Clinical predictors of response to single­agent immune checkpoint inhibitors in chemotherapy­pretreated non­small cell lung cancer.

Single-agent immune checkpoint inhibitors (ICIs) are the standard option for chemotherapy-pretreated metastatic non-small cell lung cancer (NSCLC), however only a subset of patients responds to this treatment. The present study aimed at the development of a tool for personalized prediction of the efficacy of ICIs. The study included 181 epidermal growth factor receptor/anaplastic lymphoma kinase-negative patients with metastatic NSCLC receiving single-agent ICI in the second or later line of therapy. For the comparison, a total of 63 metastatic patients with NSCLC treated by chemotherapy were also analyzed. Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, never-smoking status and the baseline neutrophil-to-lymphocyte ratio (NLR) ≥4.3 were associated with reduced progression-free survival (PFS) and overall survival (OS) [ECOG PS: Hazard ratio (HR)=2.09; P=0.028 and HR=2.02; P=0.035, respectively; never-smoking: HR=3.53; P=0.007 and HR=1.80; P=0.004, respectively; NLR ≥4.3: HR=4.34; P<0.0001 and HR=4.89; P<0.0001 respectively]. Patients with an NLR <4.3, who had a favorable ECOG PS (0-1) and smoking history in the past, derived the utmost benefit from ICI [n=77; objective response rate (ORR)=35%; PFS and OS: 17.1 and 33.7 months, respectively]. The worst efficacy of ICI was observed in patients who had an NLR ≥4.3 coupled with poor ECOG PS and/or never-smoking status (n=38; ORR=8%; PFS=3.2 months and OS=7.2 months). The remaining patients belonged to the group with intermediate outcomes (n=66; ORR=17%; PFS and OS: 4.3 and 12.2 months, respectively). While combination of these factors was highly predictive for ICIs, it was not associated with outcomes of chemotherapy treatment. Easily available characteristics of the patients allow for highly accurate predictions of outcomes of single-agent ICI therapy in chemotherapy-pretreated NSCLC.

Pericentromeric satellite lncRNAs are induced in cancer-associated fibroblasts and regulate their functions in lung tumorigenesis.

The abnormal tumor microenvironment (TME) often dictates the therapeutic response of cancer to chemo- and immuno-therapy. Aberrant expression of pericentromeric satellite repeats has been reported for epithelial cancers, including lung cancer. However, the transcription of tandemly repetitive elements in stromal cells of the TME has been unappreciated, limiting the optimal use of satellite transcripts as biomarkers or anti-cancer targets. We found that transcription of pericentromeric satellite DNA (satDNA) in mouse and human lung adenocarcinoma was observed in cancer-associated fibroblasts (CAFs). In vivo, lung fibroblasts expressed pericentromeric satellite repeats HS2/HS3 specifically in tumors. In vitro, transcription of satDNA was induced in lung fibroblasts in response to TGFß, IL1α, matrix stiffness, direct contact with tumor cells and treatment with chemotherapeutic drugs. Single-cell transcriptome analysis of human lung adenocarcinoma confirmed that CAFs were the cell type with the highest number of satellite transcripts. Human HS2/HS3 pericentromeric transcripts were detected in the nucleus, cytoplasm, extracellularly and co-localized with extracellular vesicles in situ in human biopsies and activated fibroblasts in vitro. The transcripts were transmitted into recipient cells and entered their nuclei. Knock-down of satellite transcripts in human lung fibroblasts attenuated cellular senescence and blocked the formation of an inflammatory CAFs phenotype which resulted in the inhibition of their pro-tumorigenic functions. In sum, our data suggest that satellite long non-coding (lnc) RNAs are induced in CAFs, regulate expression of inflammatory genes and can be secreted from the cells, which potentially might present a new element of cell-cell communication in the TME.

Tislelizumab Versus Docetaxel in Patients With Previously Treated Advanced NSCLC (RATIONALE-303): A Phase 3, Open-Label, Randomized Controlled Trial.

