is increasing and exposure to tobacco smoke is decreasing, the search for other modifiable causes of lung cancer should be the task in the future.

Crizotinib efficacy in advanced non-squamous NSCLC patients with ALK or ROS1 rearrangement.

In patients with advanced non-small cell lung cancer (NSCLC), comprehensive genetic diagnostics is currently carried out in order to qualify for molecularly targeted therapies and immunotherapy. The aim of the study was to assess the usefulness of the reverse transcriptase (RT-PCR) method in the diagnosis of gene rearrangements, the effectiveness of EGFR, ALK, ROS1, and PD-L1 inhibitors in first-line treatment in NSCLC patients. We enrolled 95 non-squamous NSCLC patients with known status of EGFR, ALK, ROS1, MET and RET genes and PD-L1 protein expression. We used the real time PCR, fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and RT-PCR techniques for determination of predictive factors. In patients with ALK and ROS1 genes alteration, the median overall survival was 34 months in crizotinib treated patients and 6 months in patients who received chemotherapy (HR = 0.266, p = 0.0056). The risk of death was lower in patients treated with molecularly targeted therapies or immunotherapy compared to patients with predictive factors without personalized treatment (HR = 0.265, 95% CI 0.116-0.606) and to patient without predictive factors who received chemotherapy (HR = 0.42, 95% CI 0.162-1.09). Diagnosis of predictive factors and implementation of personalized treatment are key to prolonging the survival in advanced NSCLC patients.

Neoadjuvant and Adjuvant Immunotherapy in Non-Small Cell Lung Cancer-Clinical Trials Experience.

Across all tumor types, we observe that the role of immunotherapy has increased rapidly. Due to a number of potential advantages, it is considered in neoadjuvant treatment of localized tumors. In neoadjuvant settings, immunotherapy addresses micrometastatic diseases at the moment of their formation. However, some issues concerning neoadjuvant and adjuvant immunotherapy still has to be covered. The choice of drug and use of monotherapy or combination regimens remains unclear. The timing of surgery and preoperative evaluation of neoadjuvant immunotherapy efficacy is challenging. Although there is currently limited confirmed clinical data to support the use of immune checkpoint blockade in the neoadjuvant and adjuvant settings, there are many studies exploring this strategy in NSCLC patients.

Do endocrine adverse events predict longer progression-free survival among patients with non-small-cell lung cancer receiving nivolumab?

The aim of the study was to assess the occurrence and nature of immune-related endocrine adverse events (irAEs) among patients with non-small-cell lung cancer (NSCLC) treated with nivolumab. METHODS: The study group included 35 patients (15 women, 20 men, 65.8 ± 7.1 years) with NSCLC in stage IIIB (n = 16, 45.7%) and IV (n = 19,54.3%) who were treated with nivolumab. RESULTS: Of the studied patients, 34.3% (n = 12) developed endocrine irAEs (irAE group): 22.9% (n = 8) hyperthyroidism and 8.6% (n = 3) hypothyroidism, and in one case, hypophysitis was observed. The median irAEs onset time was 2 months. In the group of patients with thyroid disorders, permanent hypothyroidism eventually developed in 58.3%. The severity of the analyzed irAEs ranged from mild to moderate (Grade 1-2); the case of hypophysitis was estimated as Grade 3. The comparison of progression-free survival time (PFS) between the two groups showed longer PFS in patients in the irAE group (p = 0.021). Patients with irAE were treated significantly longer with nivolumab and they received more doses of nivolumab, however in Cox analysis we did not find patients with irAE to experience progression later than patients without them. CONCLUSIONS: Nivolumab therapy is associated with an increased risk of endocrine adverse effects, particularly thyroid dysfunction. Endocrine adverse effects can be successfully treated pharmacologically and usually do not require discontinuation of immunotherapy. The relationship between a better cancer prognosis in patients who developed endocrine irAE has not been found.

Viral Infection and Lung Cancer Immunotherapy.

