VATS phrenic nerve harvesting for brachial plexus neurotization: literature review and our experience.

INTRODUCTION: Brachial plexus traumatic lesions often lead to severe upper extremity deficits that dramatically compromise quality of life of mostly young patients. Optimal treatment aims to restore elbow flexion transferring various donor nerves. Phrenic nerve (PN) is a powerful source of transferable axons and, despite supraclavicular sectioning being the most used technique, it can be harvested through video-assisted thoracoscopic surgery (VATS). EVIDENCE ACQUISITION: About PN harvesting, less than 20 articles were found in Literature. Most of them are clinical case-reports or case-series or expert opinions. Most of these studies are from China and East Asia and very rarely from Europe; none from Italy. Therefore, we present our experience in PN VATS harvesting in two patients, first cases reported in Italy. EVIDENCE SYNTHESIS: Few papers explore risks and benefits of PN as a donor site for brachial plexus reconstruction. There is no clear consensus in the literature whether a traditional approach or minimally invasive surgery is advisable to harvest PN for neurotization. Currently there's no clear indication nor a definitive contraindication about routine use of PN for surgical treatment of BPTLs, it's mostly a matter of choosing the best donor nerve for every single patient. This choice depends on the patient's characteristics, type of traumatic lesion, time from the traumatic event and on the center's experience. The only real concern about using PN as a donor is the potential loss of pulmonary function. In our center two patients with complete brachial plexus avulsion underwent PN transfer via VATS in 2021. Usually, recovery of muscle function depends on time between injury and surgical repair. A commonly accepted recommendation is to perform surgery within six months from the traumatic lesion12. In our experience, the time between trauma and surgery was five months for patient A and six months for patient B. Even if some authors13 consider previous thoracic trauma with rib fractures a major contraindication for homolateral PN harvesting, we believe that the presence of pleural adhesions should not exclude a patient from surgery. No intra or postoperative complications were observed. Both patients were discharged on IV postoperative day. An intense rehabilitation program within three months after surgery is mandatory and regular follow-up is needed to monitor any improvement. No respiratory symptoms or discomfort is recorded up to now. CONCLUSIONS: Nerve transfer is a safe and reliable surgical reconstructive procedure and phrenic nerve, due to its pure motor nature, is a very good donor for brachial plexus injuries14. VATS is a valid procedure to guarantee a much longer nerve, avoiding any graft use, and doesn't seem to determine significant pulmonary function loss. Previous thoracic trauma, rib fractures and pneumothorax are commonly considered contraindications for VATS harvesting. However, a major trauma leading to BPTL often implies homolateral thoracic trauma with or without rib fracture or pneumothorax. This could be a reasonable justification to reconsider those contraindications and extend the potential cohort of patients that could benefit from this technique.

Early Identification of Residual Disease After Neuroendocrine Tumor Resection Using a Liquid Biopsy Multigenomic mRNA Signature (NETest).

