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Background: Pathologic confirmation of lung cancer influences treatment selection for suspected early-stage lung cancer. High pre-treatment tissue confirmation rates are recommended. We sought to define management and outcomes of patients undergoing surgery for primary lung cancer in a UK multi-centre clinical trial., Methods: VIOLET compared minimally invasive video-assisted thoracic surgery versus open surgery for known or suspected lung cancer. Diagnostic patient pathways were identified and methods of tissue confirmation were documented. The outcome of inappropriate lobectomy for benign disease or inappropriate wedge resection for primary lung cancer was compared with respect to the pathologic diagnosis., Findings: From July 2015 to February 2019, 502 patients were randomised and underwent surgery; 262 (52%) had a pre-operative pathologic confirmed diagnosis of primary lung cancer, 205 did not have a pre-operative biopsy and 35 had a non-diagnostic pre-operative biopsy. Of the 240 participants without pre-operative pathologic confirmation of primary lung cancer, intraoperative biopsy and frozen section analysis was undertaken in 144 (60%). The remaining 96 underwent direct surgical resection without tissue confirmation (19% of the entire cohort). Confirmation of histologic diagnosis before surgery was less costly than diagnosis in the operating theatre. The inappropriate surgery rate was 3.6% (18/502 participants, 7 lobectomy for benign disease, 11 wedge resection for lung cancer)., Interpretation: Low levels of inappropriate resection can be achieved at pre-operative tissue confirmation rates of 50% through a combination of intra-operative confirmatory biopsy and correct risk estimation of lung cancer. Practice needs to be monitored to ensure acceptable levels are consistently achieved., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eric Lim reports personal fees from Abbott Molecular (Abbott Park, IL, USA), GlaxoSmithKline plc (Brentford, UK), Pfizer Inc. (New York, NY, USA), Novartis Pharmaceuticals UK Ltd (London, UK), Medtronic plc/Covidien (Dublin, Ireland), Roche Diagnostics (Hertford, UK), Lilly Oncology (Indianapolis, IN, USA), Boehringer Ingelheim (Bracknell, UK), Medela (Baar, Switzerland), Johnson & Johnson/Ethicon (New Brunswick, NJ, USA), AstraZeneca (Cambridge, UK) and Bristol-Myers Squibb (New York, NY, USA); grants from Clearbridge BioMedics (Singapore Science Park, Singapore), Illumina (San Diego, CA, USA) and Guardant Health (Redwood City, CA, USA); and grants and personal fees from ScreenCell (Sarcelles, France) outside the submitted work. In addition, Eric Lim has patents P52435GB and P57988GB issued to Imperial Innovations (London, UK). Timothy Batchelor reports personal fees from Johnson & Johnson, Medtronic plc, Medela and AstraZeneca outside the submitted work., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Surgery through a single port may be less painful because access is supplied by 1 intercostal nerve or more painful because multiple instruments are used in 1 port. We analyzed data collected from the video-assisted thoracoscopic surgery group of a randomized controlled trial to compare differences in pain up to 1 year., Methods: Groups were compared in a prespecified exploratory analysis using direct (regression) and indirect comparison (difference with respect to thoracotomy). In-hospital visual analogue scale pain scores were used, and analgesic ratios were calculated. After discharge, pain was evaluated using European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core 30 scores up to 1 year., Results: From July 2015 to February 2019, we randomized 503 participants. After excluding 50 participants who did not receive lobectomy, surgery was performed using a single port in 42 participants (predominately by a single surgeon), multiple ports in 166 participants, and thoracotomy in 245 participants. No differences were observed in-hospital between single- and multiple-port video-assisted thoracoscopic surgery when modeled using a direct comparison, mean difference of -0.24 (95% CI, -1.06 to 0.58) or indirect comparison, mean difference of -0.33 (-1.16 to 0.51). Mean analgesic ratio (single/multiple port) was 0.75 (0.64 to 0.87) for direct comparison and 0.90 (0.64 to 1.25) for indirect comparison. After discharge, pain for single-port video-assisted thoracoscopic surgery was lower than for multiple-port video-assisted thoracoscopic surgery (first 3 months), and corresponding physical function was higher up to 12 months., Conclusions: There were no consistent differences for in-hospital pain when lobectomy was undertaken using 1 or multiple ports. However, better pain scores and physical function were observed for single-port surgery after discharge., Competing Interests: E.L. reports personal fees from Abbott Molecular, GlaxoSmithKline plc, Pfizer Inc, Novartis Pharmaceuticals UK Ltd, Medtronic plc/Covidien, Roche Diagnostics, Lilly Oncology, Boehringer Ingelheim, Medela, Johnson & Johnson/Ethicon, AstraZeneca, and Bristol-Myers Squibb; grants from Clearbridge BioMedics, Illumina, and Guardant Health; and grants and personal fees from ScreenCell outside the submitted work. In addition, E.L. has patents P52435GB and P57988GB issued to Imperial Innovations. T.B. reports personal fees from Johnson & Johnson, Medtronic plc, Medela, and AstraZeneca outside the submitted work. J.D. reports personal fees from Cambridge Medical Robotics, ArtiSential, and Medtronic plc/Covidien outside the submitted work. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2024 The Author(s).)

Objective: Surgical mortality has traditionally been assessed at arbitrary intervals out to 1 year, without an agreed optimum time point. The aim of our study was to investigate the time-varying risk of death after lobectomy to determine the optimum period to evaluate surgical mortality rate after lobectomy for lung cancer., Methods: We performed a retrospective study of patients undergoing lobectomy for lung cancer at our institution from 2015 to 2022. Parametric survival models were assessed and compared with a nonparametric kernel estimate. The hazard function was plotted over time according to the best-fit statistical distribution. The time points at which instantaneous hazard rate peaked and stabilized in the 1-year period after surgery were then determined., Results: During the study period, 2284 patients underwent lobectomy for lung cancer. Cumulative mortality at 30, 90, and 180 days was 1.3%, 2.9%, and 4.9%, respectively. Log-logistic distribution showed the best fit compared with other statistical distribution, indicated by the lowest Akaike information criteria value. The instantaneous hazard rate was greatest during the immediate postoperative period (0.129; 95% confidence interval, 0.087-0.183) and diminishes rapidly within the first 30 days after surgery. Instantaneous hazard rate continued to decrease past 90 days and stabilized only at approximately 180 days., Conclusions: In-hospital mortality is the optimal follow-up period that captures the early-phase hazard during the immediate postoperative period after lobectomy. Thirty-day mortality is not synonymous to "early mortality," as instantaneous hazard rate remains elevated well past the 90-day time point and only stabilizes at approximately 180 days after lobectomy., Competing Interests: E.L. reports personal fees from Covidien, Roche, Lilly Oncology, Boehringer Ingelheim, Medela, Ethicon, AstraZeneca, Beigene, Roche, and BMS; grants and personal fees from ScreenCell; and grants from Clearbridge Biomedics, Illumina, and Guardant Health, outside the submitted work. In addition, E.L. has patents P52435GB and P57988GB issued to Imperial Innovations. E.L. is Chief Investigator for VIOLET NIHR HTA (13/04/03), MARS 2 NIHR HTA (15/188/31), and RAMON NIHR HTA (131306); and founder of My Cancer Companion Healthcare Companion, Ltd. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Crown Copyright © 2023 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery.)

