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Purpose Lung cancer relapse may be associated with the presence of a small population of cancer stem cells (CSCs) with unlimited proliferative potential. Our study assessed the relationship between CSCs and the relapse rate in patients harboring adenocarcinoma (ADL) and squamous cell carcinoma of the lung (SCCL). Experimental design This is an observational prospective cohort study (NCT04634630) assessing the influence of CSC frequency on relapse rate after major lung resection in 35 patients harboring early (I-II) (n = 21) and locally advanced (IIIA) (n = 14) ADL and SCCL. There was a 2-year enrollment period followed by a 1-year follow-up period. Surgical tumor specimens were processed, and CSCs were quantified by cytofluorimetric analysis. Results Cancer stem cells were expressed in all patients with a median of 3.1% of the primary cell culture. Primary analysis showed no influence of CSC frequency on the risk of relapse (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 0.85-1.30). At secondary analysis, patients with locally advanced disease with higher CSC frequency had an increased risk of relapse (HR = 1.26, 95% CI = 1.14-1.39), whereas this was not observed in early-stage patients (HR = 0.90, 95% CI = 0.65-1.25). Conclusion No association was found between CSC and relapse rates after major lung resection in patients harboring ACL and SCCL. However, in locally advanced-stage patients, a positive correlation was observed between CSC frequency and risk of relapse. These results indicate a need for further molecular investigations into the prognostic role of CSCs at different lung cancer stages. Clinical Trial Registration NCT04634630.

Supplementary Figure 1 from Adipose-Derived Mesenchymal Stem Cells as Stable Source of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Delivery for Cancer Therapy

Supplementary Figure 5 from Adipose-Derived Mesenchymal Stem Cells as Stable Source of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Delivery for Cancer Therapy

Supplementary Figure 4 from Adipose-Derived Mesenchymal Stem Cells as Stable Source of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Delivery for Cancer Therapy

Supplementary Figure 3 from Adipose-Derived Mesenchymal Stem Cells as Stable Source of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Delivery for Cancer Therapy

Supplementary Materials and Methods, Figure Legends 1-5 from Adipose-Derived Mesenchymal Stem Cells as Stable Source of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Delivery for Cancer Therapy

Supplementary Figure 2 from Adipose-Derived Mesenchymal Stem Cells as Stable Source of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Delivery for Cancer Therapy

Highlights • Indications for the surgical correction of pectus excavatum. • Pectus excavatum repair was proposed by Ravitch in 1949. • The goal is to remove abnormal rib cartilage in a more anatomic manner. • A case of bilateral pectoralis muscle flap transposition during modified Ravitch procedure. • Significant reduction in late complications and better functional and aesthetic outcomes., Background Indications for the surgical correction of pectus excavatum include functional/physiological, cosmetic, and psychosocial reasons. The most popular open technique for pectus excavatum repair was proposed by Ravitch in 1949 as an open approach that requires partial resection of the costal cartilage, xiphoid excision, and osteotomy of the sternum. The goal is to remove abnormal rib cartilage while preserving the perichondrium, allowing regrowth of the rib cartilage to the sternum in a more anatomic manner. Operative technique. We present a case of bilateral pectoralis muscle flap transposition during a modified Ravitch procedure is presented herein. Conclusion: This approach allows for a significant reduction in late complications and improves both functional and aesthetic outcomes.