INTRODUCTION: The phase 3 RATIONALE-303 trial (NCT03358875) investigated the efficacy and safety of tislelizumab versus docetaxel in pretreated patients with advanced NSCLC. Here, we report the efficacy and safety results and describe the exploratory biomarker analyses. METHODS: A total of 805 patients aged more than or equal to 18 years with locally advanced or metastatic squamous or nonsquamous NSCLC were randomized 2:1 to intravenous tislelizumab 200 mg or docetaxel 75 mg/m2 every 3 weeks. Co-primary end points were overall survival (OS) in the intent-to-treat (ITT) and programmed death-ligand 1 (PD-L1) tumor cell expression greater than or equal to 25% populations. The exploratory biomarker analyses included PD-L1 expression, tumor mutation burden, and gene expression profile. RESULTS: At the prespecified interim analysis (August 10, 2020), the co-primary end point of OS in the ITT population was met, with a statistically significant and clinically meaningful improvement in OS with tislelizumab versus docetaxel (median 17.2 versus 11.9 mo, respectively; hazard ratio [HR] = 0.64, p < 0.0001). At the final analysis (July 15, 2021), the other co-primary end point of OS in the PD-L1 tumor cell greater than or equal to 25% population was further met (median 19.3 versus 11.5 mo, respectively; HR = 0.53, p < 0.0001), and OS continued to improve in the ITT population (median 16.9 versus 11.9 mo, respectively, HR = 0.66). Exploratory biomarker analyses revealed the potential association of NOTCH1-4 mutations with improved tislelizumab efficacy for both OS and progression-free survival, whereas tissue tumor mutation burden correlated with progression-free survival benefit, but not OS benefit. No new safety signals were identified. CONCLUSIONS: Tislelizumab was found to have a significantly improved and long-term clinical benefit in OS versus docetaxel in pretreated patients with advanced NSCLC, regardless of PD-L1 expression.

Inflammatory and autoimmune predictive markers of response to anti-PD-1/PD-L1 therapy in NSCLC and melanoma.

Immune checkpoint inhibitors (ICI) are a standard in cancer therapy, but few patients respond to the treatment. The aim of the present study was the determination of immunological markers for monitoring response to ICI. The present study included 74 patients receiving ICI in subsequent [group 1; non-small cell lung cancer (NSCLC)] and first-line setting (group 2; melanoma) and 30 patients with NSCLC receiving first-line chemotherapy. In groups 1 and 2 ß-2 microglobulin (B2-MG), neopterin (NPT), IL-6, IL-18, HLA-DRB1 and autoantibodies were assessed after two months of ICI, and before the start of next administration in group 3. In group 1 low level of B2-MG (P<0.0001), NPT (P<0.0001), IL-6 (P<0.0001), IL-18 (P=0.0003), HLA-DRB1*03 (P=0.016) and anti-TPO antibodies (P=0.016) were associated with response >six months. In group 2 high level of B2-MG (P=0.0001), NPT (P=0.0016), IL-6 (P=0.013) and IL-18 (P=0.032) were associated with early disease progression (

Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients. METHODS: IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting). FINDINGS: Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%). INTERPRETATION: IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC. FUNDING: F Hoffmann-La Roche and Genentech.

Surgical Staplers: The History of Conception and Adoption.

The paper explores not well-known aspects of the development of surgical staplers. It is based on the review of the selected literature. It covers the novel idea of using metal staples that was successfully executed in 1908 by the Hungarian surgeon Hültl, and acknowledges contribution of Soviet specialists to the development of the mechanical suturing devices for many thoracic, abdominal, and vascular procedures. The paper also reflects on an almost detective story of how Ravitch, an American surgeon visiting the USSR in 1957, managed to bring to the United States a Russian stapler, which became a prototype for modern devices.

Photodynamic theranostics of central lung cancer: Present state and future prospects.