Background: Lung cancer is the leading cause of cancer death. Surgery remains the main method of managing early-stage disease. Minimal-access video-assisted thoracoscopic surgery results in less tissue trauma than open surgery; however, it is not known if it improves patient outcomes., Objective: To compare the clinical effectiveness and cost-effectiveness of video-assisted thoracoscopic surgery lobectomy with open surgery for the treatment of lung cancer., Design, Setting and Participants: A multicentre, superiority, parallel-group, randomised controlled trial with blinding of participants (until hospital discharge) and outcome assessors conducted in nine NHS hospitals. Adults referred for lung resection for known or suspected lung cancer, with disease suitable for both surgeries, were eligible. Participants were followed up for 1 year., Interventions: Participants were randomised 1 : 1 to video-assisted thoracoscopic surgery lobectomy or open surgery. Video-assisted thoracoscopic surgery used one to four keyhole incisions without rib spreading. Open surgery used a single incision with rib spreading, with or without rib resection., Main Outcome Measures: The primary outcome was self-reported physical function (using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) at 5 weeks. Secondary outcomes included upstaging to pathologic node stage 2 disease, time from surgery to hospital discharge, pain in the first 2 days, prolonged pain requiring analgesia at > 5 weeks, adverse health events, uptake of adjuvant treatment, overall and disease-free survival, quality of life (Quality of Life Questionnaire Core 30, Quality of Life Questionnaire Lung Cancer 13 and EQ-5D) at 2 and 5 weeks and 3, 6 and 12 months, and cost-effectiveness., Results: A total of 503 patients were randomised between July 2015 and February 2019 (video-assisted thoracoscopic surgery, n  = 247; open surgery, n  = 256). One participant withdrew before surgery. The mean age of patients was 69 years; 249 (49.5%) patients were men and 242 (48.1%) did not have a confirmed diagnosis. Lobectomy was performed in 453 of 502 (90.2%) participants and complete resection was achieved in 429 of 439 (97.7%) participants. Quality of Life Questionnaire Core 30 physical function was better in the video-assisted thoracoscopic surgery group than in the open-surgery group at 5 weeks (video-assisted thoracoscopic surgery, n  = 247; open surgery, n  = 255; mean difference 4.65, 95% confidence interval 1.69 to 7.61; p  = 0.0089). Upstaging from clinical node stage 0 to pathologic node stage 1 and from clinical node stage 0 or 1 to pathologic node stage 2 was similar ( p  ≥ 0.50). Pain scores were similar on day 1, but lower in the video-assisted thoracoscopic surgery group on day 2 (mean difference -0.54, 95% confidence interval -0.99 to -0.09; p  = 0.018). Analgesic consumption was 10% lower (95% CI -20% to 1%) and the median hospital stay was less (4 vs. 5 days, hazard ratio 1.34, 95% confidence interval 1.09, 1.65; p  = 0.006) in the video-assisted thoracoscopic surgery group than in the open-surgery group. Prolonged pain was also less (relative risk 0.82, 95% confidence interval 0.72 to 0.94; p  = 0.003). Time to uptake of adjuvant treatment, overall survival and progression-free survival were similar ( p  ≥ 0.28). Fewer participants in the video-assisted thoracoscopic surgery group than in the open-surgery group experienced complications before and after discharge from hospital (relative risk 0.74, 95% confidence interval 0.66 to 0.84; p  < 0.001 and relative risk 0.81, 95% confidence interval 0.66 to 1.00; p  = 0.053, respectively). Quality of life to 1 year was better across several domains in the video-assisted thoracoscopic surgery group than in the open-surgery group. The probability that video-assisted thoracoscopic surgery is cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year is 1., Limitations: Ethnic minorities were under-represented compared with the UK population (< 5%), but the cohort reflected the lung cancer population., Conclusions: Video-assisted thoracoscopic surgery lobectomy was associated with less pain, fewer complications and better quality of life without any compromise to oncologic outcome. Use of video-assisted thoracoscopic surgery is highly likely to be cost-effective for the NHS., Future Work: Evaluation of the efficacy of video-assisted thoracoscopic surgery with robotic assistance, which is being offered in many hospitals., Trial Registration: This trial is registered as ISRCTN13472721., Funding: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 48. See the NIHR Journals Library website for further project information.

Background: Chest compressions during cardiopulmonary resuscitation (CPR) may cause sternal or rib fractures and chest wall instability. This can complicate medical management and significantly impair respiratory function. Surgical management of flail chest is technically demanding, and it becomes even more challenging if the patient requires a concomitant cardiac procedure., Case Presentation: A 78-year-old male suffered a cardiac arrest and sustained sternal and bilateral rib fractures during a successful CPR. He underwent a concomitant coronary artery bypass grafting and aortic valve replacement combined with stabilization of the chest wall. We discuss the possibility of fixation of bilateral rib fractures and its role in postoperative recovery after cardiac surgery., Conclusions: Chest wall stabilization for an already fragile patient, with impaired respiratory system performance, could help improve overall outcomes, pulmonary function, weaning from mechanical ventilation, and rehabilitation. It may be used together with a cardiac procedure for a life-threatening cardiac pathology., (© 2022 Wiley Periodicals LLC.)

BACKGROUND: There is limited randomized evidence on the comparative outcomes of early-stage lung cancer resection by video-assisted thoracoscopic surgery (VATS) versus open resection. METHODS: We conducted a parallel-group multicenter randomized trial that recruited participants with known or suspected early-stage lung cancer and randomly assigned them to open or VATS resection of their lesions. The primary outcome was physical function at 5 weeks as a measure of recovery using the European Organisation for Research and Treatment of Cancer core health-related quality of life questionnaire (QLQ-C30) (scores range from 0 to 100, with higher scores indicating better function; the clinical minimally important difference for improvement is 5 points). We followed the patients for an additional 47 weeks for other outcomes. RESULTS: A total of 503 participants were randomly assigned (247 to VATS and 256 to open lobectomy). At 5 weeks, median physical function was 73 in the VATS group and 67 in the open surgery group, with a mean difference of 4.65 points (95% confidence interval, 1.69 to 7.61). Of the participants allocated to VATS, 30.7% had serious adverse events after discharge compared with 37.8% of those allocated to open surgery (risk ratio, 0.81 [95% confidence interval, 0.66 to 1.00]). At 52 weeks, there were no differences in cancer progression-free survival (hazard ratio, 0.74 [0.43 to 1.27]) or overall survival (hazard ratio, 0.67 [0.32 to 1.40]). CONCLUSIONS: VATS lobectomy for lung cancer is associated with a better recovery of physical function in the 5 weeks after random assignment compared with open surgery. Long-term oncologic outcomes will require continued follow-up to assess. (Funded by the National Institute for Health Research Health Technology Assessment programme [reference number 13/04/03]; ISRCTN number, ISRCTN13472721.)

Background: DNA double strand breaks can affect genome integrity potentially leading to cancer. RAD51-associated protein 1 (RAD51AP1), an accessory protein to RAD51, is critical for homologous recombination, a key DNA damage response pathway. Emerging studies indicate a novel role for RAD51AP1 in carcinogenesis. Here we provide additional insight into the role of RAD51AP1 in ovarian cancer (OvCa)., Methods: Gene expression and patient phenotype data were obtained from TCGA and GTEX project consortia for bioinformatics analysis. Immunohistochemistry of OvCa tissue microarray was undertaken. Functional analyses were performed in a SKOV3 OvCa cell line with down-regulation of RAD51AP1 using siRNA., Results: RAD51AP1 is overexpressed at gene level in primary and recurrent OvCa compared to controls. At protein level, RAD51AP1 was up-regulated in low grade serous tumors compared to high grade OvCa. There was higher expression of RAD51AP1 in OvCa metastatic to lymph nodes compared to primary cancer samples. Gene enrichment analyses identified 12 differentially expressed genes (DEGs) related to OvCa, eight of which are also common in tissue from patients with type 2 diabetes mellitus (T2DM)., Conclusions: RAD51AP1 is overexpressed in OvCa, Given the link between OvCa and T2DM, the eight-gene signature shows potential for predictive value.

