A multigenomic liquid biopsy biomarker for neuroendocrine tumor disease outperforms CgA and has surgical and clinical utility.

BACKGROUND: Biomarkers are key tools in cancer management. In neuroendocrine tumors (NETs), Chromogranin A (CgA) was considered acceptable as a biomarker. We compared the clinical efficacy of a multigenomic blood biomarker (NETest) to CgA over a 5-year period. PATIENTS AND METHODS: An observational, prospective, cross-sectional, multicenter, multinational, comparative cohort assessment. Cohort 1: NETest evaluation in NETs (n = 1684) and cancers, benign diseases, controls (n = 731). Cohort 2: (n = 1270): matched analysis of NETest/CgA in a sub-cohort of NETs (n = 922) versus other diseases and controls (n = 348). Disease status was assessed by response evaluation criteria in solid tumors (RECIST). NETest measurement: qPCR [upper limit of normal (ULN: 20)], CgA (EuroDiagnostica, ULN: 108 ng/ml). STATISTICS: Mann-Whitney U-test, AUROC, chi-square and McNemar' test. RESULTS: Cohort 1: NETest diagnostic accuracy was 91% (P < 0.0001) and identified pheochromocytomas (98%), small intestine (94%), pancreas (91%), lung (88%), gastric (80%) and appendix (79%). NETest reflected grading: G1: 40 ± 1, G2 (50 ± 1) and G3 (52 ± 1). Locoregional disease levels were lower (38 ± 1) than metastatic (52 ± 1, P < 0.0001). NETest accurately stratified RECIST-assessed disease extent: no disease (21 ± 1), stable (43 ± 2), progressive (62 ± 2) (P < 0.0001). NETest concordance with imaging (CT/MRI/68Ga-SSA-PET) 91%. Presurgery, all NETs (n = 153) were positive (100%). After palliative R1/R2 surgery (n = 51) all (100%) remained elevated. After curative R0-surgery (n = 102), NETest levels were normal in 81 (70%) with no recurrence at 2 years. In the 31 (30%) with elevated levels, 25 (81%) recurred within 2 years. Cohort #2: NETest diagnostic accuracy was 87% and CgA 54% (P < 0.0001). NETest was more accurate than CgA for grading (chi-square = 7.7, OR = 18.5) and metastatic identification (chi-square = 180, OR = 8.4). NETest identified progressive disease (95%) versus CgA (57%, P < 0.0001). Imaging concordance for NETest was 91% versus CgA (46%) (P < 0.0001). Recurrence prediction after surgery was NETest-positive in >94% versus CgA 11%. CONCLUSION: NETest accurately diagnoses NETs and is an effective surrogate marker for imaging, grade, metastases and disease status compared to CgA. A multigenomic liquid biopsy is an accurate biomarker of NET disease.

Clinical management of patients with thymic epithelial tumors: the recommendations endorsed by the Italian Association of Medical Oncology (AIOM).

The Italian Association of Medical Oncology recommendations on thymic epithelial tumors, which have been drawn up for the first time in 2020 through an evidence-based approach, report indications on all the main aspects of clinical management of this group of rare diseases, from diagnosis and staging, to new available systemic treatments, such as targeted therapies and immunotherapies. A summary of key recommendations is presented here and complete recommendations are reported as Supplementary Materials, available at https://doi.org/10.1016/j.esmoop.2021.100188.

Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids.

BACKGROUND: Pulmonary carcinoids (PCs) are rare tumors. As there is a paucity of randomized studies, this expert consensus document represents an initiative by the European Neuroendocrine Tumor Society to provide guidance on their management. PATIENTS AND METHODS: Bibliographical searches were carried out in PubMed for the terms 'pulmonary neuroendocrine tumors', 'bronchial neuroendocrine tumors', 'bronchial carcinoid tumors', 'pulmonary carcinoid', 'pulmonary typical/atypical carcinoid', and 'pulmonary carcinoid and diagnosis/treatment/epidemiology/prognosis'. A systematic review of the relevant literature was carried out, followed by expert review. RESULTS: PCs are well-differentiated neuroendocrine tumors and include low- and intermediate-grade malignant tumors, i.e. typical (TC) and atypical carcinoid (AC), respectively. Contrast CT scan is the diagnostic gold standard for PCs, but pathology examination is mandatory for their correct classification. Somatostatin receptor imaging may visualize nearly 80% of the primary tumors and is most sensitive for metastatic disease. Plasma chromogranin A can be increased in PCs. Surgery is the treatment of choice for PCs with the aim of removing the tumor and preserving as much lung tissue as possible. Resection of metastases should be considered whenever possible with curative intent. Somatostatin analogs are the first-line treatment of carcinoid syndrome and may be considered as first-line systemic antiproliferative treatment in unresectable PCs, particularly of low-grade TC and AC. Locoregional or radiotargeted therapies should be considered for metastatic disease. Systemic chemotherapy is used for progressive PCs, although cytotoxic regimens have demonstrated limited effects with etoposide and platinum combination the most commonly used, however, temozolomide has shown most clinical benefit. CONCLUSIONS: PCs are complex tumors which require a multidisciplinary approach and long-term follow-up.

