A 24-Year-Old Man with Spontaneous Right Tension Pneumothorax Presenting with Abdominal Pain with an Initial Symptomatic Diagnosis of Acute Pancreatitis.

BACKGROUND Tension pneumothorax (TP) is a medical emergency resulting in air accumulation in the pleural cavity of the affected side. Later, this air applies pressure on the mediastinal structures, leading to a shift of these structures toward the contralateral side. This shift results in a picture of obstructive shock with a possibly fatal consequence if not detected and treated early. Treatment should not await radiological confirmation, and the red flags in the history and physical examination are enough to proceed with decompressing the affected hemithorax with a large-bore needle. Usually, patients with TP present to the Emergency Department with pleuritic chest pain and shortness of breath, but rare presentations are still possible. CASE REPORT We report a case of a 24-year-old male patient with TP who presented to the Emergency Department with severe epigastric abdominal pain with a clinical picture of acute pancreatitis. X-ray showed a right-sided TP. Immediately, we performed a needle decompression followed by chest tube insertion. Four days later, the patient was discharged home uneventfully. CONCLUSIONS In this case report, we aim to draw the attention of physicians in the Emergency Department to the need to consider the possibility of upper abdominal pain elicited by chest pathologies. Furthermore, we need to investigate the effect of TP on coronary perfusion.

MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity. Suppression of MAPK signaling by clinically approved MEK inhibitors (MEKi) elicits PARP1 to protect MPM cells from the cytotoxic effects of MAPK pathway blockage. Mechanistically, MEKi induces impairment of homologous recombination (HR) repair proficiency and mitochondrial metabolic activity, which is counterbalanced by pleiotropic PARP1. Consequently, the combination of MEK with PARP inhibitors enhances apoptotic cell death in vitro and in vivo that occurs through coordinated upregulation of cytotoxic ROS in MPM cells, suggesting a mechanism-based, readily translatable strategy to treat this daunting disease. Collectively, our studies uncover a previously unrecognized scenario that hyperactivation of the MAPK pathway is an essential feature of MPM and provide unprecedented evidence that MAPK signaling cooperates with PARP1 to homeostatically maintain ROS levels and escape ROS-mediated apoptosis.

Thoracic outlet syndrome: a retrospective analysis of robotic assisted first rib resections.

Thoracic Outlet Syndrome (TOS) is caused by compression of the neurovascular bundle between the first rib and the clavicula, which can cause a large panel of symptoms and has a reported incidence of approximately 2-4/100.000. Surgical treatment consists of the resection of the first rib and is historically performed using an open, mainly transaxillary, approach. Recent developments resulted in a minimally invasive approach using Robotic Assisted Thoracic Surgery (RATS). With this study, the investigators want to provide a descriptive study of first rib resection using RATS approach at two different centers. We reviewed the files of 47 patients affected by TOS and who benefited from first rib resection using RATS approach between 2016 and 2021. Patient characteristics as well as Length of Stay (LOS), affected side, operative time (OT), complications, etiology, VAS score and post-operative QOL were gathered in the database. Statistical analysis was performed using IBM SPSS statistics 25 ®. Results were reported in mean and standard deviation. 47 patients affected by TOS received first rib resection using robotic approach. Mean age was 47 ± 12 yrs. 16 patients were operated on the left side and 31 on the right side. All the patients reported complete resolution of symptoms. At 1-year follow-up, no patient suffered from recurrence. There were no intraoperative complications. Postoperative complications occurred in two patients, one patient developed pneumothorax after chest tube removal and one patient developed recurrent pleural effusion which required surgery. Mean LOS was 3 ± 1 days and mean OT was 122 ± 40 min. First rib resection performed using a RATS approach is a safe technique with excellent outcomes and which is beneficial for the patient in terms of LOS, pain and symptom resolution.

Adjuvant treatment for patients with incidentally resected limited disease small cell lung cancer-a retrospective study.