Background: Pulmonary carcinoids are rare tumors originating from neuroendocrine cells in the lungs. Because of their potentially infiltrative nature, surgical resection remains the treatment of choice. However, not all patients with technically resectable disease will be able to undergo surgery, primarily because of poor lung function or medical co-morbidities. Centrally located, intraluminal tumors have been reported to be amenable to bronchoscopic treatment. We specifically examined the role of cryotherapy in the treatment of bronchial carcinoid tumors., Methods: Sixty-three patients (52.38% female) who underwent a combined total of 243 cryotherapy procedures for treatment of bronchial carcinoid between 1992 and 2020 in our institution were included in the study. Following discussion in multidisciplinary meetings, patients were considered for first-line cryotherapy when lung resection was deemed not possible or when they had rejected surgery., Results: Cryotherapy resulted in complete remission in 21 (33.33%) patients with maximum tumor diameter less than 20 mm (mean: 11.08 mm, 95% confidence interval: 8.76-13.40), and allowed 22 (34.92%) patients with larger lesions (mean: 24.04 mm, 95% confidence interval: 18.78-29.30) to proceed with parenchymal sparing resections. Marked symptomatic relief (P<0.001) was reported by 58 (92.06%) patients. The median follow-up was 33 months (range: 0 to 243 mo). One (1.59%) patient was diagnosed with recurrence in a contralateral lobe 3 years after surgery and was treated with radiofrequency ablation., Conclusions: In the absence of a definitive randomized controlled trial comparing bronchoscopic treatment with surgical resection, we provide evidence on the safety and efficacy of cryotherapy and encourage wider adoption of this inexpensive and minimally invasive technique for treatment of bronchial carcinoids., Competing Interests: Disclosure: There is no conflict of interest or other disclosures., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The type of lung cancer surgery impacts on tumour manipulation during surgery and may drive dissemination of cancer cells into the vasculature, thus facilitating metastatic spread. The aim of this study was to investigate the impact of surgically induced trauma using peripheral blood from preoperative and postoperative patients with non-small cell lung cancer (NSCLC) undergoing thoracotomy or video-assisted thoracoscopic surgery (VATS) resection., Methods: Imaging flow cytometry was used to measure circulating cancer-associated cells (CCs). Circulating cell-free DNA (ccfDNA) isolation was performed using Promega dsDNA HS Assay Kit. DNA integrity measurements were calculated by the ALU247 to ALU115 ratio and cytokine levels measured using the Luminex screening assay., Results: CCs were increased in postoperative blood samples in 54 patients with NSCLC. Patients who underwent thoracotomy instead of VATS had higher numbers of EpCAM (p=0.004) and PanCK-labelled (p=0.03) CCs postoperatively. ccfDNA and DNA integrity index were also significantly increased in postoperative samples (p=0.0009 and p=0.04), with concomitant increase in interleukin 6 and interleukin 10 levels in the same cohorts (p=0.0004 and p=0.034, respectively)., Conclusions: In this study we have shown the potential clinical utility of several biomarkers from liquid biopsies to guide perioperative management, as well as provide a snapshot of the type of surgical resection in terms of circulating tumour cell release. Obtaining reliable readouts from blood can provide crucial information for disease progression, as well as being of prognostic value monitoring patients' response to treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: SARS-CoV-2 has challenged health service provision worldwide. This work evaluates safe surgical pathways and standard operating procedures implemented in the high volume, global city of London during the first wave of SARS-CoV-2 infection. We also assess the safety of minimally invasive surgery(MIS) for anatomical lung resection., Methods: This multicentre cohort study was conducted across all London thoracic surgical units, covering a catchment area of approximately 14.8 Million. A Pan-London Collaborative was created for data sharing and dissemination of protocols. All patients undergoing anatomical lung resection 1st March-1st June 2020 were included. Primary outcomes were SARS-CoV-2 infection, access to minimally invasive surgery, post-operative complication, length of intensive care and hospital stay (LOS), and death during follow up., Findings: 352 patients underwent anatomical lung resection with a median age of 69 (IQR: 35-86) years. Self-isolation and pre-operative screening were implemented following the UK national lockdown. Pre-operative SARS-CoV-2 swabs were performed in 63.1% and CT imaging in 54.8%. 61.7% of cases were performed minimally invasively (MIS), compared to 59.9% pre pandemic. Median LOS was 6 days with a 30-day survival of 98.3% (comparable to a median LOS of 6 days and 30-day survival of 98.4% pre-pandemic). Significant complications developed in 7.3% of patients (Clavien-Dindo Grade 3-4) and 12 there were re-admissions(3.4%). Seven patients(2.0%) were diagnosed with SARS-CoV-2 infection, two of whom died (28.5%)., Interpretation: SARS-CoV-2 infection significantly increases morbidity and mortality in patients undergoing elective anatomical pulmonary resection. However, surgery can be safely undertaken via open and MIS approaches at the peak of a viral pandemic if precautionary measures are implemented. High volume surgery should continue during further viral peaks to minimise health service burden and potential harm to cancer patients., Funding: This work did not receive funding., Competing Interests: None of the authors have conflict of interests to declare., (© 2021 The Author(s).)

Background: The p38MAPK family of Mitogen Activated Protein Kinases are a group of signalling molecules involved in cell growth, survival, proliferation and differentiation. The widely studied p38α isoform is ubiquitously expressed and is implicated in a number of cancer pathologies, as are p38γ and p38δ. However, the mechanistic role of the isoform, p38β, remains fairly elusive. Recent studies suggest a possible role of p38β in both breast and endometrial cancer with research suggesting involvement in bone metastasis and cancer cell survival. Female tissue specific cancers such as breast, endometrial, uterine and ovary account for over 3,000,000 cancer related incidents annually; advancements in therapeutics and treatment however require a deeper understanding of the molecular aetiology associated with these diseases. This study provides an overview of the MAPK signalling molecule p38β (MAPK11) in female cancers using an in-silico approach., Methods: A detailed gene expression and methylation analysis was performed using datasets from cBioportal, CanSar and MEXPRESS. Breast, Uterine Endometrial, Cervical, Ovarian and Uterine Carcinosarcoma TCGA cancer datasets were used and analysed., Results: Data using cBioportal and CanSAR suggest that expression of p38β is lower in cancers: BRCA, UCEC, UCS, CESC and OV compared to normal tissue. Methylation data from SMART and MEXPRESS indicate significant probe level variation of CpG island methylation status of the gene MAPK11. Analysis of the genes' two CpG islands shows that the gene was hypermethylated in the CpG1 with increased methylation seen in BRCA, CESC and UCEC cancer data sets with a slight increase of expression recorded in cancer samples. CpG2 exhibited hypomethylation with no significant difference between samples and high levels of expression. Further analysis from MEXPRESS revealed no significance between probe methylation and altered levels of expression. In addition, no difference in the expression of BRCA oestrogen/progesterone/HER2 status was seen., Conclusion: This data provides an overview of the expression of p38β in female tissue specific cancers, showing a decrease in expression of the gene in BRCA, UCEC, CESC, UCS and OV, increasing the understanding of p38β MAPK expression and offering insight for future in-vitro investigation and therapeutic application.

Video-assisted thoracoscopic surgery (VATS) has been increasingly used to resect lung nodules avoiding thoracotomy thus reducing morbidity and hospitalisation time. One of the main challenges is to localise the target, because very often they are not palpable and small. Various nodule localisation techniques have been used to assist VATS resection including metallic marker implantation adjacent to the lesion of interest. These markers have been known to migrate, more often in the pleural space. We report an unusual case of metallic marker migration to the contralateral lung., (© 2021 The Authors. Published by the British Institute of Radiology.)