// Valentina Masciale 1 , * , Giulia Grisendi 2 , * , Federico Banchelli 3 , * , Roberto D’Amico 3 , Antonino Maiorana 4 , Pamela Sighinolfi 4 , Alessandro Stefani 1 , Uliano Morandi 1 , Massimo Dominici 2 , * and Beatrice Aramini 1 , * 1 Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy 2 Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy 3 Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy 4 Institute of Pathology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy * Co-first/last authors Correspondence to: Beatrice Aramini, email: beatrice.aramini@unimore.it Keywords: immunophenotype; cancer stem cells; cancer stem-like cells; non-small cell lung cancer (NSCLC); target therapy Received: February 08, 2020 Accepted: April 03, 2020 Published: April 28, 2020 ABSTRACT Objectives: Several studies demonstrated that aldehyde dehydrogenase (ALDH) and CD44 are the most considered cancer stem cells (CSC) markers. However, a comparison between ALDH high cells and CD44+ cells have been previously described with no significant correlation. Indeed, the aim of the present research is to identify a superficial marker able to match with ALDH high cells population in freshly isolated human lung cancer cells. Materials and Methods: This cross-sectional study analyzed the expression of ALDH high/low cells and the positivity for CD44 and epithelium cell adhesion molecule (EPCAM) antigens in surgical lung cancer tissues. The main approach was a cytofluorimetric analysis of ALDH expression and positivity for CD44/EPCAM on primary cell population obtained from 23 patients harboring NSCLC. Results: There was a highly positive correlation between the expressions of ALDH high and CD44+/EPCAM+ cells, with a Pearson’s correlation coefficient equal to 0.69 (95% CI 0.39–0.86; P = 0.0002), and Spearman’s correlation coefficient equal to 0.52 ( P = 0.0124). The average paired difference between the expression of ALDH high and CD44+/EPCAM+ cells was very close to 0, being 0.1% (SD 2.5%); there was no difference between these subpopulations in terms of means (95% CI = –1.0; 1.2%, P = 0.8464). These results highlight a strong similarity between ALDH high and CD44+/EPCAM+ cells. Conclusions: Our study is the first attempt which identifies a high correlation between the ALDH high and the CD44+/EPCAM+ cells, thus suggesting the possibility to use this superficial marker for future target treatments against lung cancer stem cells.

Purpose Cancer stem cells (CSCs) are described as resistant to chemotherapy and radiotherapy. It has been shown that CSCs influence disease-free survival in patients undergoing surgery for lung cancer (NCT04634630). We recently described an overexpression of CSCs recurrence-related genes (RG) in lung cancer. This study aims to investigate CSC frequency and RG expression as predictors of disease-free survival in lung cancer. Experimental Design This secondary analysis of a prospective cohort study involved 22 surgical tumor specimens from 22 patients harboring early (I-II) and locally advanced (IIIA) stages ACL and SCCL. Cell population frequency analysis of ALDHhigh (CSCs) and ALDHlow (cancer cells) was performed on each tumor specimen. In addition, RG expression was assessed for 31 target genes separately in ALDHhigh and ALDHlow populations. CSCs frequency and RG expression were assessed as predictors of disease-free survival by Cox analysis. Results CSCs frequency and RG expression were independent predictors of disease-free survival. CSC frequency was not related to disease-free survival in early-stage patients (HR = 0.84, 95%CI = 0.53-1.33, P = .454), whereas it was a risk factor for locally advanced-stage patients (HR = 1.22, 95%CI = 1.09-1.35, P = .000). RG expression—if measured in CSCs—was related to a higher risk of recurrence (HR = 1.19, 95%CI = 1.03-1.39, P = .021). The effect of RG expression measured in cancer cells on disease-free survival was lower and was not statistically significant (HR = 1.12, 95%CI = 0.94-1.33, P = .196). Conclusions CSCs frequency and RG expression are independent predictors of relapse in lung cancer. Considering these results, CSCs and RG may be considered for both target therapy and prognosis.

Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process.

