Minimally Invasive Surgery in Non-Small Cell Lung Cancer: Where Do We Stand?

In the last two decades, robotic-assisted thoracoscopic surgery (RATS) has gained popularity as a minimally invasive surgical (MIS) alternative to multi- and uniportal video-assisted thoracoscopic surgery (VATS). With this approach, the surgeon obviates the known drawbacks of conventional MIS, such as the reduced in-depth perception, hand-eye coordination, and freedom of motion of the instruments. Previous studies have shown that a robotic approach for operable lung cancer has treatment outcomes comparable to other MIS techniques such as multi-and uniportal VATS, but with less blood loss, a lower conversion rate to open surgery, better lymph node dissection rates, and improved ergonomics for the surgeon. The thoracic surgeon of the future is expected to perform more complex procedures. More patients will enter a multimodal treatment scheme making surgery more difficult due to severe inflammation. Furthermore, due to lung cancer screening programs, the number of patients presenting with operable smaller lung nodules in the periphery of the lung will increase. This, combined with the fact that segmentectomy is becoming an increasingly popular treatment for small peripheral lung lesions, indicates that the future thoracic surgeons need to have profound knowledge of segmental resections. New imaging techniques will help them to locate these lesions and to achieve a complete oncologic resection. Current robotic techniques exist to help the thoracic surgeon overcome these challenges. In this review, an update of the latest MIS approaches and nodule detection techniques will be given.

Good's syndrome and COVID-19: case report and literature review.

Background: Good's syndrome (GS) is an adult-onset acquired immunodeficiency, in which patients present with thymoma and hypogammaglobulinemia (HGG). GS is characterized by low to absent peripheral B cells and impaired T-cell mediated immunity, often resulting in various (opportunistic) infections and concurrent autoimmune disorders. In this case report, we present a case of a patient with GS and coronavirus disease 2019 (COVID-19) infection after surgical removal of a thymoma. The simultaneous occurence of these two entities is extremely rare. Case Description: A 55-year-old man presented with oral lichen planus and cutaneous lesions. Additional symptoms included a weight loss of 5 kilograms in the last six months. Computed tomography (CT) and positron emission tomography (PET) of the chest showed a large anterior mediastinal mass with a maximum diameter of 10 centimetres. A core needle biopsy was performed, which led to a pathological diagnosis of thymoma type AB. In addition to these earlier findings, laboratory analysis revealed HGG. The combination of a thymoma and HGG led to a diagnosis of GS. Induction chemotherapy with cisplatin-etoposide was started, however, the patient developed COVID-19 after 2 cycles. Treatment with remdesivir was initiated and, subsequently, a thymectomy via sternotomy was performed. Final pathology confirmed a thymoma type AB of 14 centimetres, fully encapsulated, and without invasion. Resection margins were negative and the tumour was classified as pT1aN0, R0 resection. The patient has received immunoglobulin treatments every 4 weeks for his GS and has not developed any new infections since the start of this therapy. Conclusions: Patients with GS are prone to developing (pulmonary) infections. Clinicians should be aware of the possible clinical effects of COVID-19 infections in this patient population.

OrBITS: label-free and time-lapse monitoring of patient derived organoids for advanced drug screening.

BACKGROUND: Patient-derived organoids are invaluable for fundamental and translational cancer research and holds great promise for personalized medicine. However, the shortage of available analysis methods, which are often single-time point, severely impede the potential and routine use of organoids for basic research, clinical practise, and pharmaceutical and industrial applications. METHODS: Here, we developed a high-throughput compatible and automated live-cell image analysis software that allows for kinetic monitoring of organoids, named Organoid Brightfield Identification-based Therapy Screening (OrBITS), by combining computer vision with a convolutional network machine learning approach. The OrBITS deep learning analysis approach was validated against current standard assays for kinetic imaging and automated analysis of organoids. A drug screen of standard-of-care lung and pancreatic cancer treatments was also performed with the OrBITS platform and compared to the gold standard, CellTiter-Glo 3D assay. Finally, the optimal parameters and drug response metrics were identified to improve patient stratification. RESULTS: OrBITS allowed for the detection and tracking of organoids in routine extracellular matrix domes, advanced Gri3D®-96 well plates, and high-throughput 384-well microplates, solely based on brightfield imaging. The obtained organoid Count, Mean Area, and Total Area had a strong correlation with the nuclear staining, Hoechst, following pairwise comparison over a broad range of sizes. By incorporating a fluorescent cell death marker, intra-well normalization for organoid death could be achieved, which was tested with a 10-point titration of cisplatin and validated against the current gold standard ATP-assay, CellTiter-Glo 3D. Using this approach with OrBITS, screening of chemotherapeutics and targeted therapies revealed further insight into the mechanistic action of the drugs, a feature not achievable with the CellTiter-Glo 3D assay. Finally, we advise the use of the growth rate-based normalised drug response metric to improve accuracy and consistency of organoid drug response quantification. CONCLUSION: Our findings validate that OrBITS, as a scalable, automated live-cell image analysis software, would facilitate the use of patient-derived organoids for drug development and therapy screening. The developed wet-lab workflow and software also has broad application potential, from providing a launching point for further brightfield-based assay development to be used for fundamental research, to guiding clinical decisions for personalized medicine.