Severe acute respiratory syndrome (SARS) coronavirus‑2 (SARS‑CoV‑2), the causative viral agent for the ongoing COVID‑19 pandemic, enters its host cells primarily via the binding of the SARS‑CoV‑2 spike (S) proteins to the angiotensin‑converting enzyme 2 (ACE2). A number of other cell entry mediators have also been identified, including neuropilin‑1 (NRP1) and transmembrane protease serine 2 (TMPRSS2). More recently, it has been demonstrated that transmembrane protease serine 4 (TMPRSS4) along with TMPRSS2 activate the SARS‑CoV‑2 S proteins, and enhance the viral infection of human small intestinal enterocytes. To date, a systematic analysis of TMPRSS4 in health and disease is lacking. In the present study, using in silico tools, the gene expression and genetic alteration of TMPRSS4 were analysed across numerous tumours and compared to controls. The observations were also expanded to the level of the central nervous system (CNS). The findings revealed that TMPRSS4 was overexpressed in 11 types of cancer, including lung adenocarcinoma, lung squamous cell carcinoma, cervical squamous cell carcinoma, thyroid carcinoma, ovarian cancer, cancer of the rectum, pancreatic cancer, colon and stomach adenocarcinoma, uterine carcinosarcoma and uterine corpus endometrial carcinoma, whilst it was significantly downregulated in kidney carcinomas, acute myeloid leukaemia, skin cutaneous melanoma and testicular germ cell tumours. Finally, a high TMPRSS4 expression was documented in the olfactory tubercle, paraolfactory gyrus and frontal operculum, all brain regions which are associated with the sense of smell and taste. Collectively, these data suggest that TMPRSS4 may play a role in COVID‑19 symptomatology as another SARS‑CoV‑2 host cell entry mediator responsible for the tropism of this coronavirus both in the periphery and the CNS.

Reconstruction of the sternum following deep sternal wound infection (DSWI) can be challenging, and despite advances in reconstructive surgery, DSWI remains a significant cause of morbidity and mortality in cardiothoracic patients. Transplantation patients present an additional, unique challenge for the reconstructive surgeon. These patients are often on immunosuppressant therapy, with multiple comorbidities, and cannot tolerate prolonged operations for reconstruction. They often have a prior extensive surgical history, which may limit donor options; and their wounds are often in the lower third of the sternum, which is a challenging location to reconstruct with locoregional tissues.We report a case of successful lower third chest wall reconstruction in a bilateral lung transplant recipient with a combination of bilateral pectoralis advancement flaps and omentoplasty., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Malignant melanomas within the eye present different types of metabolic and metastatic behavior. Uveal melanoma (UM) affects a quarter of a million individuals in the USA; however, the molecular pathogenesis is not well understood. Although UV radiation is a risk factor in cutaneous melanomas, it is not crucial for UM progression. Apart from chromosomal abnormalities, numerous major tumorigenic signaling pathways, including the PI3K/Akt, MAPK/ERK, Ras-association domain family 1 isoform A and Yes-associated protein/transcriptional co-activator with PDZ-binding motif signaling pathways, are associated with intraocular tumors. The present review describes the current insights regarding these signaling pathways that regulate the cell cycle and apoptosis, and could be used as potential targets for the treatment of UMs., (Copyright: © Katopodis et al.)

The tumor biomarkers already have proven clinical value and have become an integral part in cancer management and modern translational oncology. The tumor tissue microenvironment (TME), which includes extracellular matrix (ECM), signaling molecules, immune and stromal cells, and adjacent non-tumorous tissue, contributes to cancer pathogenesis. Thus, TME-derived biomarkers have many clinical applications. This review is predominately based on the most recent publications (manuscripts published in a last 5 years, or seminal publications published earlier) and fills a gap in the current literature on the cancer biomarkers derived from the TME, with particular attention given to the ECM and products of its processing and degradation, ECM-associated extracellular vesicles (EVs), biomechanical characteristics of ECM, and ECM-derived biomarkers predicting response to the immunotherapy. We discuss the clinical utility of the TME-incorporating three-dimensional in vitro and ex vivo cell culture models for personalized therapy. We conclude that ECM is a critical driver of malignancies and ECM-derived biomarkers should be included in diagnostics and prognostics panels of markers in the clinic., Competing Interests: The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Petersen, Chudakova, Skorova, Anikin, Reshetov and Mynbaev.)

Long non-coding RNAs (lncRNAs) perform a wide functional repertoire of roles in cell biology, ranging from RNA editing to gene regulation, as well as tumour genesis and tumour progression. The lncRNA X-inactive specific transcript (XIST) is involved in the aetiopathogenesis of non-small cell lung cancer (NSCLC). However, its role at the molecular level is not fully elucidated. The expression of XIST and co-regulated genes TSIX, hnRNPu, Bcl-2, and BRCA1 analyses in lung cancer (LC) and controls were performed in silico. Differentially expressed genes (DEGs) were determined using RNA-seq in H1975 and A549 NSCLC cell lines following siRNA for XIST. XIST exhibited sexual dimorphism, being up-regulated in females compared to males in both control and LC patient cohorts. RNA-seq revealed 944 and 751 DEGs for A549 and H1975 cell lines, respectively. These DEGs are involved in signal transduction, cell communication, energy pathways, and nucleic acid metabolism. XIST expression associated with TSIX, hnRNPu, Bcl-2, and BRCA1 provided a strong collective feature to discriminate between controls and LC, implying a diagnostic potential. There is a much more complex role for XIST in lung cancer. Further studies should concentrate on sex-specific changes and investigate the signalling pathways of the DEGs following silencing of this lncRNA.

Aims: Nuclear grade has been recently validated as a powerful prognostic tool in epithelioid malignant pleural mesothelioma (E-MPM). In other studies histological parameters including pleomorphic features and growth patterns were also shown to exert prognostic impact. The primary aims of our study are (i) externally validate the prognostic role of pleomorphic features in E-MPM and (ii) investigate if evaluating growth pattern in addition to 2-tier nuclear grade improves prognostication., Methods and Results: 614 consecutive cases of E-MPM from our institution over a period of 15 years were retrospectively reviewed, of which 51 showed pleomorphic features. E-MPM with pleomorphic features showed significantly worse overall survival compared to those without (5.4 versus 14.7 months). Tumours with predominantly micropapillary pattern showed the worst survival (6.2 months) followed by solid (10.5 months), microcystic (15.3 months), discohesive (16.1 months), trabecular (17.6 months) and tubulo-papillary (18.6 months). Sub-classification of growth patterns into high grade (solid, micropapillary) and low grade (all others) led to good separation of overall survival (10.5 versus 18.0 months) but did not predict survival independent of 2-tier nuclear grade. A composite score comprised of growth pattern and 2-tier nuclear grade did not improve prognostication compared with nuclear grade alone. Intra-tumoural heterogeneity in growth patterns is ubiquitous., Conclusions: Our findings support the incorporation of E-MPM with pleomorphic features in the epithelioid subtype as a highly aggressive variant distinct from 2-tier nuclear grade. E-MPM demonstrates extensive heterogeneity in growth pattern but its evaluation does not offer additional prognostic utility to 2-tier nuclear grade., (© 2020 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Severe acute respiratory syndrome (SARS) coronavirus‑2 (SARS‑CoV2) is the cause of a new disease (COVID‑19) which has evolved into a pandemic during the first half of 2020. Older age, male sex and certain underlying diseases, including cancer, appear to significantly increase the risk for severe COVID‑19. SARS‑CoV‑2 infection of host cells is facilitated by the angiotensin‑converting enzyme 2 (ACE‑2), and by transmembrane protease serine 2 (TMPRSS2) and other host cell proteases such as cathepsin L (CTSL). With the exception of ACE‑2, a systematic analysis of these two other SARS‑CoV2 infection mediators in malignancies is lacking. Here, we analysed genetic alteration, RNA expression, and DNA methylation of TMPRSS2 and CTSL across a wide spectrum of tumors and controls. TMPRSS2 was overexpressed in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), uterine corpus endometrial carcinoma and uterine carcinosarcoma, with PRAD and READ exhibiting the highest expression of all cancers. CTSL was upregulated in lymphoid neoplasm diffuse large B‑cell lymphoma, oesophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, lower grade glioma, pancreatic adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, and thymoma. Hypo‑methylation of both genes was evident in most cases where they have been highly upregulated. We have expanded on our observations by including data relating to mutations and copy number alterations at pan‑cancer level. The novel hypotheses that are stemming out of these data need to be further investigated and validated in large clinical studies.