Background: With the exception of very early-stage small cell lung cancer (SCLC), surgery is not typically recommended for this disease; however, incidental resection still occurs. After incidental resection, adjuvant salvage therapy is widely offered, but the evidence supporting its use is limited. This study aimed to explore proper adjuvant therapy for these incidentally resected SCLC cases. Methods: Patients incidentally diagnosed with SCLC after surgery at the Shanghai Pulmonary Hospital in China from January 2005 to December 2014 were included in this study. The primary outcome was overall survival. Patients were classified into different group according to the type of adjuvant therapy they received and stratified by their pathological lymph node status. Patients' survival was analyzed using a Kaplan-Meier analysis and Cox regression analysis. Results: A total of 161 patients were included in this study. Overall 5-year survival rate was 36.5%. For pathological N0 (pN0) cases (n=70), multivariable analysis revealed that adjuvant chemotherapy (ad-chemo) was associated with reduced risk of death [hazard ratio (HR): 0.373; 95% confidence interval (CI): 0.141-0.985, P=0.047] compared to omission of adjuvant therapy. For pathological N1 or N2 (pN1/2) cases (n=91), taking no adjuvant therapy cases as a reference, the multivariable analysis showed that ad-chemo was not associated with a lower risk of death (HR: 0.869; 95% CI: 0.459-1.645, P=0.666), while adjuvant chemo-radiotherapy (ad-CRT) was associated with a lower risk of death (HR: 0.279; 95% CI: 0.102-0.761, P=0.013). Conclusions: Patients who incidentally receive surgical resection and are diagnosed with limited disease SCLC after resection should be offered adjuvant therapy as a salvage treatment. For incidentally resected pN0 cases, ad-chemo should be considered and for pN1/2 cases, ad-CRT should be received.

Perioperative Fully Closed-Loop Insulin Delivery in Patients Undergoing Elective Surgery: An Open-Label, Randomized Controlled Trial.

OBJECTIVE: Perioperative management of glucose levels remains challenging. We aimed to assess whether fully closed-loop subcutaneous insulin delivery would improve glycemic control compared with standard insulin therapy in insulin-requiring patients undergoing elective surgery. RESEARCH DESIGN AND METHODS: We performed a single-center, open-label, randomized controlled trial. Patients with diabetes (other than type 1) undergoing elective surgery were recruited from various surgical units and randomly assigned using a minimization schedule (stratified by HbA1c and daily insulin dose) to fully closed-loop insulin delivery with fast-acting insulin aspart (closed-loop group) or standard insulin therapy according to local clinical practice (control group). Study treatment was administered from hospital admission to discharge (for a maximum of 20 days). The primary end point was the proportion of time with sensor glucose in the target range (5.6-10.0 mmol/L). RESULTS: Forty-five patients were enrolled and assigned to the closed-loop (n = 23) or the control (n = 22) group. One patient (closed-loop group) withdrew from the study before surgery and was not analyzed. Participants underwent abdominal (57%), vascular (23%), orthopedic (9%), neuro (9%), or thoracic (2%) surgery. The mean proportion of time that sensor glucose was in the target range was 76.7 ± 10.1% in the closed-loop and 54.7 ± 20.8% in the control group (mean difference 22.0 percentage points [95% CI 11.9; 32.0%]; P < 0.001). No episodes of severe hypoglycemia (<3.0 mmol/L) or hyperglycemia with ketonemia or any study-related adverse events occurred in either group. CONCLUSIONS: In the context of mixed elective surgery, the use of fully closed-loop subcutaneous insulin delivery improves glucose control without a higher risk of hypoglycemia.

Electrocautery smoke exposure and efficacy of smoke evacuation systems in minimally invasive and open surgery: a prospective randomized study.

Worldwide, health care professionals working in operating rooms (ORs) are exposed to electrocautery smoke on a daily basis. Aims of this study were to determine composition and concentrations of electrocautery smoke in the OR using mass spectrometry. Prospective observational study at a tertiary care academic center, involving 122 surgical procedures of which 84 were 1:1 computer randomized to smoke evacuation system (SES) versus no SES use. Irritating, toxic, carcinogenic and mutagenic VOCs were observed in OR air, with some exceeding permissible exposure limits (OSHA/NIOSH). Mean total concentration of harmful compounds was 272.69 ppb (± 189 ppb) with a maximum total concentration of harmful substances of 8991 ppb (at surgeon level, no SES). Maximum total VOC concentrations were 1.6 ± 1.2 ppm (minimally-invasive surgery) and 2.1 ± 1.5 ppm (open surgery), and total maximum VOC concentrations were 1.8 ± 1.3 ppm at the OR table 'at surgeon level' and 1.4 ± 1.0 ppm 'in OR room air' away from the operating table. Neither difference was statistically significant. In open surgery, SES significantly reduced maximum concentrations of specific VOCs at surgeon level, including aromatics and aldehydes. Our data indicate relevant exposure of health care professionals to volatile organic compounds in the OR. Surgical technique and distance to cautery devices did not significantly reduce exposure. SES reduced exposure to specific harmful VOC's during open surgery.Trial Registration Number: NCT03924206 (clinicaltrials.gov).