IntroductionLung cancer is one of the most common cancers in the world, causing over 1.7 million deaths in 2018. Thus far, no effective treatments against lung cancer for advanced stages have been found. For early stages, although surgery is considered the gold standard treatment, 30–55% of patients develop recurrence within the first 5 years of surgery. Our aim is to assess whether cancer stem cells (CSC) display overexpression of a pool of genes that were previously identified for adenocarcinoma recurrence in patients with early and locally advanced stages of non-small cell lung cancer (NSCLC).MethodsThis cross-sectional study was carried out by harvesting surgical tumor specimens obtained from patients harboring early (I-II) and locally advanced (IIIA) stages of NSCLC. For each patient, cell sorting was performed to identify and isolate the ALDHhigh (CSC) and ALDHlow (cancer cells) populations. The mRNA expressions of 31 recurrence-related genes (target genes) in both ALDHhigh and ALDHlow populations were then assessed and compared.ResultsSurgical specimens were obtained from 22 patients harboring NSCLC. Sixteen (51.6%) out of 31 recurrence-related genes were significantly overexpressed in ALDHhigh cells in the early stages and 9 (29.0%) were overexpressed in the locally advanced stages of NSCLC. Overall, the relative mRNA expressions for these recurrence-related genes were higher in early-stage patients. The average fold change, considering all 31 recurrence-related genes together, was 4.5 (95% CI = 3.1-6.3) in early-stage patients and 1.6 (95% CI = 1.2-2.2) in locally advanced-stage patients.ConclusionsOur study represents the first attempt toward identifying genes associated with recurrence that are overexpressed in cancer stem cells in patients with early and locally advanced stages of NSCLC. This finding may contribute to the identification of new target therapies tailored for NSCLC stages.

Background: Primary angiosarcoma of the lung is a very aggressive rare malignant disease resulting in a severe prognosis (1). This type of cancer represents about 2% of all soft tissue sarcomas and has a high rate of metastasis through the hematogenous route. For the rarity of this malignant vascular tumor it is still challenging to set a diagnosis (1). The diagnostic features that have thus far been considered include primarily clinical and radiological findings. In some cases, immunohistochemical characteristics based on the most common markers used in pathology have been described. The aim of this report is to present two cases of angiosarcoma of the lung in which the aldehyde dehydrogenase (ALDH) marker was analyzed by immunohistochemistry. Methods: We report two cases of angiosarcoma of the lung in patients underwent lung surgery at our Unit. In addition to the standard histopathological analysis for this disease, immunohistochemistry using an ALDH1A1 antibody was performed in both of the cases. For ALDH quantification, a semi-quantitative method based on the positivity of the tumor cells was used: 0 (25–50%), 3 (>50–75%), 4 (>75%). Results: One patient with recurrent lung disease survived, achieving complete remission after chemo- and radiotherapy. The second patient died of recurrent disease within 5 years of diagnosis. ALDH1A1 was evaluated in both of these cases using an immunohistochemistry scoring system based on the positivity for this marker. The scores were consistent with the patients’ clinical outcomes, as the lower (score 1) was observed in the patient with the better clinical outcome, while the higher (score 3) was seen in the patient with the worse outcome. Conclusion: Our data suggest that ALDH may be an important clinical marker in angiosarcoma of the lung. Although further studies need to be performed in a larger cohort of patients, we believe that, if the results will be confirmed, ALDH1A1 may be used to stratify patients in terms of prognosis and for targeted therapy.

Background: Inflammatory myofibroblast tumor (IMT) is a rare tumor with obscure etiopathogenesis in which different inflammatory cells and myofibroblastic spindle cells are seen histologically. Although the majority of these neoplasms have a benign clinical course, the malignant form has also been reported. The gold standard is surgical treatment for complete removal. Our report describes a 50-year-old woman who underwent surgery for IMT of the lung. The aim is to determine whether cancer stem cells may be present in IMT of the lung. Methods: In April 2018, the patient underwent surgery for tumor mass asportation through lateral thoracotomy. The histology of the tumor was consistent with IMT of the lung. The ALDEFLUOR assay, after tissue digestion, was used to identify and sort human lung cancer cells expressing high and low aldehyde dehydrogenase (ALDH) activity. SOX2, NANOG, OCT-4, and c-MYC positivity were additionally determined by immunohistochemistry. Results: The specimen contained 1.10% ALDHhigh cells among all viable lung cancer cells, which indicates the population of cancer stem cells is not negligible. Immunohistochemically assessed cell positivity for ALDH1A1, SOX2, NANOG, OCT-4, and c-MYC, which are considered as lung cancer stem-like cells markers. Conclusion: For the first time, we demonstrated the presence of cancer stem cells in a case of IMT of the lung. This finding may provide a base for considering new pathological and molecular aspects of this tumor. This perspective suggests further studies to understand the possibility of developing recurrence depending on the presence of cancer stem cells.