Efficacy of fleece-bound sealing system (TachoSil®) in delayed anterior tracheal lacerations secondary to ischemic tracheal necrosis after total thyroidectomy.

Thyroidectomy is one of the commonest surgical operations performed in endocrine surgery; results are generally excellent and morbidity and mortality usually are negligible. Total thyroidectomy's complication rates are low, with an overall incidence of 4.3% among experienced surgeons: the most frequent complications are vocal cord paresis or paralysis, hypoparathyroidism, hypocalcemia, haematoma and wound infection. Tracheal injury following thyroidectomy is even more rare. As reported from some authors, inadvertent tracheal injury has an incidence of 0-0.6% during thyroidectomy. Tracheal laceration (generally located in the posterolateral surface) is often recognized and repaired immediately, during the same intervention. Rarely, following a total thyroidectomy, a delayed tracheal rupture may occur secondary to an ischemic damage of the trachea. This has been described in few cases reported in literature. In this paper we report of a case in which delayed tracheal lacerations appeared 10 days after the patient underwent total thyroidectomy: a prompt surgical operation was efficient using both direct sutures of tracheal breaches and a patch of fibrinogen-thrombin coated collagen fleece covering the entire surface.

Preliminary results of a new small-bore percutaneous pleural catheter used for treatment of malignant pleural effusions in ECOG PS 3-4 patients.

BACKGROUND: In cancer patients with malignant pleural effusions(MPEs),the commonest procedure to treat them with palliative intention is talc pleurodesis (TP) which can be obtained with talc slurry (TS) using small-bore catheters(SBC)or with thoracoscopic poudrage. SBC use is therefore rapidly increasing. The aim of this paper is to present our preliminary TP results using a new percutaneous chest drainage system(UNICO®, Redax, Mirandola Modena, Italy). METHODS: In the period 1st March-20th of July 2011,seven consecutive ECOG PS 3-4 patients(4 females, mean age 73.2 ± 12.1 years),unfit for thoracoscopic talc poudrage, were enrolled in our study. All patients received many thoracentesis before the placement of a chest drainage(median thoracentesis number:4.42 ± 1.13).UNICO® was bedside placed in all cases and TS was administered through the drainage when the overall fluid amount didn't exceed 150-200 ml/24 h and the lung was correctly re-expanded at the chest X-ray control. RESULTS: There were no clinical complications following the placement of the drainage: its placement was easy, safe and well-tolerated by all patients. The median chest tube stay, before TS, was 7.2 ± 2.7 days while the median chest tube stay after TS was 1.5 ± 0.7 days. A satisfactory radiological lung expansion was achieved in all cases; PL effectiveness and dyspnea relief were complete in 6 and 4 cases, respectively. No patients required any further thoracentesis. CONCLUSIONS: TS through UNICO® is safe and efficient. The drainage was well-tolerated by all patients, even in case of its long-term stay. We may conclude that bedside TS through this new small-bore percutaneous drainage should be proposed as a viable clinical solution for MPEs in ECOG PS 3-4 patients, unfit for a thoracoscopic procedure. Moreover, with this device, we believe that TS might be an accessible procedure for pulmonologists and oncologists too.

Patient's home care management in persistent air leaks and chronic pneumothorax using a new drainage system.

The management of persistent air leaks (PALs) is one of the most common problems in general thoracic surgery, especially after elective pulmonary resections. The statistically most frequent air leak is caused by alveolar-pleural fistula (APF), which is defined as a link between the pulmonary parenchyma distal to a segmental bronchus, and the pleural space. Prolonged air leaks result in an increase in patient's hospital length of stay with possible infectious complications, aside from an overall hospitalization cost increase. The ability to discharge a patient who would otherwise depend on continuous aspiration, because chronic PALs represent a very important clinical and technological improvement. We describe the case of a patient with chronic PALs and pneumothorax due to pulmonary fibrosis secondary to rheumatoid arthritis, with diffuse pulmonary nodules, in which surgical attempts to manage air leaks were ineffective. He was successfully home-assisted with a new chest drainage system with automatic constant negative suction pressure.