Immunotherapy with immune checkpoint inhibitors (mainly anti-PD1 and anti-PDL1 monoclonal antibodies) became a standard of care in non-small cell lung cancer (NSCLC) patients. Most of the clinical trials excluded patients with hepatitis B (HBV), hepatis C (HCV), and human immunodeficiency virus (HIV) active infection (1-10). Despite the progress in treatment of these infections, they remain an unresolved clinical problem when lung cancer immunotherapy should be initiated in an NSCLC patient. This manuscript summarizes the data from the literature concerning this subgroup of patients including the rationale for immunotherapy initiation depending on the HBV, HCV, or HIV infection status; the risk of adverse events; and the efficacy compared to non-infected patients. One of the crucial questions is how the candidates to immunotherapy should be screened for HBV, HCV, and HIV infections. The year 2020 brought the world a new but dynamic viral problem-severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). The incorporation of known data in oncology guidelines became a burning need, and then, which group of the infected patients can be treated with immunotherapy despite the infection. Oncologists should also know if these patients should receive antiviral therapy and what are the safe combinations in these settings. We also indicate which of the adverse events should be monitored carefully during checkpoint inhibitor treatment.

Impact of copy number variant and single nucleotide polymorphism of the programmed death-ligand 1 gene, programmed death-ligand 1 protein expression and therapy regimens on overall survival in a large group of Caucasian patients with non-small cell lung carcinoma.

Anti-programmed death-1 or anti-programmed death-ligand 1 (PD-L1) blockade may be ineffective in some patients with non-small cell lung cancer (NSCLC) with high percentage of tumor cells with PD-L1 expression. In addition, immunotherapy may provide great benefits in patients without PD-L1 expression. The present study assessed PD-L1 protein expression by immunohistochemistry, copy number variation (CNV) of PD-L1 and two single nucleotide polymorphisms (SNPs), rs822335 and rs822336, in the promoter of PD-L1 by quantitative PCR in 673 patients with NSCLC. Overall survival time of patients with NSCLC depending on the assessed predictive factors (PD-L1 CNV or SNP) and the treatment methods (immunotherapy in first/second line of treatment or chemotherapy) was analyzed. The present study revealed significantly higher PD-L1 copies number in patients with ≥10% and ≥50% of tumor cells with PD-L1 expression compared to patients with lower percentage of PD-L1-positive tumor cells (P=0.02 and P=0.0002, respectively). There was a significant positive correlation (R=0.2; P=0.01) between number of PD-L1 copies and percentage of tumor cells with PD-L1 protein expression. Percentage of tumor cells with PD-L1 expression was lower in patients with TT genotype of the rs822335 polymorphism compared to those with CC genotype (P=0.03). The present study observed significantly higher risk of death in patients treated with chemotherapy compared to those treated with immunotherapy (P<0.0001; hazard ratio=2.4768; 95% confidence interval, 2.0120-3.0490). The present study demonstrated a close relationship between PD-L1 copies number, genotype of rs822335 PD-L1 polymorphism and PD-L1 protein expression on tumor cells. However, the impact of CNV and SNPs of PD-L1 on overall survival of patients with NSCLC requires further investigation.

Non-Small-Cell Lung Cancer: New Rare Targets-New Targeted Therapies-State of The Art and Future Directions.

Lung cancer is the most common cause of cancer-related death worldwide, and the prognosis for stage IV remains poor. The presence of genetic alterations in tumor cells, such as EGFR and BRAF gene mutations, as well as ALK and ROS1 gene rearrangements, are indications for targeted therapies. Many such treatments are already registered and used on a wide scale. In comparison to standard chemotherapy, they can prolong not only progression-free survival but also overall survival. Moreover, they are able to provide excellent quality of life and rapid improvement of cancer-related symptoms such as dyspnea, cough and pain. Recent years have witnessed great advances in both molecular diagnostics and new molecular therapies for non-small-cell lung cancer. This review presents new therapeutic targets in NSCLC, as well as drugs of which the activity against NTRK, RET, MET or HER2 gene alterations (including EGFR exon 20 insertions) has either been confirmed or is currently being evaluated. Although these particular genetic alterations in NSCLC are generally rare, each accounting for 1-2% of patients, in total about half of all patients have molecular alterations and may ultimately receive targeted therapies.