Biomarkers for Chronic Lung Allograft Dysfunction: Ready for Prime Time?

Chronic lung allograft dysfunction (CLAD) remains a major hurdle impairing lung transplant outcome. Parallel to the better clinical identification and characterization of CLAD and CLAD phenotypes, there is an increasing urge to find adequate biomarkers that could assist in the earlier detection and differential diagnosis of CLAD phenotypes, as well as disease prognostication. The current status and state-of-the-art of biomarker research in CLAD will be discussed with a particular focus on radiological biomarkers or biomarkers found in peripheral tissue, bronchoalveolar lavage' and circulating blood' in which significant progress has been made over the last years. Ultimately, although a growing number of biomarkers are currently being embedded in the follow-up of lung transplant patients, it is clear that one size does not fit all. The future of biomarker research probably lies in the rigorous combination of clinical information with findings in tissue, bronchoalveolar lavage' or blood. Only by doing so, the ultimate goal of biomarker research can be achieved, which is the earlier identification of CLAD before its clinical manifestation. This is desperately needed to improve the prognosis of patients with CLAD after lung transplantation.

Multimodality Treatment including Surgery Related to the Type of N2 Involvement in Locally Advanced Non-Small Cell Lung Cancer.

For patients with locally advanced non-small cell lung cancer (NSCLC) or positive N1 nodes, multimodality treatment is indicated. However, the optimal management of patients presenting with ipsilateral positive mediastinal nodes (N2 disease) has not been determined yet. Different treatment regimens consisting of chemotherapy, radiation therapy, and surgery have been proposed and implemented previously. In more recent years, immunotherapy and targeted therapies have been added as therapeutic options. The role of surgery is currently redefined. Recent studies have shown that surgical resection after induction immunotherapy or targeted therapy is feasible and yields good short-term results. In this review, we summarize the latest data on multimodality treatment options for stage IIIA-N2 locally advanced NSCLC, depending on the extent of nodal involvement.

Safety and Feasibility of Lung Cancer Surgery under the COVID-19 Circumstance.

The current coronavirus disease 2019 (COVID-19) pandemic has forced healthcare providers worldwide to adapt their practices. Our understanding of the effects of COVID-19 has increased exponentially since the beginning of the pandemic. Data from large-scale, international registries has provided more insight regarding risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and has allowed us to delineate specific subgroups of patients that have higher risks for severe complications. One particular subset of patients that have significantly higher risks of SARS-CoV-2 infection with higher morbidity and mortality rates are those that require surgical treatment for lung cancer. Earlier studies have shown that COVID-19 infections in patients that underwent lung cancer surgery is associated with higher rates of respiratory failure and mortality. However, deferral of cancer treatments is associated with increased mortality as well. This creates difficult situations in which healthcare providers are forced to weigh the benefits of surgical treatment against the possibility of SARS-CoV-2 infections. A number of oncological and surgical organizations have proposed treatment guidelines and recommendations for patients planned for lung cancer surgery. In this review, we summarize the latest data and recommendations for patients undergoing lung cancer surgery in the COVID-19 circumstance.

The role of the surgeon in the management of oligometastatic non-small cell lung cancer: a literature review.

OBJECTIVE: In this review, we aim to summarize the most recent data on the surgical management of oligometastatic non-small cell lung cancer (NSCLC). BACKGROUND: Approximately 60-70% of all patients with NSCLC initially present with advanced stages of cancer at time of diagnosis. These patients are generally treated with chemotherapy, radiation therapy, or a combination of these modalities. Patients with late-stage disease are usually not considered to be amenable for curative-intent treatments due to poor prognoses. Despite advances in systemic therapies, 5-year overall survival rates in these patients remain poor. However, technological advances in imaging modalities and new imaging strategies have substantially increased tumor detection rates and have resulted in a shift towards earlier diagnosis of NSCLC, possibly in stages in which metastatic disease is limited and still treatable. Studies in recent years have shown that there is a distinct group of patients with metastatic lesions at one or a few sites, often referred to as oligometastatic disease, that may have better survival outcomes compared to patients with more disseminated diseases. Furthermore, it is suggested that these patients may benefit from a combination of systemic treatment and local treatment aimed at the metastatic site(s). However, the role of surgery in this setting remains a controversial subject, with many unanswered questions. METHODS: The PubMed/MEDLINE database and the Cochrane database were searched to find relevant articles regarding oligometastatic NSCLC. Specifically, articles regarding definitions of oligometastatic disease, oligometastatic tumor biology, diagnosis, and the treatment of oligometastatic disease were identified. CONCLUSIONS: Oligometastatic NSCLC represents a wide spectrum of diseases and encompasses a heterogeneous patient population. Current data suggests that local ablative treatment of oligometastatic lesions with surgery or stereotactic body radiation therapy may result in improved overall survival and progression-free survival rates. However, more data from multi-center prospective trials are necessary to shed light on which therapeutic modalities are most suitable for the treatment of oligometastatic NSCLC. Integration of clinical and molecular staging data is necessary to allow for more personalized treatment approaches.