INTRODUCTION: Surgery is the only cure for neuroendocrine tumors (NETs), with R0 resection being critical for successful tumor removal. Early detection of residual disease is key for optimal management, but both imaging and current biomarkers are ineffective post-surgery. NETest, a multigene blood biomarker, identifies NETs with >90% accuracy. We hypothesized that surgery would decrease NETest levels and that elevated scores post-surgery would predict recurrence. METHODS: This was a multicenter evaluation of surgically treated primary NETs (n = 153). Blood sampling was performed at day 0 and postoperative day (POD) 30. Follow-up included computed tomography/magnetic resonance imaging (CT/MRI), and messenger RNA (mRNA) quantification was performed by polymerase chain reaction (PCR; NETest score: 0-100; normal ≤20). Statistical analyses were performed using the Mann-Whitney U-test, Chi-square test, Kaplan-Meier survival, and area under the receiver operating characteristic curve (AUROC), as appropriate. Data are presented as mean ± standard deviation. RESULTS: The NET cohort (n = 153) included 57 patients with pancreatic cancer, 62 patients with small bowel cancer, 27 patients with lung cancer, 4 patients with duodenal cancer, and 3 patients with gastric cancer, while the surgical cohort comprised patients with R0 (n = 102) and R1 and R2 (n = 51) resection. The mean follow-up time was 14 months (range 3-68). The NETest was positive in 153/153 (100%) samples preoperatively (mean levels of 68 ± 28). In the R0 cohort, POD30 levels decreased from 62 ± 28 to 22 ± 20 (p < 0.0001), but remained elevated in 30% (31/102) of patients: 28% lung, 29% pancreas, 27% small bowel, and 33% gastric. By 18 months, 25/31 (81%) patients with a POD30 NETest >20 had image-identifiable recurrence. An NETest score of >20 predicted recurrence with 100% sensitivity and correlated with residual disease (Chi-square 17.1, p < 0.0001). AUROC analysis identified an AUC of 0.97 (p < 0.0001) for recurrence-prediction. In the R1 (n = 29) and R2 (n = 22) cohorts, the score decreased (R1: 74 ± 28 to 45 ± 24, p = 0.0012; R2: 72 ± 24 to 60 ± 28, p = non-significant). At POD30, 100% of NETest scores were elevated despite surgery (p < 0.0001). CONCLUSION: The preoperative NETest accurately identified all NETs (100%). All resections decreased NETest levels and a POD30 NETest score >20 predicted radiologically recurrent disease with 94% accuracy and 100% sensitivity. R0 resection appears to be ineffective in approximately 30% of patients. NET mRNA blood levels provide early objective genomic identification of residual disease and may facilitate management.

Molecular identification of bronchopulmonary neuroendocrine tumours and neuroendocrine genotype in lung neoplasia using the NETest liquid biopsy.

OBJECTIVES: Diagnosing lung neuroendocrine neoplasia (NEN) requires a biopsy or an operation. We evaluated a 'liquid biopsy' (NETest) as an in vitro diagnostic tool for identifying NEN and compared it to chromogranin A (CgA). METHODS: We identified 4 study cohorts: patients with bronchopulmonary carcinoids (n = 99, including 62 typical and 37 atypical carcinoids), lung cancers [n = 101, including 41 adenocarcinomas, 37 squamous carcinomas (SQC), 16 small-cell lung cancers and 7 large-cell neuroendocrine carcinomas]; benign disease (50 idiopathic pulmonary fibrosis) and healthy controls (n = 102). Transcript levels measured quantitatively (activity scores: 0-100) were compared to CgA (enzyme-linked immunosorbent assay; normal < 109 ng/ml) levels. RESULTS: The results of the NETest were positive (>20) in 94% of patients with bronchopulmonary carcinoid compared to 8% of the controls (Fisher's exact test; P < 0.001) and were significantly more accurate as a diagnostic test (McNemar's test; P < 0.001, χ2 = 72) than was CgA (positive: 19% bronchopulmonary carcinoid, 15% controls). Small-cell lung cancers (87%), large-cell neuroendocrine carcinomas (86%), adenocarcinoma (42%) and SQC (35%) were also NETest-positive. Increasing the NETest cut-off score to >40 was useful for detecting all NENs and differentiating these tumours from either controls/benign lung diseases (specificity 97%) or adenocarcinoma/SQC (specificity 94%). CgA was positive in 15-44% irrespective of pathology and had no diagnostic value. CONCLUSIONS: A gene-based liquid biopsy is an effective and accurate method for diagnosing lung tumours with neuroendocrine gene expression. CgA has no value. An NETest score >40 provides an accurate (94-97%) rule-in for the diagnosis of NEN and a rule-out for benign and other neoplastic diseases. Because neuroendocrine gene expression is associated with a poor prognosis, NETest levels may have utility both in the diagnosis of and the treatment stratification for lung neoplasia.

Blood Chromogranin A Is Not Effective as a Biomarker for Diagnosis or Management of Bronchopulmonary Neuroendocrine Tumors/Neoplasms.