Endobronchial photodynamic therapy (PDT) in central lung cancer (CLC) shows feasibility even in late stage disease. Our experience with chlorin e6 based photosensitizers (PS), including in combination with medical cancer treatment, demonstrated regression of tumor lesions of the trachea and bronchi in 94 % of patients with central NSCLC. It is possible to increase the efficiency of the treatment and achieve its personalization by using fluorescent bronchoscopes, which provide fluorescence guided PDT - photodynamic theranostics (PT). PT allows to clarify localization the area of treatment due to visualization of tumor foci which are invisible in white light, to carry out targeted irradiation and at the same time to monitor its effectiveness using the effects of bleaching/flare-up of PS. PT prospects are associated with the transition to the near-infrared (NIR) region, which makes possible to increase the depth of light penetration. The first experiments using the combined NIR/visible PT system showed the possibility of detecting tumor sites using the OS-BPT method (On-Site Bronchoscopic Photodynamic Theranostics), which consists in NIR visualization of tumor when indocyanine green (ICG) is injected directly during examination in a minimal dose. This allows the technology to be used for CLC screening in the future. Further progress of endobronchial PT will be determined by the development of clinically available devices and new NIR PSs with targeted properties, high singlet oxygen yield and fluorescence.

Nonintubated Tracheal Surgery.

The article describes an anesthetic management strategy for resection of the cervical trachea due to benign stenosis without using an endotracheal tube. The strategy includes: (1) insertion of an airway stent in the stenotic area, (2) insertion of a supraglottic airway device (SGAD), and (3) advancing a jet ventilation catheter through the SGAD. The stent is removed during surgery together with the resected part of the trachea. The technique of nonintubated tracheal resection allows the surgeon to work most comfortably and helps the anesthesiologist properly maintain the patient's vital functions in the operating room.

Recurrent respiratory papillomatosis with lung involvement.

Recurrent respiratory papillomatosis (RRP) is a rare disease caused by human papillomavirus. Aggressive forms of RRP require repeated cytoreductive surgery to restore airway patency. Tracheal disease is even less common and lung parenchyma is involved in less than 1% of patients. We present reports of three cases of RRP with progressive lung disease in adult patients.

Potential of indocyanine green near-infrared fluorescence imaging in experimental and clinical practice.

BACKGROUND: Visualization of Indocyanine Green (ICG) near-infrared (NIR) fluorescence is a promising technique for biomedical applications because of its deep tissue penetration, low autofluorescence, weak dependence on ambient light, safety for patients and medical staff. METHODS: To apply this technique to animal studies and clinical practice, we developed multispectral NIR fluorescence imaging system FLUM-808, which can be used in experimental studies and clinical practice, in open and endoscopic surgery (fluorescence-guided surgery). The object is illuminated either directly or through an illumination channel depending on what optical instrument is used (camera lens, fiber endoscope, rigid endoscope, surgical microscope, etc.). The system is able to simultaneously display NIR images and images captured under white light. RESULTS: This article provides examples of imaging techniques used during open and endoscopic surgery with ICG as an NIR fluorescent dye and photosensitizer, demonstrates applications of the technique for experimental and clinical purposes: for intraoperative imaging of blood and lymphatic vessels; for detection of tumors and sentinel lymph nodes; for assessment of tissue, organ, or anastomotic blood supply. CONCLUSIONS: This method significantly helps to accurately assign the areas of increased fluorescence to certain anatomical structures during surgery. NIR fluorescence diagnosis can be used in important experimental studies and in clinical practice. The described results of ICG studies can help in developing new fluorescence-based diagnostic and theranostic approaches employing more effective exogenous fluorophores and photosensitizers.

EGFR T790M Mutation in TKI-Naïve Clinical Samples: Frequency, Tissue Mosaicism, Predictive Value and Awareness on Artifacts.