Pulmonary metastasectomy in colorectal carcinoma.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. It is estimated that 50% of all patients with CRC develop metastases, most commonly in the liver and the lung. Lung metastases are seen in approximately 10-15% of all patients with CRC. A large number of these patients with metastatic CRC can only receive palliative treatment due to invasion of other organs and disseminated disease. However, a subset of these patients present with potentially resectable metastases. Pulmonary metastasectomy is considered to be a potentially curative treatment for selected patients with resectable metastatic CRC. Current data suggest that patients that undergo pulmonary metastasectomy have 5-year survival rates of approximately 40%. However, the majority of data published regarding lung metastasectomy is based on small, retrospective case series. Due to this lack of prospective data, it is still unclear which subset of patients will benefit most from curative-intent surgery. Furthermore, there is also controversy regarding which prognostic and genetic factors are related to survival outcomes and whether there is a difference between open and thoracoscopic approaches in terms of overall and disease-free survival. In this review, we aim to summarize the latest data on prognostic factors and survival outcomes after pulmonary metastasectomy in patients with metastatic CRC.

Evaluation of Temporal Artery Duplex Ultrasound for Diagnosis of Temporal Arteritis.

BACKGROUND: Temporal arteritis or giant cell arteritis is a form of systemic inflammatory vasculitis closely associated with polymyalgia rheumatica. It may have serious systemic, neurologic, and ophthalmic consequences as it may lead to impaired vision and blindness. Definitive diagnosis is made after histopathologic analysis of a superficial temporal artery (TA) biopsy, which requires a small surgical procedure often under local anesthesia. We investigated whether a noninvasive technique such as duplex ultrasound of the TA could replace histopathological analysis. METHODS: Eighty-one patients referred to our department for TA biopsy were first screened with a duplex ultrasound for a surrounding halo and/or occlusion of the TA. Presence of visual disturbances and unilateral pain (headache and/or tongue/jaw claudication) was noted before TA biopsy. Pathological analysis was considered the gold standard. Correlation between duplex findings, symptoms, and pathology was determined by Spearman's Rho test. The predictive value of a halo and TA occlusion on duplex were determined by ROC curve analysis. RESULTS: A halo or TA occlusion was found in 16.0% and 3.7% of patients, respectively. Unilateral pain was reported in 96% of cases while 82% complained of visual disturbances. Correlation coefficients for halo and occlusion were 0.471 and 0.404, respectively (P < 0.0001), suggesting a moderate correlation between duplex and biopsy. There was no significant correlation between visual impairment or pain and histologic findings. The ROC curve analysis showed a sensitivity of 53.3% and 20.0%, and specificity of 91.9% and 100% for presence of a halo and occlusion of the TA on duplex, respectively. CONCLUSIONS: Arterial duplex is a moderately sensitive but highly specific test for exclusion of temporal arteritis. We observed a moderate correlation between these findings on duplex and histopathological analysis as a gold standard. Arterial duplex may serve as a valuable diagnostic addition to prevent unnecessary surgical procedures and can even substitute biopsy in patients where surgery is not an option.

Evaluation of mediastinoscopy in mediastinal lymph node staging for non-small-cell lung cancer.