BACKGROUND: Identification of circulating tumor markers for clinical management in bronchopulmonary (BP) neuroendocrine tumors/neoplasms (NET/NEN) is of considerable clinical interest. Chromogranin A (CgA), a "universal" NET biomarker, is considered controversial as a circulating biomarker of BPNEN. AIM: Assess utility of CgA in the diagnosis and management of BPNEN in a multicentric study. MATERIAL AND METHODS: CgA diagnostic metrics were assessed in lung NET/NENs (n = 200) and controls (n = 140), randomly assigned to a Training and Test set (100 BPC and 70 controls in each). Assay specificity was evaluated in neoplastic lung disease (n = 137) and nonneoplastic lung disease (n = 77). CgA efficacy in predicting clinical status was evaluated in the combined set of 200 NET/NENs. CgA levels in bronchopulmonary neuroendocrine tumor (BPNET) subtypes (atypical [AC] vs. typical [TC]) and grade was examined. The clinical utility of an alteration of CgA levels (±25%) was evaluated in a subset of 49 BPNET over 12 months. CgA measurement was by NEOLISATM kit (EuroDiagnostica). RESULTS: Sensitivity and specificity in the training set were 41/98%, respectively. Test set data were 42/87%. Training set area under receiver operator characteristic analysis differentiated BPC from control area under the curve (AUC) 0.61 ± 0.05 p = 0.015. Test set the data were AUC 0.58 ± 0.05, p = 0.076. In the combined set (n = 200), 67% BPNET/NEN (n = 134) had normal CgA levels. CgA levels did not distinguish histological subtypes (TC vs. AC, AUC 0.56 ± 0.04, p = 0.21), grade (p = 0.45-0.72), or progressive from stable disease (AUC 0.53 ± 0.05 p = 0.47). There was no correlation of CgA with Ki-67 index (Pearson r = 0.143, p = 0.14). For nonneoplastic diseases (chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis), CgA was elevated in 26-37%. For neoplastic disease (NSCLC, squamous cell carcinoma), CgA was elevated in 11-16%. The neuroendocrine SCLC also exhibited elevated CgA (50%). Elevated CgA was not useful for differentiating BPNET/NEN from these other pathologies. Monitoring BPNET/NEN over a 12-month period identified neither CgA levels per se nor changes in CgA were reflective of somatostatin analog treatment outcome/efficacy or the natural history of the disease (progression). CONCLUSIONS: Blood CgA levels are not clinically useful as a biomarker for lung BPNET/NEN. The low specificity and elevations in both nonneoplastic as well as other common neoplastic lung diseases identified limited clinical utility for this biomarker.

Surgical management of chronic diaphragmatic hernias.

Chronic diaphragmatic hernia (CDH) is an uncommon disease which may be associated with significant morbidity and mortality. Antecedent (even many months or years before CDH development) blunt or penetrating thoracic/thoraco-abdominal trauma is generally recognized. A wide spectrum of different mechanisms of injury, timing in presentation, size of the diaphragmatic defect, types and amount of abdominal viscera herniated into the chest cavity, clinical symptoms are observed in CDHs. Thoracic and abdominal CT scan (with coronal, axial and sagittal reconstructions) is the best diagnostic tool; sometimes thoracic MRI is needed to better define the extent of the diaphragmatic defect and the number of abdominal organs displaced into the chest cavity. Surgery (sometimes urgent) represents the treatment of choice for CDH; diaphragmatic hernia direct repair with a tension-free suture is generally attempted; in case of very large defects or when a tension-free suture is deemed unfeasible, the use of prosthesis is recommended. This review article will discuss about CDH aetiology, clinical presentation diagnosis and surgical treatment.

NETest Liquid Biopsy Is Diagnostic of Lung Neuroendocrine Tumors and Identifies Progressive Disease.