BACKGROUND: This study evaluated the distribution of epidermal growth factor receptor (EGFR) T790M mutations in treatment-naïve tumor and normal samples obtained from cancer patients. METHODS: We utilized allele-specific PCR (AS-PCR), digital droplet PCR (ddPCR) and next generation sequencing (NGS) to detect EGFR T790M allele in several collections of tumor and normal human tissues. RESULTS: AS-PCR analysis of treatment-naïve tumor samples revealed somatic T790M mutation in 3/394 (1%) non-small cell lung carcinomas (NSCLC) carrying the tyrosine kinase inhibitor (TKI)-sensitizing EGFR mutation, but in none of 334 NSCLC lacking EGFR exon 19 deletions (ex19del) or L858R substitutions and in none of 235 non-lung tumors. Use of highly sensitive and quantitative assays, such as ddPCR and NGS, produced a high number of T790M-specific signals even in presumably T790M-negative DNA specimens. This background noise was evidently higher in degraded DNA isolated from formalin-fixed paraffin-embedded tissues as compared to high molecular weight DNA. A combination of AS-PCR, ddPCR and NGS revealed mosaic EGFR T790M allele in 2/68 (3%) NSCLC treated with the first-generation TKI. Both these tumors produced evident and durable response to gefitinib. CONCLUSION: Detection of mosaic EGFR T790M mutation in treatment-naïve samples may be compromised by yet unresolved technical issues and may have limited clinical value.

Good surgeon: A search for meaning.

The art and philosophy of surgery are not as often discussed as scientific discoveries and technological advances in the modern era of surgery. Although these are difficult to teach and pass on to the next generations of surgeons they are no less important for training good surgeons and maintaining their high standards. The authors of this review and opinion article tried to define what being a good surgeon really means and to look into the subject by analysing the essential conditions for being a good surgeon and the qualities that such a specialist should possess. In addition to a strong theoretic knowledge and practical skills and among the several described professional and personal characteristics, a good surgeon is expected to have common sense. It enables a surgeon to make a sound practical judgment independent of specialized medical knowledge and training. The possible ways of developing and/or enhancing common sense during surgical training and subsequent practice require separate analysis.

Endobronchial photodynamic therapy under fluorescence control: Photodynamic theranostics.

BACKGROUND: Photodynamic therapy (PDT) has several advantages. However, one of the disadvantages is its inability to be individualized according to biological characteristics of malignant tumors. The objective of this study was to investigate a strategy for individualized endobronchial PDT in the treatment of centrally located non-small cell lung cancer. METHODS: New approach suggests taking fluorescence-based measurements of chlorine E6 photosensitizer (PS) accumulation in the malignant tumor tissue, and assess PS consumption rate during PDT. Two randomized groups of 45 patients took part in the comparative study of standard PDT procedure, 662nm, pulse-periodic mode, therapeutic light (reference group - RG) versus the investigated individualized approach under fluorescence control after irradiation with violet light, 408nm, diagnostic light (study group - SG). The PDT-treatment parameters and results of follow-up bronchoscopy were compared between the groups. RESULTS: 43 (96%) of 45 patients in SG demonstrated intense fluorescence in the area of the tracheal/bronchial tumor stenosis. 4 (9%) of 45 patients (SG) demonstrated fluorescence of mucosa areas distant from the main tumor lesion after violet light irradiation. Mean fluence during the whole PDT procedure was 95±20J/cm2 (range 60-130J/cm2), which was significantly lower than in RG (p=0.01). Total exposure time was significantly lower in SG (365±65s), compared with RG (690±65s), P=0.001. According to the follow-up bronchoscopy the difference in the PDT-treatment results between the groups is statistically insignificant. CONCLUSIONS: The investigated strategy suggests using fluorescence control of the efficacy of PDT-treatment (photodynamic theranostics) to optimize and individualize the PDT procedure.

Awake video-assisted thoracic surgery in acute infectious pulmonary destruction.