Successful thoracoscopic management of iatrogenic left subclavian arterial injury: a case report.

The subclavian artery at the thoracic outlet is in the deepest position of the thoracic cavity and is difficult to repair in this narrow space once injured, even if the surgery is converted to a thoracotomy. This article presents a successful left subclavian artery repair procedure at the thoracic outlet using a thoracoscopic approach, with a video demonstration, and describes its technical characteristics. The patient was planned for a left upper lobectomy through three-port thoracoscopic approach. Severe adhesions were found intraoperatively and an accidental left subclavian arterial injury occurred when dissecting the adhesions. We first clamped the proximal portion of the subclavian artery and then directly clamped the rupture site. Our first suture failed due to the limited suture angle and the mutual restriction between the needle holder and atraumatic vascular clamp. To freely control the needle holder, another assistant port was made in the seventh intercostal space (ICS). The arterial injury was finally successfully repaired using pledgetted suture. The operation time was 235 minutes and intraoperative blood loss was 800 mL. The pulsation of the left radial artery was normal postoperatively, and the patient was discharged on postoperative day 6. Appropriate strategies allow attempts to manage intraoperative hyperbaric arterial bleeding from the systemic circulation, such as bleeding caused by subclavian arterial injuries, by means of a thoracoscopic approach without conversion to thoracotomy.

Combination of endobronchial bronchoscopic debulking and bronchoplastic segmentectomy of an obstructive neuroendocrine tumour: probably the least invasive approach.

We report the case of a female patient with an obstructing well-differentiated neuroendocrine tumour in the apical segment of the completely atelectatic right lower lobe. Bronchoscopic debulking of the tumour lead to re-ventilation of the remaining lobe, allowing to perform a lung-sparing bronchoplastic resection of the affected segment by uniportal video-assisted thoracic surgery.

Operative versus non-operative management of rib fractures in flail chest after cardiopulmonary resuscitation manoeuvres.

OBJECTIVES: Blunt chest trauma after mechanical resuscitation manoeuvres appears to have a significant impact on the often complicated course. Due to a lack of data in the literature, the purpose of this study was to investigate the feasibility and immediate outcome of chest wall stabilization for flail chest in this vulnerable patient population. METHODS: We retrospectively reviewed the medical records of patients after cardiopulmonary resuscitation between January 2014 and December 2018 who were diagnosed with flail chest. We attempted to compare patients after surgery with those after conservative treatment. RESULTS: Of a total of 56 patients with blunt chest trauma after mechanical resuscitation and after coronary angiography, 25 were diagnosed with flail chest. After the exclusion of 2 patients because of an initial decision to palliate, 13 patients after surgical stabilization could be compared with 10 patients after conservative therapy. Although there was no significant difference in the total duration of ventilatory support, there was a significant advantage when the time after stabilization to extubation was compared with the duration of ventilation in the conservative group. The presence of pulmonary contusion, poor Glasgow Coma Scale score or the development of pneumonia negatively affected the outcome, but additional sternal fracture did not. CONCLUSIONS: Surgical stabilization for chest wall instability is well tolerated even by this vulnerable patient population. Our results should be used for further randomized controlled approaches. It is necessary to evaluate the situation with all parameters in an interdisciplinary manner and to decide on a possible surgical therapy at an early stage if possible.

Surgical smoke: modern mobile smoke evacuation systems improve occupational safety in the operating theatre.

