Concomitant cardiac surgery and fixation of bilateral rib fractures sustained during cardiopulmonary resuscitation.

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.

Presence of pleomorphic features but not growth patterns improves prognostic stratification of epithelioid malignant pleural mesothelioma by 2-tier nuclear grade.

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.

Identification of cancer biomarkers of prognostic value using specific gene regulatory networks (GRN): a novel role of RAD51AP1 for ovarian and lung cancers.

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.

Circulating tumour cells in patients with lung cancer undergoing endobronchial cryotherapy.

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.

Outcomes of single- versus multi-port video-assisted thoracoscopic surgery: Data from a multicenter randomized controlled trial of video-assisted thoracoscopic surgery versus thoracotomy for lung cancer.

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.

Determining the optimal time to report mortality after lobectomy for lung cancer: An analysis of the time-varying risk of death.

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.

Treatment of Pulmonary Carcinoid Tumors With Bronchoscopic Cryotherapy: A 28-Year Single-center Experience.

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.

Differential Expression of RAD51AP1 in Ovarian Cancer: Effects of siRNA In Vitro.

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.

Impact of video-assisted thoracoscopic lobectomy versus open lobectomy for lung cancer on recovery assessed using self-reported physical function: VIOLET RCT.

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: Lung cancer is a common cause of cancer death worldwide. If the disease is caught early, the part of the lung containing the tumour can be removed in an operation called a lobectomy. The operation can be carried out through a large cut so that the surgeon has a full view of the lung, which is called open surgery, or using several small cuts and a camera, which is called video-assisted thoracoscopic (keyhole) surgery. It is thought that, as keyhole surgery is less invasive, patients recover quicker. However, to the best of our knowledge, there are no high-quality research studies that are applicable to UK practice to support this. This study was conducted so that it could be determined, based on high-quality evidence, which operation provides the best treatment and recovery for patients. WHO PARTICIPATED?: Five hundred and three adults referred for lobectomy for known or suspected lung cancer from nine hospitals in the UK. WHAT WAS INVOLVED?: Participants were randomly allocated to either receive keyhole or open surgery. Participants were followed up for 12 months. We collected information on further treatment, hospital visits, safety information and disease progression over this period. Participants were also asked to complete questionnaires about their health and recovery. WHAT DID THE TRIAL FIND?: For patients with early-stage lung cancer who underwent a lobectomy, keyhole surgery led to less pain, less time in hospital and better quality of life than open surgery, without having a detrimental effect on cancer progression or survival. Keyhole surgery was found to be cost-effective and to provide excellent value for money for the NHS.

Video-Assisted Thoracoscopic or Open Lobectomy in Early-Stage Lung Cancer.

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.)

Lower third chest wall reconstruction in a bilateral sequential lung transplant recipient.

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.

Migration of a nodule localisation marker to the contralateral lung.

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.

Molecular characteristics of uveal melanoma and intraocular tumors.

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.

p38ß - MAPK11 and its role in female cancers.

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, p38ß, remains fairly elusive. Recent studies suggest a possible role of p38ß 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 p38ß (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 p38ß 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 p38ß in female tissue specific cancers, showing a decrease in expression of the gene in BRCA, UCEC, CESC, UCS and OV, increasing the understanding of p38ß MAPK expression and offering insight for future in-vitro investigation and therapeutic application.

Circulating tumour cells and circulating cell-free DNA in patients with lung cancer: a comparison between thoracotomy and video-assisted thoracoscopic surgery.

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.

COVID­19 and SARS­CoV­2 host cell entry mediators: Expression profiling of TMRSS4 in health and disease.

Severe acute respiratory syndrome (SARS) coronavirus­2 (SARS­CoV­2), the causative viral agent for the ongoing COVID­19 pandemic, enters its host cells primarily via the binding of the SARS­CoV­2 spike (S) proteins to the angiotensin­converting enzyme 2 (ACE2). A number of other cell entry mediators have also been identified, including neuropilin­1 (NRP1) and transmembrane protease serine 2 (TMPRSS2). More recently, it has been demonstrated that transmembrane protease serine 4 (TMPRSS4) along with TMPRSS2 activate the SARS­CoV­2 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 COVID­19 symptomatology as another SARS­CoV­2 host cell entry mediator responsible for the tropism of this coronavirus both in the periphery and the CNS.

Maintaining safe lung cancer surgery during the COVID-19 pandemic in a global city.

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.

Lack of association between Screencell-detected circulating tumour cells and long-term survival of patients undergoing surgery for non-small cell lung cancer: A pilot clinical study.

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.

The Extracellular Matrix-Derived Biomarkers for Diagnosis, Prognosis, and Personalized Therapy of Malignant Tumors.

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.