Digital air leak monitoring after lobectomy for primary lung cancer in patients with moderate COPD: can a fast-tracking algorithm reduce postoperative costs and complications?

AIM: Prolonged air leaks remain one of the most important complication after pulmonary resection. The aim of this study was to test a new fast-track chest tube removal protocol using a new drainage system, which digitally records postoperative air leaks, compared to the traditional one, with subjective visual air leak assessment. METHODS: Patients with moderate COPD undergoing lobectomy for primary lung cancer at the Department of Thoracic Surgery of the University of Torino were randomised in two groups with different chest drainage systems and different removal protocols: in Group A the drainage was removed after digitally recordered measurement of air leaks; in Group B the tube was removed according to the air leaks visualization by bubbling in the water column. The following variables were evaluated: first and second drainage removal day; overall hospital length of stay; overall hospitalization costs. RESULTS: First and second drainages were removed sooner in those patients with the digital drainage system. An earlier drainage removal is associated with significative reduction in hospital length of stay and overall hospitalization costs. CONCLUSION: The digital and continuous air leak measurement reduces the hospital length of stay by a more accurate and reproductive air leaks measurement. Further studies are mandatory to corroborate our preliminary results.

Chest wall and hemidiaphragm reconstruction with Gore-Tex mesh and omolateral latissimus dorsi flap. A case report.

There are various method of reconstruction when chest wall resection is performed for the treatment of tumors of the chest wall. In this case a chest wall resection and reconstruction was performed using an omolateral latissimus dorsi flap, together with Gore-Tex mesh. A 42-year-old woman was diagnosed as having a huge low grade chondrosarcoma and underwent surgical resection which interested the anterior chest wall from the level of the IV to X rib and the right hemidiaphragm. Gore-Tex mesh was fixed to the residual chest wall and an ipsilateral pedicled latissimus dorsi muscle flap was placed on the alloplastic mesh. The patient was discharged from the hospital 17 days postoperatively. The postoperative course was uneventful and the wound was fine.

The role of surgery in the management of solitary pulmonary nodule in breast cancer patients.

AIMS: To assess the role of surgery in the diagnosis and treatment of a solitary pulmonary nodule (SPN) in patients who had received previous surgery for breast cancer. METHODS: A series of 79 consecutive patients who underwent surgery for an SPN between 1990 and 2003 after a curative resection for breast cancer were reviewed. RESULTS: Surgical diagnosis was obtained by open procedure before 1996 (37 cases), and by video-assisted thoracoscopic surgery (VATS) after 1996 (33 out of 42 cases, 9 open procedures) and intraoperative evaluation. Histology of SPN was primary lung cancer in 38 patients, pulmonary metastasis of breast cancer in 27, and benign condition in 14. VATS was converted to open procedure for anatomical resection in primary lung cancer and for the palpation of the lung in metastatic disease. Average disease-free interval from the initial mastectomy was significantly longer in primary lung cancer than in metastatic patients (179+/-107 vs 51+/-27 moths). Manual palpation identified multiple pulmonary nodules in 3 out of 27 metastatic patients. Five-year survival rate after pulmonary metastasectomy was 38% and was significantly influenced by disease-free interval; 5-year survival rate after resection of primary lung cancer was 43% and was significantly influenced by the pathological stage. CONCLUSIONS: VATS is a good procedure for diagnostic management of peripheral SPN. As SPN in breast cancer patients is primary lung cancer in half cases, it deserves confirmation of pathological diagnosis and appropriate surgical treatment. When breast cancer metastasis is demonstrated, open procedure must be performed to palpate the entire lung to exclude previously unknown nodules.

Lung donors selection criteria: a review.

Lung transplantation has had increasing success worldwide and it became an acceptable treatment modality in end-stage pulmonary diseases. The insufficient supply of donor lungs, resulting in prolonged waiting time, and the significant rise of patients on the waiting list, have forced the most experienced transplantation centers to redefine the acceptable lung donor criteria including marginal allografts. Existing standard lung donor criteria have been established in the first period of lung transplantation activity, based mainly on opinions and individual experiences rather than on existing evidences: the paucity of donors may be also explained by the rigid application of these criteria. The quality of donor organs has a significant impact on early and long-term recipient outcome. Recent studies have demonstrated that the use of marginal donors did not affect early and late recipient outcome, and significantly increased the number of transplants performed. The aim of this paper is to review how the main lung donor selection criteria have been changed and how they influence the recipient outcome.

Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series.

Neuroendocrine tumors may occur in the setting of multiple endocrine neoplasia type 1 (MEN1) syndrome. Among these, a probably underestimated prevalence of well differentiated neuroendocrine thymic carcinoma (carcinoid), a neoplasm characterized by very aggressive behavior, has been described. We report characterization of the seven Italian cases in which this association occurred among a series of 221 MEN1 patients (41 sporadic and 180 familial cases; prevalence, 3.1%). All of the patients were male, and six of seven (85%) were heavy smokers. No associated hormonal hypersecretion was detected. The first diagnosis was between the second and fifth decades. Familial clusters were present in three of seven (42.8%). No genotype-phenotype correlation was found. All seven cases were associated with hyperparathyroidism. In one patient, prophylactic thymectomy revealed a small nodular lesion suggestive of a thymic carcinoid, providing evidence that preventive thymectomy might prevent additional growth of an occult thymic carcinoid. These findings confirm that thymic carcinoids are associated with a very high lethality, with a near-total prevalence in smoker males. Therefore, prophylactic thymectomy should be considered at neck surgery for primary hyperparathyroidism in MEN1 male patients, especially for smokers, and, due to the frequent familial clusters distribution of this pathology, in subjects with affected relatives presenting this feature. Thus, we recommend screening every patient affected with a neuroendocrine thymic neoplasm for MEN1 syndrome.

The significance of associated pre-invasive lesions in patients resected for primary lung neoplasms.

OBJECTIVE: To evaluate the prevalence and clinico/prognostic significance of the presence of pre-invasive lesions in patients resected for primary lung neoplasm. METHODS: From 1993 to 2002, 1090 patients received resection for primary lung carcinomas. Of these, 73 presented an associated pre-invasive lesion in the surgical specimen distant from the primary tumour. Classification of pre-invasive lesions included Atypical Adenomatous Hyperplasia (AAH); Carcinoma In Situ (CIS) either diffuse or at the bronchial resection margin; Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH). Correlation between the presence of pre-invasive lesion and the following variables were calculated by logistic regression analysis: sex, age, median tumour size, histology, histologic differentiation, histologic evidence of invasiveness (vascular and perineural invasion), peritumoural lymphocytic infiltrate, pTNM, lobe location, history of previous malignancy. Survival rates were computed using Kaplan-Meier method and survival differences with the total patient population of resected lung carcinomas were tested using the log-rank method. RESULTS: There were 28 AAH, 42 CIS (5 at the bronchial resection margin) and 3 DIPNECH. Histology of the primary tumor included bronchioloalveolar carcinoma (9 patients), adenocarcinoma (19), squamous cell carcinoma (39), typical carcinoid tumour (3) and adenosquamous carcinoma (3). Overall prevalence of pre-invasive lesion was 6.7%. A strong correlation was found between the presence of AAH and the co-existence of either adenocarcinoma, bronchioloalveolar carcinoma or mixed adenocarcinoma-containing tumours (P = 0.00002) between CIS and squamous cell carcinoma (P = 0.009) and between DIPNECH and carcinoid tumours (P = 0.001). No significant correlation was found between the presence of any type of pre-invasive lesion and sex, age, median tumour size, histologic differentiation, histologic evidence of invasiveness, pTNM, lobe location and history of previous malignancy or the probability to develop a second primary lung carcinoma in the remaining lobe(s) after resection. Survival rates in the patients with AAH and CIS were not significantly different from those of patients without pre-invasive lesion (P = 0.3 and P = 0.1). CONCLUSIONS: Associated pre-invasive lesions in patients resected for primary lung neoplasms are not infrequent. AAH is associated with adenocarcinoma, CIS with squamous cell carcinoma, DIPNECH with typical carcinoid tumours. Our experience indicates that in these patients histology, stage distribution and survival do not differ from the total population of resected patients with lung tumors.

[Chronic inflammation and airway remodeling in asthma. Importance of an early treatment]. / Flogosi cronica e rimodellamento delle vie aeree nell'asma. Importanza dell'intervento precoce.

Chronic inflammation in asthma stimulates complex repair mechanisms which ultimately lead to deep structural changes in the bronchial tree, defined as airway remodeling, consisting principally in the thickening of the bronchial wall. These processes contribute to progressive airway narrowing with incomplete responsiveness to bronchodilating agents: clinical conditions of patients are irreversibly impaired. There is evidence that remodeling is a process that begins in early childhood and continues into adult life. These observations provide the rationale for early intervention with antiinflammatory drugs like inhaled corticosteroids, which effectively reduce airway inflammation and possibly prevent the progression to lung damage. Several clinical and pharmacological studies have demonstrated that these drugs inhibit cellular processes involved remodeling.