OBJECTIVES: Evaluation of smoke capture efficiency of different mobile smoke evacuation devices with respect to volatile organic compounds and their noise emission. METHODS: Electrosurgical incisions were performed on fresh porcine liver in an operating room with vertical laminar flow. The generated surgical smoke was analysed with proton-transfer-reaction mass spectrometry with and without the use of a mobile smoke evacuation system consisting of a smoke evacuator machine, a suction hose and a handpiece. The inlet of the mass spectrometer was positioned 40 cm above the specimen. Various devices were compared: a hard plastic funnel, a flexible foam funnel, an on-tip integrated aspirator of an electrosurgical knife and a standard secretion suction (Yankauer). Also, sound levels were measured at a distance of 40 cm from the handpieces' inlet. RESULTS: The smoke capture efficiency of the secretion suction was only 53%, while foam funnel, plastic funnel and integrated aspirator were all significantly more effective with a clearance of 95%, 91% and 91%, respectively. The mean sound levels were 68 and 59 A-weighted decibels with the plastic and foam funnel, respectively, 66 A-weighted decibels with the integrated aspirator and 63 A-weighted decibels with the secretion suction. CONCLUSIONS: Carcinogenic, mutagenic and reprotoxic volatile organic compounds in surgical smoke can be efficiently reduced by mobile smoke evacuation system, providing improved protection for medical personnel. Devices specifically designed for smoke evacuation are more efficient than standard suction tools. Noise exposure for the surgeon was lowest with the flexible foam funnel and higher with the other handpieces tested.

A Breakthrough Brought about by Targeting KRASG12C: Nonconformity Is Punished.

KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRASG12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable-that is, until the advent of G12C inhibitors, which put an end to this legend by covalently targeting the G12C (glycine to cysteine) substitution in the switch-II pocket of the protein, inhibiting the affinity of the mutant KRAS with GTP and subsequently the downstream signaling pathways, such as Raf/MEK/ERK. KRASG12C-selective inhibitors, e.g., the FDA-approved AMG510 and MRTX849, have demonstrated potent clinical efficacy and selectivity in patients with KRASG12C-driven cancers only, which spares other driver KRAS mutations (e.g., G12D/V/S, G13D, and Q61H) and has ushered in an unprecedented breakthrough in the field in recent decades. However, accumulating evidence from preclinical and clinical studies has shown that G12C-targeted therapeutics as single agents are inevitably thwarted by drug resistance, a persistent problem associated with targeted therapies. A promising strategy to optimize G12C inhibitor therapy is combination treatments with other therapeutic agents, the identification of which is empowered by the insightful appreciation of compensatory signaling pathways or evasive mechanisms, such as those that attenuate immune responses. Here, we review recent advances in targeting KRASG12C and discuss the challenges of KRASG12C inhibitor therapy, as well as future directions.

Tumor-infiltrating lymphocytes are functionally inactivated by CD90+ stromal cells and reactivated by combined Ibrutinib and Rapamycin in human pleural mesothelioma.

Rationale: Despite evidence suggesting that the tumor microenvironment (TME) in malignant pleural mesothelioma (MPM) is linked with poor prognosis, there is a lack of studies that functionally characterize stromal cells and tumor-infiltrating lymphocytes (TILs). Here, we aim to characterize the stromal subsets within MPM, investigate their relationship to TILs, and explore the potential therapeutic targets. Methods: We curated a core set of genes defining stromal/immune signatures expressed by mesenchymal cells within the TME using molecular analysis of The Cancer Genome Atlas (TCGA) MPM cohort. Stromal and immune profiles were molecularly characterized using flow cytometry, immunohistochemistry, microarray, and functionally evaluated using T cell-activation/expansion, coculture assays and drug compounds treatment, based on samples from an independent MPM cohort. Results: We found that a high extracellular matrix (ECM)/stromal gene signature, a high ECM score, or the ratio of ECM to an immune activation gene signature are significantly associated with poor survival in the MPM cohort in TCGA. Analysis of an independent MPM cohort (n = 12) revealed that CD8+ and CD4+ TILs were characterized by PD1 overexpression and concomitant downregulation in degranulation and CD127. This coincided with an increase in CD90+ cells that overexpressed PD-L1 and were enriched for ECM/stromal genes, activated PI3K-mTOR signaling and suppressed T cells. Protein array data demonstrated that MPM samples with high PD-L1 expression were most associated with activation of the mTOR pathway. Further, to reactivate functionally indolent TILs, we reprogrammed ex vivo TILs with Ibrutinib plus Rapamycin to block interleukin-2-inducible kinase (ITK) and mTOR pathways, respectively. The combination treatment shifted effector memory (TEM) CD8+ and CD4+ TILs towards T cells that re-expressed CD45RA (TEMRA) while concomitantly downregulating exhaustion markers. Gene expression analysis confirmed that Ibrutinib plus Rapamycin downregulated coinhibitory and T cell signature pathways while upregulating pathways involved in DNA damage and repair and immune cell adhesion and migration. Conclusions: Our results suggest that targeting the TME may represent a novel strategy to redirect the fate of endogenous TILs with the goal of restoring anti-tumor immunity and control of tumor growth in MPM.