OBJECTIVES: The purpose of this study was to assess the quality of video-assisted cervical mediastinoscopy (VACM) in the staging of non-small-cell lung cancer (NSCLC) at the Antwerp University Hospital with a focus on test effectiveness indicators, morbidity and unforeseen pN2 results. METHODS: All consecutive VACM workups of cases of NSCLC performed between January 2010 and December 2015 were included to assess overall test quality and effectiveness. Quality assurance was performed in accordance with the recommendations of the European Society of Gastrointestinal Endoscopy and European Society of Thoracic Surgeons (ESTS) where appropriate. RESULTS: A total of 168 video-assisted cervical mediastinoscopies were included. A total of 91.7% of the procedures were performed in accordance with the ESTS guideline. An unforeseen pN2 staging was identified in 10 anatomical lung resections (8.6%). Statistical analysis showed no significant association between VACM performed in accordance with the ESTS guideline and the presence of pN2 positive lymph nodes [χ2 (1) = 0.61; P = 0.57] and no association between VACM performed in accordance with the ESTS guideline and overall futile thoracotomy [χ2 (1) = 0.76; P = 0.50]. Calculations revealed a sensitivity of 81.8 [95% confidence interval (CI) 69.1-90.9], specificity of 100%, positive predictive value of 100%, negative predictive value of 91.9% (95% CI 86.6-95.2) and diagnostic accuracy of 94.1% (95% CI 89.33-97.11). CONCLUSIONS: Overall, 91.7% of the VACM were performed in accordance with the ESTS guideline. This process resulted in a sensitivity of 81.8%, a negative predictive value of 91.9% and an unforeseen pN2 rate of 8.6%.

Robotic first rib resection for venous thoracic outlet syndrome.

Thoracic outlet syndrome is a collective term for symptoms that occur due to the impingement of the neurovascular structures in the thoracic outlet. Diagnosing thoracic outlet syndrome can be challenging since it can give rise to a broad spectrum of symptoms. Transaxillary or supraclavicular first rib resection are the most commonly used approaches for surgical treatment after failure of conservative measures.  In this video tutorial we demonstrate a robotic-assisted thoracoscopic surgery first rib resection for achieving a decompression of the thoracic outlet.

Robotic-assisted thoracoscopic lobectomy of the right middle lobe.

Robotic-assisted thoracoscopic surgery has increased in popularity during the past two decades because it offers 3-dimensional optics, increased instrument and wrist flexibility compared to classical video-assisted thoracoscopic surgery, and, for patients, improved quality of life and shorter hospital stays compared to open surgery.  In this video tutorial, we demonstrate a robotic-assisted thoracoscopic surgery lobectomy in a patient with a tumor in the right middle lobe. The patient had an excellent recovery with no perioperative or postoperative complications.

Extrapleural pneumonectomy: still indicated?

The optimal treatment of malignant pleural mesothelioma (MPM) has not yet been established and is still under investigation. Surgery is one of the pillars in the multimodality approach with the purpose of removing as much as visible tumor as possible and to relieve symptoms. To date, two major surgical procedures are available for removal or debulking of MPM that is considered to be resectable: [extended (e)] pleurectomy/decortication (P/D) and extrapleural pneumonectomy (EPP). Historically, EPP was regarded as the only way to achieve a macroscopic complete resection. However, in the last years, there is a shift in literature towards (e)P/D as the preferred surgical procedure whenever possible as several retrospective studies and meta-analyses showed a similar or lower long-term survival and higher perioperative mortality and postoperative morbidity in patients who been treated with EPP. On the other hand, no randomized-controlled trials regarding surgical treatment with (e)P/D or EPP exist and therefore level A evidence favoring one surgical procedure is lacking. In this review we provide a nuanced and well-considered answer to the question whether EPP is still indicated in the surgical treatment of MPM.

Surgical Management of Stage IIIA Non-Small Cell Lung Cancer.

According to the eighth edition of the tumor-node-metastasis classification, stage III non-small cell lung cancer is subdivided into stages IIIA, IIIB, and IIIC. They represent a heterogeneous group of bronchogenic carcinomas with locoregional involvement by extension of the primary tumor and/or ipsilateral or contralateral lymph node involvement. Surgical indications have not been definitely established but, in general, long-term survival is only obtained in those patients in whom a complete resection is obtained. This mini-review mainly focusses on stage IIIA disease comprising patients with locoregionally advanced lung cancers. Different subcategories of N2 involvement exist, which range from unexpected N2 disease after thorough preoperative staging or "surprise" N2, to bulky N2 involvement, mostly treated by chemoradiation, and finally, the intermediate category of potentially resectable N2 disease treated with a combined modality regimen. After induction therapy for preoperative N2 involvement, best surgical results are obtained with proven mediastinal downstaging when a lobectomy is feasible to obtain a microscopic complete resection. However, no definite, universally accepted guidelines exist. A relatively new entity is salvage surgery applied for recurrent disease after full-dose chemoradiation when no other therapeutic options exist. Equally, only a small subset of patients with T4N0-1 disease qualify for surgical resection after thorough discussion within a multidisciplinary tumor board on the condition that a complete resection is feasible. Targeted therapies and immunotherapy have recently become part of our therapeutic armamentarium, and it might be expected that they will be incorporated in current regimens after careful evaluation in randomized clinical trials.