Circulating tumour cells (CTCs) are cancer cells of epithelial origin that are present in peripheral blood samples. ScreenCell detection of CTCs and the association with long term survival in non-small cell lung cancer (NSCLC) patients was evaluated in the present study. A total of 33 patients undergoing surgical resection for NSCLC were recruited. Patients were followed up for 5-years post-operatively. Pre-operative patient bloods samples were processed using ScreenCell. CTCs were detected in 26 (79%) patients. In patients who were positive for CTCs, a total of 9 (35%) patients succumbed to the disease, whereas in patients negative for CTCs, a total of 4 (57%) patients succumbed to the disease (P=0.29). No association was identified between positive CTCs and poorer survival (Chi-squared 1.47, P=0.23; hazard ratio, 0.42; 95% confidence interval: 0.1-1.7). The presence of CTCs detected with ScreenCell does not influence prognosis in patients with NSCLC that was operated on. The high rate of CTC detection is encouraging in supporting this technology to aid early lung cancer diagnosis., (Copyright: © Barr et al.)

Nuclear grading systems for epithelioid malignant pleural mesothelioma (MPM) have been proposed but it remains uncertain if they could be applied in a biopsy-heavy setting. Using the proposed system, we conducted an independent, external validation study using 563 consecutive cases of epithelioid MPM diagnosed at our institution between 2003 and 2017, of which 87% of patients underwent biopsies only. The median number of sites sampled was 1, with a median maximum tissue dimension of 17 mm (biopsy) and 150 mm (resection). The median overall survival (OS) was 14.7 months. The frequencies of grade I, II, and III tumors were 31% (132/563), 52% (292/563), and 17% (94/563). Grade I tumors were associated with the most favorable median OS (24.7 mo) followed by grades II (12.7 mo) and III (7.2 mo). The 2-tier nuclear grade separated tumors into low grade (19.3 mo) and high grade (8.9 mo). In multivariate analysis, 3-tier nuclear grade, 2-tier nuclear grade, and mitosis-necrosis score predicted OS independent of age, procedural type, solid-predominant growth pattern, necrosis, and atypical mitosis (all P<0.001 except 2-tier nuclear grade, P=0.001). In the scenario of a single- site biopsy with tissue dimension ≤10 mm, none but age (P=0.002) were independently predictive. Our data also suggested sampling 3 sites or a maximum tissue dimension of at least 20 mm from a single site is optimal for nuclear grade assessment. In conclusion our study confirmed the utility of nuclear grade in epithelioid MPM using a biopsy-heavy cohort provided the tissue sample met minimum dimensional criteria.

Background : Mandibular reconstruction, after extensive resection of the mandible for the treatment of oral cancer, is a well-known procedure, however, relatively little is known about bone integration into the titanium implant after reconstruction with a temporary plastic implant. The main goal of this experimental study was to study the process of osseous integration into the titanium implant in an in vivo experiment following prior mandibular reconstruction with a temporary plastic implant. Materials and Methods : Four ewes initially underwent a partial one-sided resection of the mandible, with the formation of an approximately 3 × 1 cm defect. All of the subjects received reconstruction with an implantation of a plastic plate (3 cm). The plastic plate was removed and replaced by a titanium implant at 1, 3, 6, and 12 months, accordingly. Both plastic and titanium implants were made via 3D-printing technology and personalized modeling. A total of 6 months after titanium implantation, a histological evaluation of biointegration was performed. Results : All surgeries were uncomplicated. The integration of osseous tissue into the titanium implant was seen in all cases. Histologically, each case showed variable integration of dense fibrotic tissue with fibroblasts and non-mature bone tissue with a definitive layer of bone matrix with many osteoblasts on the periphery. The prior implantation of the plastic plate did not interfere with bone integration into the titanium implant. Conclusion : Preliminary results demonstrated that a temporary plastic implant for mandibular reconstruction does not interfere with the consequent osseous biointegration of a permanent titanium implant. This shows that temporary reconstruction is a safe solution when delayed mandibular reconstruction is required due to disease severity.

Ovarian cancer is fifth in the rankings of cancer deaths among women, and accounts for more deaths than any other gynecological malignancy. Despite some improvement in overall-(OS) and progression-free survival (PFS) following surgery and first-line chemotherapy, there is a need for development of novel and more effective therapeutic strategies. In this mini review, we provide a summary of the current landscape of the clinical use of tyrosine kinase inhibitors (TKIs) and mechanistic target of rapamycin (mTOR) inhibitors in ovarian cancer. Emerging data from phase I and II trials reveals that a combinatorial treatment that includes TKIs and chemotherapy agents seems promising in terms of PFS despite some adverse effects recorded; whereas the use of mTOR inhibitors seems less effective. There is a need for further research into the inhibition of multiple signaling pathways in ovarian cancer and progression to phase III trials for drugs that seem most promising.

: Background: Current diagnosis and staging of advanced epithelial ovarian cancer (aEOC) has important limitations and better biomarkers are needed. We investigate the performance of non-haematopoietic circulating cells (CCs) at the time of disease presentation and relapse. Methods: Venous blood was collected prospectively from 37 aEOC patients and 39 volunteers. CCs were evaluated using ImageStream Technology TM and specific antibodies to differentiate epithelial cells from haematopoetic cells. qRT-PCR from whole blood of relapsed aEOC patients was carried out for biomarker discovery. Results: Significant numbers of CCs (CK + /WT1 + /CD45 - ) were identified, quantified and characterised from aEOC patients compared to volunteers. CCs are abundant in women with newly diagnosed aEOC, prior to any treatment. Evaluation of RNA from the CCs in relapsed aEOC patients (n = 5) against a 79-gene panel revealed several differentially expressed genes compared to volunteers (n = 14). Size differentiation of CCs versus CD45 + haematopoietic cells was not reliable. Conclusion: CCs of non-haematopoetic origin are prevalent, particularly in patients with newly diagnosed aEOC. Exploiting a CC-rich population in aEOC patients offers insights into a part of the circulating microenvironment., Competing Interests: The authors declare no conflict of interest.

Background: Liquid biopsies offer a promising alternative to tissue samples, providing non-invasive diagnostic approaches or serial monitoring of disease evolution. However, certain challenges remain, and the full potential of liquid biopsies has yet to be reached. Here we report several methodological approaches to interrogate liquid biopsies using circulating tumour cell (CTC) enumeration and characterisation, transcriptomics, Raman spectroscopy, and copy number instability (CNI) scores using blood samples of lung cancer (LC) patients. Methods : We choose LC; since it still is the most common cause of cancer-related mortality worldwide, and therefore there is a need for development of new non-invasive diagnostic/prognostic technologies. Changes in gene expression were assessed using RNA-seq, and in CTCs using ImageStream, an imaging flow-cytometer. CNI scores, from paired tissue/ctDNA were also explored. Raman spectroscopy was used to provide chemical fingerprints of plasma samples. Results : CTCs were detected in all LC patients ( n = 10). We observed a significant increase in CTC levels in LC patients ( n = 10) compared to controls ( n = 21). A similar CNI was noted in the tissue and plasma of 2 patients, where higher CNI scores corresponded with poorer outcome. Significant changes in Raman spectra (carotenoid concentrations) were noted in LC patients ( n = 20) compared to controls ( n = 10). RNA-seq revealed differential expression of 21 genes between LC cases and controls in both LC tissue and blood samples. Conclusions : Liquid biopsies can potentially provide a more comprehensive picture of the disease compared to a single tissue biopsy. CTC enumeration is feasible and sensitive for LC patients. Molecular profiling of CTCs is also possible from total blood. CNI scores and Raman spectra require further investigation. Further work is being undertaken to explore these methods of detection in a larger LC cohort.