Metabolic synthetic lethality by targeting NOP56 and mTOR in KRAS-mutant lung cancer.

BACKGROUND: Oncogenic KRAS mutations are prevalent in human cancers, but effective treatment of KRAS-mutant malignancies remains a major challenge in the clinic. Increasing evidence suggests that aberrant metabolism plays a central role in KRAS-driven oncogenic transformation. The aim of this study is to identify selective metabolic dependency induced by mutant KRAS and to exploit it for the treatment of the disease. METHOD: We performed an integrated analysis of RNAi- and CRISPR-based functional genomic datasets (n = 5) to identify novel genes selectively required for KRAS-mutant cancer. We further screened a customized library of chemical inhibitors for candidates that are synthetic lethal with NOP56 depletion. Functional studies were carried out by genetic knockdown using siRNAs and shRNAs, knockout using CRISPR/Cas9, and/or pharmacological inhibition, followed by cell viability and apoptotic assays. Protein expression was determined by Western blot. Metabolic ROS was measured by flow cytometry-based quantification. RESULTS: We demonstrated that nucleolar protein 5A (NOP56), a core component of small nucleolar ribonucleoprotein complexes (snoRNPs) with an essential role in ribosome biogenesis, confers a metabolic dependency by regulating ROS homeostasis in KRAS-mutant lung cancer cells and that NOP56 depletion causes synthetic lethal susceptibility to inhibition of mTOR. Mechanistically, cancer cells with reduced NOP56 are subjected to higher levels of ROS and rely on mTOR signaling to balance oxidative stress and survive. We also discovered that IRE1α-mediated unfolded protein response (UPR) regulates this process by activating mTOR through p38 MAPK. Consequently, co-targeting of NOP56 and mTOR profoundly enhances KRAS-mutant tumor cell death in vitro and in vivo. CONCLUSIONS: Our findings reveal a previously unrecognized mechanism in which NOP56 and mTOR cooperate to play a homeostatic role in the response to oxidative stress and suggest a new rationale for the treatment of KRAS-mutant cancers.

Completely Thoracoscopic 3-Port Robotic First Rib Resection for Thoracic Outlet Syndrome.

BACKGROUND: In thoracic outlet syndrome, the constriction between bony and muscular structures leads to compression of the neurovascular bundle to the upper extremity. Traditional surgical techniques using supraclavicular, infraclavicular, or transaxillary approaches to remove the first rib do not usually allow good exposure of the entire rib and neurovascular bundle. We have therefore developed a robotic approach to overcome these limitations. METHODS: Between January 2015 and November 2020, 38 consecutive first rib resections for neurogenic, venous, or arterial thoracic outlet syndrome were performed in 34 patients at our institutions. For our completely portal approach, we used two 8-mm working ports and one 12-mm camera port. RESULTS: The surgery time was between 71 and 270 minutes (median ± SD: 133 ± 44.7 minutes) without any complications. Chest tube was removed on postoperative day 1 in all patients and the hospital stay after surgery ranged from 1-7 days (2 ± 2.1 days). No relevant intraoperative or postoperative complications were observed and complete or subtotal resolution of symptoms was seen in all patients. CONCLUSIONS: The robotic technique described here for first rib resection has proven to be a safe and effective approach. The unsurpassed exposure of the entire first rib and possibility for a robotic-assisted meticulous surgical dissection has prevented both intraoperative and postoperative complications. This makes this technique unique as the safest and most minimally invasive approach to date. It helps improve patient outcomes by reducing perioperative morbidity with an easily adoptable procedure.

Thymic tumours: a single center surgical experience and literature review on the current diagnosis and management of thymic malignancies.