Highlights • Vacuum-assisted closure is a well-established technical resource for treating complicated wounds. • In cases of suspicion of bone infection, VAC therapy is not enough to prevent bar removal. • Multiple surgical debridement sessions are mandatory before wound closure in cases of infection. • We present a case of surgical wound dehiscence with hardware exposure. • After VAC therapy and surgical debridement, the bilateral pectoralis muscle flap mobilization has been used., Introduction Multiple surgical debridement sessions are mandatory before wound closure in cases of infection after a modified Ravitch procedure for pectus excavatum. Vacuum-assisted closure (VAC) is a well-established technical resource for treating complicated wounds; however, in cases of suspicion of bone infection, this approach is not enough to prevent bar removal. Presentation of the case We present a case of surgical wound dehiscence with hardware exposure in a patient who had undergone chondrosternoplasty for pectus excavatum. Several sessions of debridement (three) and VAC were applied every time. The final result was achieved without the necessity to remove the hardware; however, to avoid the risk of infection, a bilateral pectoralis muscle flap mobilization was performed as the final step after the surgical wound revisions, although this approach is suggested to be used during the modified Ravitch procedure. This approach allows for a significant reduction in late complications and improves morphological outcomes. Discussion In summary, the pectoralis muscle flap transposition is very useful not only for aesthetical results but also in combination with multiple surgical revisions for conservative management in case of wound infection during a modified Ravitch procedure. In our case, this technique was adopted after accurate care of the wound and before the final closure, which helps to maintain good vascularization and a very satisfying result. Conclusion It is important to consider this approach during the modified Ravitch procedure, not only for better aesthetical results but also to prevent infections or wound dehiscence at the level of the bar.

Purposes. The aim of this study was to investigate if laser-assisted resection is appropriate for large and/or central lung metastases, when stapler wedge resection is not feasible, to determine whether this technique can be an alternative to lobectomy. Methods. All patients who underwent laser-assisted resection for large and/or central metastases were selected for the study. For comparison, patients who underwent lobectomy for metastases between 2005 and 2017 were reviewed. All resections were performed with a 1318-nm Nd:YAG laser. Perioperative features and long-term oncological outcomes were investigated. Some aspects and drawbacks of laser resection were also investigated. Results. Among 89 patients, 42 (47%) underwent laser resection and 47 underwent lobectomy. Complete resection was achieved in 91% of laser resections and in 98% of lobectomies. The operative time, postoperative drainage time and length of stay were significantly shorter in patients who underwent laser resection than in those who underwent lobectomy. Severe postoperative complications tended to be more frequent after lobectomy. The 5-year survival was 66% and 54% after laser resection and lobectomy respectively, the 5-year disease-free survival was 35% and 32% after laser resection and lobectomy respectively. No differences were found in long-term outcomes between the two techniques. Conclusions. Our experience showed that laser resection, when performed for large/central metastases, resulted in comparable survival and obtained better perioperative outcomes with respect to lobectomy. We believe that laser resection can be proposed as a reliable and advantageous lung-sparing technique, as an alternative to lobectomy for metastasectomy, when stapler wedge resection is not feasible.

Background: Lung cancer stem cells (LCSCs) are endowed with high aldehyde dehydrogenase (ALDH) expression and play roles in tumor proliferation, metastasis, and drug resistance. Their elusive nature may allow them to escape the immune response by tumor-infiltrating lymphocytes (TILs), which can positively affect the outcome in non-small cell lung cancer (NSCLC) patients. Despite independent investigations on both LCSCs and TILs, the relationship between the two has been very marginally considered. We analyzed whether these two cell types may be related as a prerequisite for novel diagnostic and therapeutic approaches. Methods: In this cross-sectional study, NSCLC human surgical specimens from 12 patients were tested by ALDEFLUOR assay to identify ALD Hhigh cells. Fluorescence-activated cell sorting (FACS) analyses for CD3+, CD4+, and CD8+ TILs were performed in combination with immunohistochemistry evaluation. Results: Statistically positive correlations were found between ALDH+ and CD8+, and between ALDH+ and CD3+ cells populations; no correlation was found between ALDH+ and CD4+ cells. The expression of CD3+ and CD8+ by cells accounted for 40.1% and 58.7%, respectively, of the variability of ALDH+ cell expression by an R-squared index, which highlights the strong correlation between TILs and LCSCs. Immunohistochemistry revealed 6–25% positive cells. Conclusions: We report a correlation between cytotoxic TILs and LCSCs, which may contribute to the future development of targeted therapies focusing on the different roles of lymphocytes against lung cancer.