BACKGROUND: Many of thoracic minimally invasive interventions have been proven to be possible without general anesthesia. This article presents results of video-assisted thoracic surgery (VATS) application under local anesthesia in patients with lung abscesses and discusses its indications in detail. METHODS: The study involved prospective analysis of treatment outcomes for all acute infectious pulmonary destruction (AIPD) patients undergoing VATS under local anesthesia and sedation since January 1, 2010, till December 31, 2013. Patients with pulmonary destruction cavity at periphery of large size (>5 cm) underwent non-intubated video abscessoscopy (NIVAS). Patients with pyopneumothorax (lung abscess penetration into pleural cavity) underwent non-intubated video thoracoscopy (NIVTS). Indications for NIVAS and NIVTS were as follows: cavity debridement and washing, necrotic sequestra removal, adhesion split, biopsy. All interventions were done under local anesthesia and sedation without trachea intubation and epidural anesthesia. RESULTS: Sixty-five enrolled patients had 42 NIVAS and 32 NIVTS interventions, nine patients underwent two surgeries. None of the patients required trachea intubation or epidural anesthesia. In none of our cases with conversion to thoracotomy was required. Post-surgical complications developed after 11 interventions (13%): subcutaneous emphysema (five cases), chest wall phlegmon (three cases), pulmonary bleeding (two cases), and pneumothorax (one case). One patient died due to the main disease progression. In 50 patients NIVAS and NIVTS were done within 5 to 8 days after abscess/pleural cavity draining, while in other 15 patients-immediately prior to draining; both pulmonary bleeding episodes and all cases of chest wall phlegmon took place in the latter group. CONCLUSIONS: NIVAS and NIVTS under local anesthesia and sedation are well tolerated by patients, safe and should be used more often in AIPD cases. Timing of NIVAS and NIVTS procedures was found to be of paramount importance for ensuring complete therapeutic effectiveness.

Preoperative endobronchial photodynamic therapy improves resectability in initially irresectable (inoperable) locally advanced non small cell lung cancer.

OBJECTIVES: This report describes the result of prospective randomized trial to assess effectiveness and safety of neoadjuvant photodynamic therapy (PDT) and chemotherapy as well as possibility for further surgery for locally advanced NSCLC. METHODS: Patients with stage IIIA and IIIB central NSCLC (main bronchus/distal trachea involvement) who were not initially eligible for surgery but might be considered as surgery candidates after neoadjuvant therapy were enrolled in the study. They were randomized to either neoadjuvant chemotherapy and endobronchial PDT or chemotherapy alone followed by surgical resection. PDT was done with photosensitizer agent chlorine E6 and 662nm laser light before each of the three courses of chemotherapy. RESULTS: From January 2008 to December 2011, 42 patients were assigned to PDT arm (n=21) and No-PDT arm (n=21). Groups were similar with respect to age, sex, tumor stage, and histology. No PDT major complications were observed. After neoadjuvant treatment partial response revealed in 19pts (90%) in PDT arm and 16pts (76%) in No-PDT arm (p=0.460), these patients underwent thoracotomy. After thoracotomy tumor was unresectable in 3pts of No-PDT arm (19%). There were 14 pneumonectomies and 5 lobectomies in PDT arm vs. 10 pneumonectomies and 3 lobectomies in No-PDT arm. Completeness of resection was significantly higher in PDT arm (R0-89%, R1-11%) vs. No-PDT arm (R0-54%, R1-46%), p=0.038. CONCLUSIONS: The study demonstrated that neoadjuvant PDT along with chemotherapy is effective, safe and it makes possible to convert to surgery candidates and to improve resection completeness in stage III central NSCLC patients.

Fast-growing large cell neuroendocrine carcinoma of mediastinum.

Neuroendocrine carcinomas combine a heterogeneous group of tumors occurring in lungs on a rare occasion, and in some cases, they appear to have extraordinary quick growth and extrapulmonary localization. In this case we present a 42-year-old patient who underwent a right upper lobectomy for emphysema, and 6 months later, the tumor developed again into a giant neuroendocrine carcinoma of the mediastinum.

Pleural effusion as a result of chronic renal ischemia.

We would like to present a case of patient with a transudative pleural effusion as a result of atherosclerotic occlusion of renal arteries. About 50 liters of fluid were drained from the right pleural cavity during 10 months period of observation. Successful revascularization of kidneys improved left ventricular function, stabilized hemodynamic of the pulmonary circulation and thus led to elimination of pleural effusion.