OBJECTIVE: This study aimed to provide an extensive overview of clinical and pathological findings along with various therapeutic options analyzing in addiction, retrospectively, the surgical outcomes of a single center cohort. BACKGROUND: Thymic neoplasms are rare thoracic tumors which commonly are located in the anterior mediastinum and are associated with a wide spectrum of clinical presentations. They may run an indolent course or could present a very aggressive biologic progression with infiltration of mediastinal structures and presence of distant metastases. The pathogenesis of these tumors is so far not completely clear. Several treatment modalities in a multidisciplinary setting have to be considered in order to provide the best treatment for patients affected by thymic tumors. METHODS: We conducted a retrospective cohort analysis of all patients who underwent surgery due to thymic tumor in a university hospital located in Switzerland (Bern University Hospital) and then we performed a narrative review of the English literature using PubMed, Embase, Cochrane Database of Systematic Reviews and Scopus. CONCLUSIONS: Minimally invasive techniques play an important role in the treatment of thymic tumors. A careful patients selection in a multidisciplinary setting is mandatory in order to offer the best treatment for patients affected by thymic tumors.

Pneumonectomy for lung cancer in the elderly: lessons learned from a multicenter study.

BACKGROUND: 60% of patients diagnosed with lung cancer are older than 65 years and are at risk for substandard treatment due to a reluctance to recommend surgery. Pneumonectomy remains a high risk procedure especially in elderly patients. Nevertheless, the impact of age and neoadjuvant treatment on outcomes after pneumonectomy is still not well described. METHODS: We performed a multicentric retrospective study, analyzing outcomes of patients older than 70 years who underwent pneumonectomy for central primary lung malignancy between January 2009 and June 2019 in 7 thoracic surgery departments: Lucerne and Bern (Switzerland), Hamilton (Canada), Alicante (Spain), Monza (Italy), London (UK), Leuven (Belgium). Survival was estimated with Kaplan-Meier, and differences in survival were determined by log-rank analysis. We investigated pre- and post-operative prognostic factors using Cox proportional hazards regression model; multivariable analysis was performed only with variables, which were statistically significant at the invariable analysis. RESULTS: A total of 136 patients were included in the study. Mean age was 73.8 years (SD 3.6). 24 patients (17.6%) had an induction treatment (chemotherapy alone in 15 patients and chemo-radiation in 9). Mean length of stay (LOS) was 12.6 days (SD 10.39) and 74 patients (54.4%) had experienced a post-operative complication: 29 (21.3%) had a pulmonary complication, 33 (24.3%) had a cardiac complication and in 12 cases (8.8%) patients experienced both cardiac and pulmonary complications. 16 patients were readmitted [median LOS 13.7 days (range, 2-39 days)] and of those 14 (10.3%) required redo surgery. Median overall survival (OS) of the entire cohort was 38 months (95% CI: 29.9-46.1 months); in-hospital mortality was 1.5%, 30-day mortality rate was 3.7%, while 90-day mortality was 8.8% accounting for 5 and 12 patients respectively. Patients receiving neo-adjuvant therapy did not experience a higher incidence of postoperative complications (P=0.633), did not have a longer postoperative course (P=0.588), nor did they have an increased mortality rate (P=0.863). CONCLUSIONS: Age should not be considered an absolute contraindication for pneumonectomy in elderly patients even after neoadjuvant treatment. It has become apparent that especially in these patients, a patient-tailored approach with a careful selection should be used to define the risk-benefit balance.

Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer.

BACKGROUND: Although T cell abundance in solid tumours is associated with better outcomes, it also correlates with a stroma-mediated source of immune suppression driven by TGFß1 and poor overall survival. Whether this also is observed in non-small cell lung cancer (NSCLC) is unknown. METHODS: We utilized molecular analysis of The Cancer Genome Atlas (TCGA) NSLCC cohort to correlate immune activation (IA) gene expression and extracellular matrix/stromal (ECM/stromal) gene expression with patient survival. In an independent cohort of NSCLC samples, we used flow cytometry to identify mesenchymal subsets and ex vivo functional studies to characterize their immune regulatory function. FINDINGS: We observed a high enrichment in a core set of genes defining an IA gene expression signature in NSCLC across TCGA Pan-cancer cohort. High IA signature score correlates with enrichment of ECM/stromal gene signature across TCGA NSCLC datasets. Importantly, a higher ratio of ECM/stromal to IA gene signature score was associated with shorter overall survival. In tumours resected from a separate cohort of NSCLC patients, we identified CD90+CD73+ peritumoral cells that were enriched in the ECM/stromal gene signature, which was amplified by TGFß1. IFNγ and TNFα-primed peritumoral CD90+CD73+ cells upregulate immune checkpoint molecules PD-L1 and IDO1 and secrete an array of cytokines/chemokines including TGFß1. Finally, immune primed peritumoral CD90+CD73+ cells suppress T cell function, which was relieved following combined blockade of PD-L1 and TGFß1 with IDO1 inhibition but not PD-L1 or anti-CD73 alone. INTERPRETATION: Our findings suggest that targeting PD-L1 together with independent biological features of the stroma may enhance host antitumor immunity in NSCLC. FUNDING: LW and HY are supported by a 4-year China Scholarship Council award. This work was funded, in part, by a grant from the Cancer League of Bern, Switzerland to SRRH. Laser scanning microscopy imaging was funded by the R'Equip grant from the Swiss National Science Foundation Nr. 316030_145003.