BACKGROUND: There are no effective biomarkers for the management of bronchopulmonary carcinoids (BPC). We examined the utility of a neuroendocrine multigene transcript "liquid biopsy" (NETest) in BPC for diagnosis and monitoring of the disease status. AIM: To independently validate the utility of the NETest in diagnosis and management of BPC in a multicenter, multinational, blinded study. MATERIAL AND METHODS: The study cohorts assessed were BPC (n = 99), healthy controls (n = 102), other lung neoplasia (n = 101) including adenocarcinomas (ACC) (n = 41), squamous cell carcinomas (SCC) (n = 37), small-cell lung cancer (SCLC) (n = 16), large-cell neuroendocrine carcinoma (LCNEC) (n = 7), and idiopathic pulmonary fibrosis (IPF) (n = 50). BPC were histologically classified as typical (TC) (n = 62) and atypical carcinoids (AC) (n = 37). BPC disease status determination was based on imaging and RECIST 1.1. NETest diagnostic metrics and disease status accuracy were evaluated. The upper limit of normal (NETest) was 20. Twenty matched tissue-blood pairs were also evaluated. Data are means ± SD. RESULTS: NETest levels were significantly increased in BPC (45 ± 25) versus controls (9 ± 8; p < 0.0001). The area under the ROC curve was 0.96 ± 0.01. Accuracy, sensitivity, and specificity were: 92, 84, and 100%. NETest was also elevated in SCLC (42 ± 32) and LCNEC (28 ± 7). NETest accurately distinguished progressive (61 ± 26) from stable disease (35.5 ± 18; p < 0.0001). In BPC, NETest levels were elevated in metastatic disease irrespective of histology (AC: p < 0.02; TC: p = 0.0006). In nonendocrine lung cancers, ACC (18 ± 21) and SCC (12 ± 11) and benign disease (IPF) (18 ± 25) levels were significantly lower compared to BPC level (p < 0.001). Significant correlations were evident between paired tumor and blood samples for BPC (R: 0.83, p < 0.0001) and SCLC (R: 0.68) but not for SCC and ACC (R: 0.25-0.31). CONCLUSIONS: Elevated -NETest levels are indicative of lung neuroendocrine neoplasia. NETest levels correlate with tumor tissue and imaging and accurately define clinical progression.

Application of the coaxial smart drain in patients with a large air leak following anatomic lung resection: a prospective multicenter phase II analysis of efficacy and safety.

BACKGROUND: The presence of air leak following lung resection remains a frequent problem, which may prolong hospital stay and increase hospital costs. In the past, some studies documented the efficacy of soft and flexible chest tube in patients who underwent thoracic surgery. Nevertheless, safety in case of post-operative large air or liquid leak remains questionable. The objective of this study was to verify through a multicentre study the safety and the effectiveness of the coaxial chest tube in a consecutive series of selected patients who underwent anatomical pulmonary resection and with an active and large air leak. METHODS: Between October 2016 and September 2017, data from patients submitted to anatomical lung resection with curative intent and operated in two Department of Thoracic Surgery of two different were prospectively collected. The inclusion criteria consisted in the presence of an air leak greater than 50 mL/min measured with a digital drainage system during the 3 postoperative hours. A descriptive statistic was used to report the incidence of complications assumed to be associated with the use of the coaxial drain. RESULTS: Forty-eight consecutive patients (27 males) submitted to lobectomy (37 patients: 77%) or anatomic segmentectomies (11 patients) were included in the analyses. Thirty-four operations (71%) were performed by video-assisted thoracic surgery (VATS). The median duration of chest tubes was 13 days [interquartile range (IQR), 4-19] and the median duration of air leak was 9 days (IQR, 2-17.5). No patient had undrained postoperative pleural effusion judged to require an additional chest tube placement. There were 12 (25%) cases of clinically or radiologically significant surgical emphysema; in none of these patients any additional procedure or re-operation was required, and they were treated conservatively by increasing the level of suction. CONCLUSIONS: Our experience with this novel Coaxial Drain was satisfactory with no clinically relevant complication caused using this drain, no need to insert additional drain or replace the existing one with another drain a duration of air leak and chest tubes as well as the incidence of subcutaneous emphysema that was in line with what observed in the daily practice in similar highly selected patients with large air leak.

The utility of blood neuroendocrine gene transcript measurement in the diagnosis of bronchopulmonary neuroendocrine tumours and as a tool to evaluate surgical resection and disease progression.