Introduction and importance Mediastinal paragangliomas are rare neuroendocrine tumors that originate from extra-adrenal paraganglia, occasionally secreting catecholamines. Nonfunctional mediastinal paragangliomas present nonspecific clinical and radiological features and represent a diagnostic challenge. Case presentation A 53-year old woman presented with cough and dyspnea increasing over time. CT-scan and ultrasonography showed a large vascularized cervico-mediastinal mass, consistent with an intrathoracic ectopic goiter. Preoperative angiography showed a blood supply from neck vessels. The lesion was completely removed through a cervical approach. The diagnosis of paraganglioma was a histological surprise. The patient is alive without recurrence 30 months after surgery. Clinical discussion When preoperatively diagnosed, the treatment of choice of a mediastinal paraganglioma is surgical excision. However, a preoperative diagnosis of mediastinal paraganglioma is difficult to obtain, especially in cases of nonfunctional lesions. Distinction between an intrathoracic goiter and a nonfunctional paraganglioma can be extremely difficult and, given the rarity of the latter, an ectopic goiter is suspected in first instance. CT-scan and ultrasonography are of little use in the differential diagnosis. However, scintigraphy with 123I-metaiodobenzylguanidine can be an useful diagnostic tool when a paraganglioma is suspected. In case of vascularized cervico-mediastinal mass, such as paragangliomas or intrathoracic goiter, preoperative angiography should be performed to study the blood supply and orient the surgical approach. Conclusion Although uncommon, paragangliomas should be considered in the differential diagnosis of mediastinal masses, especially when an ectopic goiter is suspected., Highlights • Clinical diagnosis of mediastinal nonfunctioning paragangliomas is challenging. • Mediastinal paragangliomas can mimic intrathoracic goiters. • If a clinical suspicion of paraganglioma is raised, 123I-MIBG can be useful. • In case of a vascularized cervico-mediastinal mass, an angiography is recommended. • Angiography can detect the blood supply and guide the surgical approach.

Background Elastofibroma dorsi (ED) is a benign soft-tissue tumor of the chest wall located near the tip of the scapula. Clinical presentation includes swelling, pain and impairment of shoulder movements. The present literature relies only on few small case series. The aim of this study was to analyze the surgical management of ED, focusing on the debated topics regarding preoperative evaluation, operative technique, post-operative outcome and follow-up. Methods We conducted a single-center retrospective cohort analysis of patients operated for ED between 2003 and 2018. Diagnostic techniques were ultrasonography (US), computed tomography (CT-scan) and magnetic resonance imaging (MRI). CT-scan represented our preferred imaging study for preoperative assessment. Surgery was proposed for symptomatic and/or large lesions. Marginal excision through a muscle-sparing approach was performed. An open-door follow-up policy was adopted. All clinical, radiological, perioperative and pathological variables were matched in a univariate analysis. A multivariate analysis was performed to investigate risk factors for postoperative complications. Correlations analysis between radiological and pathological measurements of elastofibroma was conducted. Results Seventy elastofibromas were excised in 59 patients. Mean age was 59 years and female prevalence was 59%. All elastofibromas were completely resected with no recurrence. Postoperative complications rate was 17%. Complications were mild in most cases. At the univariate analysis, patients with body mass index (BMI) >25 had a longer operative time (P=0.048), patients on antiplatelet medications experienced a prolonged drainage time (P=0.006) and a higher rate of complications (P=0.038); the occurrence of complications resulted in prolonged drainage time (P=0.047) and length of stay (P=0.023). A BMI ≤25 was the only independent risk factor for postoperative morbidity (OR 8.71, P=0.024). CT-scan showed the highest correlation with pathological size (r=0.819), US the lowest (r=0.421). Conclusions Marginal resection through a muscle-sparing approach is safe and effective for the treatment of ED. CT-scan can be adequate for preoperative assessment. Giving the benign nature of the lesion and the absence of recurrence after complete resection, an open-door follow-up may be appropriate.