Severe hypoglycaemia associated with a giant solitary fibrous tumor of the pleura.

Solitary fibrous tumors (SFT) of the pleura are a rare neoplasm, with benign biological behaviour. Recurrences are rare, and no distant metastases are described in the literature. SFT can secrete hormone-like substances, responsible for paraneoplastic syndromes. The authors describe a case of severe hypoglycaemia due to insulin-like growth factor II (IGF-2)'s secretion by a giant SFT of the pleura. Hypoglycaemia was controlled by the resection of the tumor. Diagnosis and surgical management of these neoplasms are also discussed.

[Bronchopulmonary carcinoid tumours]. / I tumori carcinoidi broncopolmonari.

Carcinoids are neuroendocrine neoplasms. Bronchial carcinoids are unusual, malignant primary neoplasms that characteristically involve the central airways and typically exhibit well-defined margins and bronchial-related growth. Bronchial carcinoids include low-grade typical carcinoids and the more aggressive atypical ones. They usually affect patients in the 3rd through the 7th decade of life who are often symptomatic with cough, hemoptysis or obstructive pneumonia. Rarely, the initial symptoms are related to the secretion of hormones causing carcinoid or other endocrine syndromes. Bronchial carcinoids radiologically manifest as hilar or perihilar masses, with or without associated atelectasis, pneumonia or bronchiectasis. At CT-scan the relationship of these tumors with the bronchial tree is usually seen, and they show contrast enhancement or calcification. Even if the radiological signs may be suggestive for bronchial carcinoid, the definitive diagnosis is reached only by the tissue sampling. Bronchoscopic biopsy is the more effective way to identify the nature of carcinoid tumors because of their frequent central location. The treatment of choice is the surgical resection which should be carried out with maximum respect for the residual lung and bronchial tissues. Endoscopic ablations in well defined cases, bronchotomy and lung resections with or without bronchoplastic procedures have been described. Hilar and mediastinal lymph node sampling and examination should be ever performed during open procedures. Positivity of the nodal tissues could influence the resection procedure and is related with the prognosis, specially for the atypical carcinoids. Chemo- and radiation therapy are not effective in improving the long-term outcome in those patients with advanced disease. The long-term outcome is strictly related with the histological subtype and the lymph node status. Local recurrences and distant metastases are more frequent in the atypical carcinoids which manifest a more aggressive behavior. During the last decade, the importance of the use of somatostatine analogues (octreotide) in the staging, early detection of the recurrent disease and its management such as that of the associated carcinoid syndrome became clear.

Supraventricular arrhythmias after resection surgery of the lung.

OBJECTIVE: Two hundred consecutive patients undergoing resection surgery of the lung during 1999 were retrospectively reviewed to define prevalence, type, clinical course and risk factors for postoperative supraventricular arrhythmias (SVA) with particular reference to atrial fibrillation or flutter (AF). METHODS: Records of 200 lung patients were collected and analysed with particular attention to preoperative physiologic values and associated pathologies, lung functional status, electrocardiogram registration, extent of surgical resection of the lung and were also analysed to confirm or exclude correlation between them and postoperative AF; three patients were excluded as they were affected preoperatively by SVA. RESULTS: Forty-five episodes of SVA, 41 of AF were identified in 197 patients (22%) and were more prevalent in several groups of patients such as those with increased age, pneumonectomy and superior lobectomy. Rhythm disturbances were most likely to develop on the second day after surgery. Ninety-eight percent of AF disappeared within a day of discharge and sinus rhythm was restored with digitalis or other antiarrhythmic drugs in all patients except one who was discharged with persistent atrial fibrillation. Arrhythmias were not direct causes of any in-hospital deaths. There is a tendency in the difference of the AF rate between pneumonectomy and upper lobectomy patients versus inferior lobectomy ones, probably related to the different anatomic structure of the proximal trunks of the upper and inferior veins of the lung, respectively. CONCLUSIONS: Statistical analysis revealed that increased age, extent and type of pulmonary resection, such as pneumonectomy and superior lobectomy were significant risk factors. Despite these factors, arrhythmias after lung surgery could be managed easily and were not closely related to higher mortality. Direct cause of AF after lung resection surgery remains unclear; anatomical substrate such as surgical damage to the cardiac plexus or to the proximal trunks of the pulmonary veins covered by myocardial sleeves with electrical properties are to be considered.