Introduction: Lung cancer survival remains poor in the western world due to late presentation in most cases, leading to difficulty of treatment in these advanced and metastatic patients. Therefore, the development of a robust biomarker for prognosis and to monitor treatment response and relapse would be of great benefit. The use of Alu repeats and DNA Integrity Index has been shown to hold both diagnostic and prognostic value, and as it is obtained from the plasma of patients, it can serve as a non-invasive tool for routine monitoring. This study evaluates the efficiency of this technique in malignant lung cancer patients., Methods: Plasma samples were collected from 48 patients, consisting of 29 lung cancer patients and 19 non-cancer controls. Alu repeat ratio and confounders were measured., Results: Observations showed a higher Alu repeat ratio amongst the cancer group compared to controls ( p=0.035) , mean Alu ratio 0.38 (range 0.01-0.93) and 0.22 (0.007-0.44) respectively, ROC curve analysis AUC 0.61 (p=0.22) . Analysis by staging was more promising, whereby a higher DNA Integrity Index was seen in advanced cases compared to both early stage and controls, p<0.0001; AUC: 0.92 (P=0.0002) and p=0.0006, AUC - 0.88 (p=0.0007) respectively, however no significant difference was observed in the early stage compared to controls. Short term survival data also showed a DNA Integrity Index of >0.5 to be associated with poorer overall survival p=0.03 ., Conclusion: The results of this study show a potential use of Alu repeats ratios for prognostic purposes in the advanced setting for lung cancer patients., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

The role of surgery in malignant pleural mesothelioma (MPM) remains debatable; nonetheless the relative advantages of different surgical approaches are frequently reassessed and reconsidered. While extensive operations and longer recovery periods can be justified for a group of carefully selected patients, many will present at an advanced stage of their disease or with associated co-morbidities which will exclude them from selection criteria for radical treatment. For these patients, minimally invasive video-assisted procedures may be considered, for purposes of cytoreduction and/or symptomatic relief. Even though there is currently not enough clinical evidence to suggest an improvement in overall survival with limited debulking procedures, it has been suggested that they can improve quality of life over drainage and pleurodesis alone. We consider video-assisted PlasmaJet ablation to potentially have a role in mesothelioma surgery, as it may be used for effective cytoreduction while minimising the risk for complications often associated with extensive pleurectomy procedures, and we report on the use of the PlasmaJet Surgical System in our centre for surgical management of a patient with MPM. After demonstrating safety and absence of major adverse events with this approach, we feel justified in offering the procedure to more of our patients as we aim to collect additional data., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

To date, microarray analyses have led to the discovery of numerous individual 'molecular signatures' associated with specific cancers. However, there are serious limitations for the adoption of these multi-gene signatures in the clinical environment for diagnostic or prognostic testing as studies with more power need to be carried out. This may involve larger richer cohorts and more advanced analyses. In this study, we conduct analyses-based on gene regulatory network-to reveal distinct and common biomarkers across cancer types. Using microarray data of triple-negative and medullary breast, ovarian and lung cancers applied to a combination of glasso and Bayesian networks (BNs), we derived a unique network-containing genes that are uniquely involved: small proline-rich protein 1A (SPRR1A), follistatin like 1 (FSTL1), collagen type XII alpha 1 (COL12A1) and RAD51 associated protein 1 (RAD51AP1). RAD51AP1 and FSTL1 are significantly overexpressed in ovarian cancer patients but only RAD51AP1 is upregulated in lung cancer patients compared with healthy controls. The upregulation of RAD51AP1 was mirrored in the bloods of both ovarian and lung cancer patients, and Kaplan-Meier (KM) plots predicted poorer overall survival (OS) in patients with high expression of RAD51AP1. Suppression of RAD51AP1 by RNA interference reduced cell proliferation in vitro in ovarian (SKOV3) and lung (A549) cancer cells. This effect appears to be modulated by a decrease in the expression of mTOR-related genes and pro-metastatic candidate genes. Our data describe how an initial in silico approach can generate novel biomarkers that could potentially support current clinical practice and improve long-term outcomes.

Objectives: The aim of this study is to collate multi-institutional data to determine the value by defining the diagnostic performance of fluorodeoxyglucose positron emission tomography (FDG PET)/CT for malignancy in patients undergoing surgery with an anterior mediastinal mass in order to ascertain the clinical utility of PET/CT to differentiate malignant from benign aetiologies in patients presenting with an anterior mediastinal mass SETTING: DECiMaL Study is a multicentre, retrospective, collaborative cohort study in seven UK surgical sites., Participants: Between January 2002 and June 2015, a total of 134 patients were submitted with a mean age (SD) of 55 years (16) of which 69 (51%) were men. We included all patients undergoing surgery who presented with an anterior mediastinal mass and underwent PET/CT. PET/CT was considered positive for any reported avidity as stated in the official report and the reference was the resected specimen reported by histopathology using WHO criteria., Primary and Secondary Outcome Measures: Sensitivity, specificity, positive and negative predicted values of [18F]-FDG PET in determining malignant aetiology for an anterior mediastinal mass., Results: The sensitivity and specificity of PET/CT to correctly classify malignant disease were 83% (95% CI 74 to 89) and 58% (95% CI 37 to 78). The positive and negative predictive values were 90% (95% CI 83% to 95%) and 42% (95% CI 26% to 61%)., Conclusions: The results of our study suggest reasonable sensitivity but no specificity implying that a negative PET/CT is useful to rule out the diagnosis of malignant disease whereas a positive result has no value in the discrimination between malignant and benign diseases of the anterior mediastinum., Competing Interests: Competing interests: Outside this work, EL reports personal fees from Abbott Molecular, personal fees from Glaxo Smith Kline, personal fees from Pfizer, personal fees from Novartis, personal fees from Covidien, personal fees from Roche, personal fees from Lily Oncology, personal fees from Boehringer Ingelheim, personal fees from Medela, grants and personal fees from ScreenCell, personal fees from Ethicon, outside the submitted work, and is the founder of Informative Genomics, a blood-based molecular diagnostic company in London., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Never-smokers with lung cancer often present late as there are no established aetiological risk factors. The aim of the study is to define the frequency over time and characterise clinical features of never-smokers presenting sufficiently early to determine if it is possible to identify patients at risk., Methods: We retrospectively analysed data from a prospectively collected database of patients who underwent surgery. The frequency was defined as number of never-smokers versus current and ex-smokers by year. Clinical features at presentation were collated as frequency., Results: A total of 2170 patients underwent resection for lung cancer from March 2008 to November 2014. The annual frequency of developing lung cancer in never-smokers increased from 13% to 28%, attributable to an absolute increase in numbers and not simply a change in the ratio of never-smokers to current and ex-smokers. A total of 436 (20%) patients were never-smokers. The mean age was 60 (16 SD) years and 67% were female. Presenting features were non-specific consisting of cough in 34%, chest infections in 18% and haemoptysis in 11%. A total of 14% were detected on incidental chest film, 30% on computed tomography, 7% on positron-emission tomography/computed tomography and 1% on MRI., Conclusions: We observed more than a double of the annual frequency of never-smokers in the last 7 years. Patients present with non-specific symptoms and majority were detected on incidental imaging, a modality that is likely to play an increasingly important role for early detection in this cohort that does not have any observable clinical risk factors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This study aims to evaluate surgical approaches to the management of retrosternal goitre. Between 2004 and 2014, 35 patients (eight males; mean age 67.4 ± 10.9 years) with retrosternal goitre (mainly right-sided in 9, left-sided in 14 and bilateral in 12) underwent surgery. A palpable neck mass was found in 11 (31.4%), stridor in 10 (28.6%) and thyrotoxicosis in 4 (11.4%) cases. 4 (11.4%) patients were asymptomatic. Tracheal compression was detected radiologically in 27 (77.2%) patients with deviation in 18 (51.4%). A collar incision was performed in 34 patients, 6 (17.1%) of whom required additional sternotomy, 1 (2.9%) was assisted by an anterior mediastinotomy. 1 (2.9%) had a right lateral thoracotomy. There was no operative mortality. Transient vocal changes occurred in 3 (8.6%) patients, recurrent laryngeal nerve palsy in 3, atrial fibrillation in 2, and wound complications in 2 (5.7%). Hospital stay ranged from 2 to 12 days (5.5 ± 2.0). Multinodular goitre was found in 33 patients, diffuse goitre in 1 and ectopic thyroid in 1. The average vertical length of goitres in the collar incision group was 7.6 cm compared to 10.6 cm in the sternotomy group. The average weight of specimens was 156.3 g in patients with collar incisions and 307.5 g in the sternotomy group. Removal of retrosternal goitre is more commonly performed via a cervical collar incision with mandatory availability of sternotomy. Radiological measurement of craniocaudal length may predict the risk of sternotomy. Surgical outcomes are not affected by surgical approach.