Introduction and importance Pleomorphic carcinoma of the lung is a rare malignant epithelial tumor. Due to its rarity, its clinicopathological characteristics are not clear, and there is no defined therapeutic path for this type of tumor. Case presentation We retrospectively analyzed the medical and pathological reports of 8 patients who underwent surgical resection for pleomorphic carcinoma between 2007 and 2010. Clinical discussion Eight patients were analyzed (7 males and 1 female, mean age 60). All patients underwent CT scans, and the average diameter of the nodules was 56 mm. Four patients were also investigated with FDG-PET with hypermetabolic activity in all four cases. In four patients, the carcinomatous component was adenocarcinoma (all with sarcomatoid component of spindle cell and giant cell carcinoma), although in two patients, it was squamous cell carcinoma (one with spindle cell and one with giant cell). In the two remaining patients, one showed a non-small cell carcinoma with giant cell carcinoma, and the other was a non-small cell carcinoma and squamous cell carcinoma with spindle and giant cell carcinoma. All cases were treated with surgical resection. Only two patients underwent neoadjuvant chemotherapy. At the time of data analysis, only one patient treated with neoadjuvant chemotherapy was alive. Conclusion The prognosis for these patients with a diagnosis of pleomorphic carcinoma undergoing surgery is generally better than those not treated with surgical resection, however the survival remains poor. Although with low number of patients, our research would suggest to consider neoadjuvant chemotherapy an appropriate approach for improving the outcomes before surgery., Highlights • Pleomorphic carcinoma of the lung • Rare malignant epithelial tumor • Clinicopathological characteristics unclear • Not defined therapeutic path • Neoadiuvant chemotherapy improves the prognosis.

BackgroundThe notion that smoking cannabis may damage the respiratory tract has been introduced in recent years but there is still a paucity of studies on this subject. The aim of this study was to investigate the relationship between cannabis smoking, pneumothorax and bullous lung disease in a population of operated patients.Methods and findingsWe performed a retrospective study on patients operated on for spontaneous pneumothorax. Patients were divided into three groups according to their smoking habit: cannabis smokers, only-tobacco smokers and nonsmokers. Cannabis lifetime exposure was expressed in dose-years (1d/y = 1 gram of cannabis/week for one year). Clinical, radiological and perioperative variables were collected. The variables were analyzed to find associations with smoking habit. The impact of the amount of cannabis consumption was also investigated by ROC curves analysis. Of 112 patients, 39 smoked cannabis, 23 smoked only tobacco and 50 were nonsmokers. Median cannabis consumption was 28 dose/years, median tobacco consumption was 6 pack/years. Cannabis smokers presented with more severe chronic respiratory symptoms and bullous lung disease and with a higher incidence of tension pneumothorax than both tobacco smokers and nonsmokers. Cannabis smokers also developed a larger pneumothorax, experienced prolonged postoperative stay and demonstrated a higher incidence of pneumothorax recurrence after the operation than nonsmokers did. The risk of occurrence of chronic respiratory symptoms and bullous lung disease in cannabis smokers was dose-related.ConclusionsCannabis smoking seems to increase the risk of suffering from respiratory complaints and can have detrimental effects on lung parenchyma, in a dose-dependent manner. Cannabis smoking also negatively affected the outcome of patients operated for spontaneous pneumothorax. A history of cannabis abuse should always be taken in patients with pneumothorax. There may be need for a specific treatment for pneumothorax in cannabis smokers.