OBJECTIVES: The management of bronchopulmonary neuroendocrine tumours (BPNETs) is difficult, since imaging, histology and biomarkers have a limited value in diagnosis, predicting outcome and defining therapeutic efficacy. We evaluated a NET multigene blood test (NETest) to diagnose BPNETs, assess disease status and evaluate surgical resection. METHODS: (i) Diagnostic cohort: BP carcinoids (n = 118)-typical carcinoid, n = 67 and atypical carcinoid, n = 51; other lung NEN (large-cell neuroendocrine carcinoma and small-cell lung carcinoma, n = 13); adenocarcinoma, (n = 26); squamous cell carcinoma (n = 23); controls (n = 90) and chronic obstructive pulmonary disease (n = 18). (ii) Surgical cohort, n = 28: BP carcinoids (n = 16: typical carcinoid 12; atypical carcinoid 4); large-cell neuroendocrine carcinoma, n = 3; lung adenocarcinoma, n = 8 and squamous cell carcinoma, n = 1. Blood sampling was performed presurgery and 30 days post-surgery. Transcript levels measured by quantitative polymerase chain reaction were calculated as activity scores (0-100% scale: normal < 14%) and compared with chromogranin A (enzyme-linked immunosorbent assay; normal <109 ng/ml). RESULTS: NETest was significantly elevated in carcinoids (48.7 ± 27%) versus controls (6 ± 6%, P < 0.001) with metrics: sensitivity 93%, specificity 89%, positive predictive value 92% and negative predictive value 91%. NETest differentiated progressive disease (73 ± 22%) from stable disease (36 ± 19%, P < 0.001) and R0 resections (10 ± 5%, P < 0.001, area under the curve: 0.98). Levels in chronic obstructive pulmonary disease and lung cancers were 18-24% while elevated in small-cell lung carcinoma/large-cell neuroendocrine carcinoma (59 ± 10%). In BPNETs on postoperative Day 30, NETest decreased by 60% (P < 0.001). Chromogranin A was elevated in only 40% of carcinoids and not altered by surgery. CONCLUSIONS: Blood NET gene levels accurately identified BPNETs (100%) and differentiated these from controls, benign and malignant lung disease. Progressive disease could be identified and surgical resection verified. Chromogranin A had no clinical utility. Monitoring NET transcript levels in blood will facilitate management by detecting residual tumour and identifying progressive disease.

Molecular strategies in the management of bronchopulmonary and thymic neuroendocrine neoplasms.

Thoracic NETs [bronchopulmonary NETs (BPNETs) and thymic NETs (TNET)] share a common anatomic primary location, likely a common cell of origin, the "Kulchitsky cell" and presumably, a common etiopathogenesis. Although they are similarly grouped into well-differentiated [typical carcinoids (TC) and atypical carcinoids (AC)] and poorly differentiated neoplasms and both express somatostatin receptors, they exhibit a wide variation in clinical behavior. TNETs are more aggressive, are frequently metastatic, and have a lower 5-year survival rate (~50% vs. ~80%) than BPNETs. They are typically symptomatic, most often secreting ACTH (40% of tumors) but both tumor groups share secretion of common biomarkers including chromogranin A and 5-HIAA. Consistently effective and accurate circulating biomarkers are, however, currently unavailable. Surgery is the primary therapeutic tool for both BPNET and TNETs but there remains little consensus about later interventions e.g., targeted therapy, or how these can be monitored. Genetic analyses have identified different topographies (e.g., significant alterations in chromatin and epigenetic remodeling in BPNETs versus frequent chromosomal abnormalities in TNETs) but there is an absence of clinically actionable mutations in both tumor groups. Liquid biopsies, tools that can measure neoplastic signatures in peripheral blood, can potentially be leveraged to detect disease early i.e., recurrence, predict tumors that may respond to specific therapies and serve as real-time monitors for treatment responses. Recent studies have identified that mRNA transcript analysis in blood effectively identifies both BPNET and TNETs. The clinical utility of this gene expression assay includes use as a diagnostic, confirmation of completeness of surgical resection and use as a molecular management tool to monitor efficacy of PRRT and other therapeutic strategies.

Neuroendocrine tumors of the thymus.