Robotic-Assisted Thoracoscopic Resection of the First Rib for Vascular Thoracic Outlet Syndrome: The New Gold Standard of Treatment?

In thoracic outlet syndrome (TOS) the narrowing between bony and muscular structures in the region of the thoracic outlet/inlet results in compression of the neurovascular bundle to the upper extremity. Venous compression, resulting in TOS (vTOS) is much more common than a stenosis of the subclavian artery (aTOS) with or without an aneurysm. Traditional open surgical approaches to remove the first rib usually lack good exposure of the entire rib and the neurovascular bundle. Between January 2015 and July 2021, 24 consecutive first rib resections for venous or arterial TOS were performed in 23 patients at our institutions. For our completely portal approach we used two 8mm working ports and one 12/8 mm camera port. Preoperatively, pressurized catheter-based thrombolysis (AngioJet®) was successfully performed in 13 patients with vTOS. Operative time ranged from 71-270 min (median 128.5 min, SD +/- 43.2 min) with no related complications. The chest tube was removed on Day 1 in all patients and the hospital stay after surgery ranged from 1 to 7 days (median 2 days, SD +/- 2.1 days). Stent grafting was performed 5-35 days (mean 14.8 days, SD +/- 11.1) postoperatively in 6 patients. The robotic approach to first rib resection described here allows perfect exposure of the entire rib as well as the neurovascular bundle and is one of the least invasive surgical approaches to date. It helps improve patient outcomes by reducing perioperative morbidity and is a procedure that can be easily adopted by trained robotic thoracic surgeons. In particular, patients with a/vTOS may benefit from careful and meticulous preparation and removal of scar tissue around the vessels.

Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer.

KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS-driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo-like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS-mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti-proliferative effects and cell death in KRAS-mutant lung and pancreatic but not colon nor KRAS wild-type cancer cells. Mechanistically, co-targeting FGFR1 and PLK1 upregulates reactive oxygen species (ROS), leading to oxidative stress-activated c-Jun N-terminal kinase (JNK)/p38 pathway and E2F1-induced apoptosis. We further delineate that autophagy protects from PLK1/FGFR1 inhibitor cytotoxicity and that antagonizing the compensation mechanism by clinically approved chloroquine fully realizes the therapeutic potential of PLK1 and FGFR1 targeting therapy, producing potent and durable responses in KRAS-mutant patient-derived xenografts and a genetically engineered mouse model of Kras-induced lung adenocarcinoma. These results suggest a previously unappreciated role for FGFR1 and PLK1 in the surveillance of metabolic stress and demonstrate a synergistic drug combination for treating KRAS-mutant cancer.

[Thoracic Outlet Syndrome: Rare, Often Missed or Over-Diagnosed?] / Das Thoracic-Outlet-Syndrom: selten, vielmals verpasst oder zu häufig diagnostiziert?

Thoracic Outlet Syndrome: Rare, Often Missed or Over-Diagnosed? Abstract. The thoracic outlet syndrome (TOS) presents with various symptoms caused by compression of the neurovascular bundle in the region of the upper thoracic aperture. Since the pathogenesis also determines the therapy of TOS, the classification according to the affected structure into neurogenic, venous and arterial TOS (nTOS, vTOS and aTOS) is useful. However, mixed forms are often to be assumed, which are then usually also classified under the term 'non-specific or disputed TOS' in the group of nTOS. In the absence of a gold standard diagnostic test, accurate history taking and clinical examination continue to be of great importance. Diagnostic experience and therapeutic advances have led to hopeful possibilities in the challenging management of this condition.