Lung cancer is a leading cause of mortality and despite surgical resection a proportion of patients may develop metastatic spread. The detection of circulating tumour cells (CTCs) may allow for improved prediction of metastatic spread and survival. The current study evaluates the efficacy of the ScreenCell® filtration device, to capture, isolate and propagate CTCs in patients with primary lung cancer. Prior to assessment of CTCs, the present study detected cancer cells in a proof-of-principle- experiment using A549 human lung carcinoma cells as a model. Ten patients (five males and five females) with pathologically diagnosed primary non-small cell lung cancer undergoing surgical resection, had their blood tested for CTCs. Samples were taken from a peripheral vessel at the baseline, from the pulmonary vein draining the lobe containing the tumour immediately prior to division, a further central sample was taken following completion of the resection, and a final peripheral sample was taken three days post-resection. A significant increase in CTCs was observed from baseline levels following lung manipulation. No association was able to be made between increased levels of circulating tumour cells and survival or the development of metastatic deposits. Manipulation of the lung during surgical resection for non-small cell lung carcinoma results in a temporarily increased level of CTCs; however, no clinical impact for this increase was observed. Overall, the study suggests the ScreenCell® device has the potential to be used as a CTC isolation tool, following further work, adaptations and improvements to the technology and validation of results.

Background: Detection of circulating tumour cells (CTCs) in the peripheral blood of lung cancer patients may predict survival. Various platforms exist that allow capture of these cells for further analysis; little work however, has been done with the ScreenCell device, an antibody-independent CTC platform. The aim of our study was to evaluate the ScreenCell device for detection of CTCs in lung cancer patients and to establish correlations of these findings with survival., Materials and Methods: Twenty-three patients, nine males, and fourteen females, underwent surgical treatment from February to May 2014 for non-small cell lung cancer. Thirteen patients had adenocarcinoma and ten squamous cell carcinoma, while eight were at an early stage (I-II) and five at a later stage (III-IV). Blood samples were obtained prior to surgery and following filtration through the ScreenCell device, were independently reviewed by 2 consultant pathologists., Results: The pathologists were able to independently identify CTCs in 78.3% (N=18) and 73.9% (N=17) of the cases examined, with overall 80.6% in early stages compared to 60.0% in late stages. The median survival times of positive vs. negative for CTC patients were 1011 and 711 days respectively, with a survival percentage rate of 77.8% and 60% in positive and negative CTC cohorts respectively., Conclusion: The results of this study suggest that the presence of CTCs analyzed by ScreenCell did not necessarily lead to a poorer prognosis in patients with lung cancer after curative surgery., (Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Routine clinical application of circulating tumour cells (CTCs) for blood based diagnostics is yet to be established. Despite growing evidence of their clinical utility for diagnosis, prognosis and treatment monitoring, the efficacy of a robust platform and universally accepted diagnostic criteria remain uncertain. We evaluate the diagnostic performance of a microfluidic CTC isolation platform using cytomorphologic criteria in patients undergoing lung cancer surgery., Methods: Blood was processed from 51 patients undergoing surgery for known or suspected lung cancer using the ClearBridge ClearCell FX system TM (ClearBridge Biomedics, Singapore). Captured cells were stained on slides with haematoxylin and eosin (H&E) and independently assessed by two pathologist teams. Diagnostic performance was evaluated against the pathologists reported diagnosis of cancer from surgically obtained specimens., Results: Cancer was diagnosed in 43.1% and 54.9% of all cases. In early stage primary lung cancer, between the two reporting teams, a positive diagnosis of CTCs was made for 50% and 66.7% of patients. The agreement between the reporting teams was 80.4%, corresponding to a kappa-statistic of 0.61±0.11 (P<0.001), indicating substantial agreement. Sensitivity levels for the two teams were calculated as 59% (95% CI, 41-76%) and 41% (95% CI, 24-59%), with a specificity of 53% for both., Conclusions: The performance of the tested microfluidic antibody independent device to capture CTCs using standard cytomorphological criteria provides the potential of a diagnostic blood test for lung cancer., Competing Interests: The authors have no conflicts of interest to declare.

Background: The ability to sub-stratify survival within stage I is an important consideration as it is assumed that survival is heterogeneous within this sub-group. Liang et al. recently published a nomogram to predict post-operative survival in patients undergoing lung cancer surgery. The aim of our study is external validation of their published nomogram in a British cohort focusing on stages IA and IB to determine applicability in selection of adjuvant chemotherapy within stage I., Methods: Patient variables were extracted and the score individually calculated. Receiver operative characteristics curve (ROC) was calculated and compared with the original derivation cohort and the discriminatory ability was further quantified using survival plots by splitting our (external) validation cohort into three tertiles and Kaplan Meier plots were constructed and individual curves tested using Cox regression analysis on Stata 13 and R 3.1.2 respectively., Results: A total of 1,238 patients were included for analysis. For all patients from stage IA to IIB the mean (SD) score was 9.95 (4.2). The ROC score comparing patients who died versus those that remained alive was 0.62 (95% CI: 0.58 to 0.67). When divided into prognostic score tertiles, survival discrimination remained evident for the entire cohort, as well as those for stage IA and IB alone. The P value comparing survival between the middle and highest score with baseline (low score) was P=0.031 and P=0.034 respectively., Conclusions: Our results of external validation suggested lower survival discrimination than reported by the original group; however discrimination between survival remained evident for stage I.

Early diagnosis of lung cancer still poses a major issue, with a large proportion of patients diagnosed at late stages. Therapeutic options and treatment remain limited in these patients. In most cases only palliative therapies are available to alleviate any severe symptoms. Endobronchial cryotherapy (EC) is one form of palliative treatment offered to patients with obstructive airway tumours. Although successful, the impact on circulating tumour cell (CTCs) spread has not been investigated in detail. This study recruited 20 patients awaiting EC treatment. Baseline and post EC blood samples were analysed for presence of CTCs. Results showed an increase in CTCs following EC in 75% of patients. Significant increases were noticeable in some cases. Although EC is a well-accepted modality of treatment to alleviate symptoms, it may lead to an increase in CTCs, which in turn may have implications for tumour dissemination and metastatic spread., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background/aim: Radiofrequency ablation (RFA) is an increasingly utilised technique in patients with surgically-untreatable lesions. The effect of this therapy on circulating tumor cells (CTCs) is unknown. As far as we are aware of, this is the first study to evaluate the effects of RFA on CTCs in patients with malignant lung tumors immediately post-treatment., Patients and Methods: Nine patients with primary or metastatic lung tumors underwent RFA therapy from June to November 2013. Blood samples were taken before and after RFA, and filtered through the ScreenCell CTC capture device., Results: A general increase in CTCs in 7 out of the 9 cases was found, the largest increases were seen in the metastatic group., Conclusion: This study demonstrates that the manipulation and ablative procedure of lung tumors leads to immediate dissemination of tumor cells, the effects of which are unknown and require further investigation., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Endobronchial metastases from extrapulmonary tumors are rare and often cause significant symptoms particularly when they present within the main bronchial tree. Cryotherapy has been shown to be effective in the treatment of primary malignancies of the endobronchial tree. This is the first detailed analysis of the application of cryotherapy to endobronchial metastatic tumors of extrapulmonary origin. This study assessed the role of endobronchial cryotherapy in the management of these patients, including control of symptoms and improvement in endobronchial patency., Methods: The details of 35 patients treated over a 17-year period were reviewed. Patients' ages ranged from 22 to 80 years. The primary tumors were mainly colorectal and renal., Results: There were no perioperative or in-patient deaths. Endobronchial cryotherapy was carried out as a day-case procedure in over 80% of cases. Of the 35 patients, 30 (85%) reported a significant improvement in their main presenting symptom. In over half the patients, endoluminal patency was increased by ≥50% following 1 treatment of cryotherapy. Survival ranged from 10 days to 4 years 8 months, with a median survival of 34 weeks. One-year survival was 37.5%., Conclusions: Endoluminal cryotherapy gives rapid resolution of symptoms and can be carried out as a day-case procedure in the vast majority of patients. We recommend that cryotherapy should be considered as a first-line palliation in patients with symptomatic metastases to the endobronchial tree.