Primary neuroendocrine tumors of the thymus (NETTs) are rare and biologically very aggressive neoplasms, usually located in the anterior mediastinal space. They are more frequently observed in males, in their fourth/fifth decades of life. In 50% of cases, NETTs are associated with endocrinopaties [Cushing's syndrome, acromegaly or Multiple Endocrine Neoplasia-1 (MEN-1) syndrome]. NETTs very often present with invasion of the surrounding mediastinal anatomical structures. Surgery, even in advanced stages, is the mainstay of treatment: a compete resection through a median sternotomy or a combined access (sternotomy + thoracotomy) should be always attempted. Induction chemotherapy (± radiotherapy) is usually administered in advanced neoplasms, with the aim to achieve tumor shinkage, increasing, therefore, the chance to obtain a complete resection. Postoperative radiotherapy (± chemotherapy) is administered in case of invasive lesions, or incomplete resections. NETTs long-term outcome is poor, even in case of completely resected tumors, due to high risk of recurrence or distant metastases development. Prognosis mainly depends on tumor stage, invasivity, completeness of resection, possible association with endocrinopaties and recurrence/distant metastases development.

Management of Chest Drains After Thoracic Resections.

Immediately after lung resection, air tends to collect in the retrosternal part of the chest wall (in supine position), and fluids in its lower part (costodiaphragmatic sinus). Several general thoracic surgery textbooks currently recommend the placement of 2 chest tubes after major pulmonary resections, one anteriorly, to remove air, and another into the posterior and basilar region, to drain fluids. Recently, several authors advocated the placement of a single chest tube. In terms of air and fluid drainage, this technique demonstrated to be as effective as the conventional one after wedge resection or uncomplicated lobectomy.

Errors and Complications in Chest Tube Placement.

Chest drain placement is one of the most common surgical procedures performed in routine clinical practice. Despite the many benefits, chest tube insertion is not always a harmless procedure, and potential significant morbidity and mortality may exist. The aim of this article was to highlight the correct chest tube placement procedure and to focus on errors and clinical complications following its incorrect insertion into the chest.

Validation of EORTC and CALGB prognostic models in surgical patients submitted to diagnostic, palliative or curative surgery for malignant pleural mesothelioma.

BACKGROUND: To assess the trend of our surgical patients affected by malignant pleural mesothelioma (MPM) and submitted to diagnostic/palliative or curative surgical procedures and to validate the European Organisation for Research and Treatment of Cancer (EORTC) prognostic score in our patient population. METHODS: This is a cohort study of patients submitted to surgery for MPM from January 2007 to December 2013. Primary outcome was overall survival (OS). Univariate and multivariate-adjusted comparisons by EORTC prognostic score for OS were accomplished using Cox method. Adjusted models included the following clinical variables: kind of procedure, smoking habit, asbestos exposure, Charlson's Comorbidity Index (CCI), clinical tumor stage, adjuvant chemotherapy, dyspnoea, chest pain and haematological variables according to the score features. Nomenclature of the surgical procedures matches the International Association for the Study Lung Cancer (IASLC)/International Mesothelioma Interest Group (iMIG). RESULTS: One-hundred sixty-six consecutive cases were collected: the median age at surgery was 73 years and 123 patients (75%) had a history of asbestos exposure. Ninty patients (54%) were submitted to a palliative/diagnostic thoracoscopy, 30 to pleurectomy/decortication (P/D), and 6 to extra-pleural pneumonectomy (EPP). Clinical TNM stages were as follows: 99 (60%) stage I-II, 34 (20%) stage III and 33 (20%) stage IV. The median follow-up (FU) was 19 months [interquartile range (IQR), 9-31 months] and the FU-completeness was 98%. By the end of the study 130 patients died (78%). One- and 3-year OS was 60% and 36%, respectively. Patients submitted to EPP and P/D showed a better survival (P=0.013). Multivariable model showed an independent prognostic value of EORTC score (HR =2.86, P<0.001). CONCLUSIONS: In selected patients, aggressive surgical approaches, although not radical, may still be beneficial. The EORTC prognostic index proved to be an independent prognostic factor in our cohort of patients and therefore is a reliable and valid instrument that may be implemented in the daily practice.