Background: Thoracoscore and the European Society Objective Score (ESOS.01) are two scoring systems used in thoracic surgery to estimate operative mortality risk. We aimed to evaluate if these are valid tools for use in the UK population., Methods: A multi-center, prospective study was carried out on patients undergoing lung resection at six UK centers. Data were submitted electronically using our online data collection tool. Data were analyzed to determine the factors affecting mortality. A receiver operating characteristic analysis determined the ability of the thoracoscore and ESOS.01 to predict in-hospital mortality., Results: Data were complete for 2,245 patients. The observed in-hospital mortality was 31 patients (1.38%). Mean thoracoscore was 2.66 (SD ± 3.21). Gender (P = 0.004, hazard ratio 4.786) and co-morbidity score (P = 0.005, hazard ratio 3.289) were identified as risk factors for mortality. A sub-analysis was performed using data from 1,912 patients with complete data for ESOS.01. In this group, mean thoracoscore was 2.55 (SD ± 2.94), mean ESOS.01 was 2.11(SD ± 1.41), and these were statistically significantly different (P < 0.0001). The observed in-hospital mortality was 28 patients (1.46%). The c-index for thoracoscore was 0.705, and for ESOS.01 was 0.739., Conclusions: Both thoracoscore and ESOS.01 overestimated mortality in the UK population. There is a continued need to develop an appropriate risk prediction system for the UK., Competing Interests: We have no conflicts of interest to declare.

Objectives: Circulating tumour cells (CTCs) are reported to be predictive for prognosis and response to treatment in advanced lung cancer. However, the clinical utility of the CTCs detection remains unknown for early stage lung cancer as the number of CTCs is reported as low, providing challenges in identification. We have evaluated diagnostic performance of filtration-based technology using cytomorphologic criteria in patients undergoing surgery for lung cancer., Material and Methods: We processed blood from 76 patients undergoing surgery for known or suspected lung cancer using ScreenCell(®) Cyto filter devices. Captured cells were stained using haematoxylin and eosin and independently assessed by two pathologists for the presence of atypical cells suspicious for cancer. Diagnostic performance was evaluated against pathologist reported diagnoses of cancer from surgically obtained specimens., Results: Cancer was diagnosed in 57 patients (77.0%), including 32 with primary lung cancer (56.1%). The proportion of patients with early stage primary lung cancer in which CTCs were identified was 18 and 21 (56.3% and 65.6%, respectively) as reported by two pathologists. The agreement between the pathologists was 77.0% corresponding to a kappa-statistic of 53.7% indicating moderate agreement. No significant differences were found for the percentage of CTCs for primary and metastatic cancer as well as for cancer stages. On sensitivity weighted analysis, a sensitivity and specificity were 71.9% (95% CI 60.5-83.0) and 52.9% (95% CI 31.1-77.0), respectively. On specificity weighted analysis, a sensitivity and specificity were 50.9% (95% CI 39.3-64.4) and 82.4% (60.4-96.2), respectively., Conclusion: The performance of the tested filter-based antibody-independent technology to capture CTCs using standard cytomorphologic criteria provides the potential of a diagnostic blood test for lung cancer., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The ability to capture and characterize peripheral blood circulating tumor cells has the potential for the development of a blood test for cancer. The aim of this study was to evaluate the diagnostic performance of microfluidic technology as a proof-of-concept study., Methods: Blood from patients undergoing surgery for known or suspected lung cancer was obtained and processed using a microfluidic biochip. Diagnostic performance was evaluated against the reference of cancer identified within surgically obtained formalin-fixed paraffin embedded specimens reported by a principal pathologist. Agreement was assessed in a sample reported by a second independent pathologist. Sensitivity- and specificity-weighted analyses were undertaken., Results: From March 2011 to October 2012, 46 patients at our institution donated blood for research. Cancer was the underlying diagnosis in 43 (94%); 34 (79%) of the patients had primary lung cancer. The proportion of patients with cancer in which atypical cells suspicious for cancer were identified on hematoxylin and eosin staining was 16/43 (37%) by the principal pathologist and 10/17 (59%) by the second pathologist. On sensitivity-weighted analysis, the sensitivity of the biochip was 54% (95% confidence interval [CI], 37-72) and the specificity was 33% (95% CI, 2-91). On specificity-weighted analysis, the sensitivity was 43% (95% CI, 21-71) and the specificity was 100% (95% CI, 5-100)., Conclusions: This work highlights the potential of microfluidic technology to develop a blood test for the diagnosis of cancer using peripheral blood; conventional clinical criteria can be used as a proof-of-concept of what may be possible with today's technology., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Phyllodes tumors are rare fibroepithelial tumors that make up less than 1% of all breast tumors. Malignant phyllodes tumors are associated with a 25% incidence of distant metastasis, which is invariably fatal within 24 months. We report successful resection of a solitary pulmonary metastasis in the left chest in a 50-year-old woman 7 years after a right-sided mastectomy for malignant phyllodes tumor.

Reoperative surgery through a previous pneumonectomy space focuses on the management of postpneumonectomy empyemas and bronchopleural fistulae. There are reports of elective tracheal resections done through the pneumonectomy space. We report two cases of successful excision of recurrent tumours (leiomyosarcoma and carcinoid) performed through the previous pneumonectomy space 2 and 13 years, respectively, after the primary surgical resection.

Pulmonary hamartomas are usually an incidental finding and range in size from 1 cm to 8 cm in diameter in various series. We report a case of a massive pulmonary hamartoma (size 25.5 x 17.5 x 6.5 cm and weighing 1134 g) in a 61 year old male who presented with a short history of breathlessness. The tumour was arising from the medial border of the right lung and occupying most of the right chest extending in to the anterior mediastinum. The tumour was compressing the right lung and there was no evidence of infiltration into the surrounding structures. It was successfully treated by surgical resection and final histology was pulmonary hamartoma with predominantly adipose and leiomyomatous differentiation.

Matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix is a major factor for tumor development and expansion. This study analysed MMP-10 protein expression and activity in human lung tumors of various grade, stage, and type to address the relationship between MMP-10 and tumor characteristics and to evaluate MMP-10 as a therapeutic target in non small cell lung carcinoma (NSCLC). Unlike the majority of MMPs, MMP-10 was located in the tumor mass as opposed to tumor stroma. MMP-10 protein was observed at low levels in normal human lung tissues and at significantly higher levels in all types of NSCLC. No correlation was observed between MMP-10 protein expression and tumor type, stage, or lymph node invasion. To discriminate between active and inactive forms of MMP-10 in samples of human NSCLC, we have developed an ex vivo fluorescent assay. Measurable MMP-10 activity was detected in 42 of 50 specimens of lung cancer and only 2 of 10 specimens of histologically normal lung tissue. No relationship was observed between MMP-10 activity levels and clinicopathologic characteristics. Our results suggest that MMP-10 is expressed and active at high levels in human NSCLC compared to normal lung tissues, and, as such, is a potential target for the development of novel therapeutics for lung cancer treatment.