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Pectus excavatum (PE) is the most common congenital chest wall deformity, affecting 1 to 8 in 1,000 live births.1 Indications for the surgical correction of congenital chest wall deformities include functional/physiological, cosmetic, and psychosocial reasons. Palpitations, exertional dyspnea, fatigue, and chest pain are commonly reported symptoms attributed to pectus deformities.2 Many patients report exercise intolerance and increasing limitations in physical activity, which they attribute to their chest deformity. Some patients with PE have been shown to suffer a dynamic restrictive pulmonary process.3 Pectus deformities are often associated with body image issues, especially in patients in their teenage years, and these issues can predispose patients to psychological distress. Surgical repair of pectus deformities was shown to improve both physical limitations and psychosocial well-being in children.3–5 The most common surgical approaches for PE treatment are the modified Ravitch technique and the minimally invasive Nuss technique.4–6 The first technique for PE repair was proposed by Ravitch in 1949 and is an open technique that requires partial resection of the costal cartilage, xiphoid excision, and osteotomy of the sternum.6 Multiple modifications to this procedure have been proposed over time, such as the placement of a metal strut to support the sternum, which is removed within 6 months to 1 year. It was not until nearly half a century later that an alternative surgical option was devised and published.7,8 The goal of the Ravitch procedure is to remove abnormal rib cartilage while preserving the perichondrium, allowing regrowth of the rib cartilage to the sternum in a more anatomic fashion. Other key elements in the operation include performing a sternal osteotomy to allow redirection of the sternum and stabilization of the sternum with a metal bar, when necessary. A modification of the established Ravitch procedure, which is applied to treat symmetric as well as asymmetric forms of PE and carinatum, was established. It requires exposure of the sternum and ribs, removal of abnormal cartilage, and fixation of the sternum in a proper anatomical position with 2 metal bars, 1 inserted into the sternum (Kirschner nail) and 1 perpendicularly (Rush wire) fixed between the bilateral corresponding ribs and the xiphoidal process. The metal bars are left in place for at least a year and then are removed with a second operation. Results have shown this technique to be effective in correcting the deformity but at the expense of a quite invasive and long-lasting surgical procedure associated with 7–10 days of hospitalization and resulting in a long scar on the anterior portion of the chest. Physical activity is also severely restricted for several months as the costal cartilage slowly grows back together. Furthermore, this procedure is associated with a 15%–20% complication rate according to different series.9 A number of complications that can be classified as immediate and late-stage may affect open sternochondroplasty. These complications include hemothorax and pneumothorax, infection, seroma, hardware dislocation, exposure, and eventually inadequate correction or deformity recurrence.9 Early complications may be prevented or solved in most instances (at the expense of a reoperation); however, late complications, such as soft tissue thinning, skin breakdown with hardware exposure, hardware dislocation, and inadequate sternocostal healing, may severely compromise the outcome, posing a relevant clinical challenge (Table ​(Table11). Table 1. Complications of Open Sternochondroplasty

Highlights • Calcified nodules in a goiter are often found when performing an ultrasound of the neck. • Analysis of different calcification patterns could contribute to discriminating between nodules. • Mixed pattern calcifications is not so frequent and not interpreted. • We believe that a better radiologic evaluation setting of thyroid nodules needs to be performed., Background Calcified nodules are often found in a goiter when performing an ultrasound of the neck. An analysis of different calcification patterns could contribute to discriminating between nodules with a lower malignancy risk and those with a higher malignancy risk. In certain cases, the results of a simple cytological analysis of a nodule are not specific enough to be completely trusted. Case presentation We present the case of a goiter with a mixed calcification pattern, including a type of calcification that is strongly associated with a malignant diagnosis, for which a completely benign diagnosis was determined. Conclusion We believe that further studies examining a combination of ultrasound (US) and computed tomography (CT) scan presentations of thyroid nodules need to be performed.

Highlights • The differential diagnosis between pneumothorax and giant bulla is not straightforward. • We emphasized how to differentiate between giant bulla and pneumothorax. • The complexity to differentiate induces to make mistakes in diagnosis and in treatment decision. • Chest CT is mandatory in case of the impossibility to understand the radiological findings., Background The differential diagnosis between pneumothorax and giant bullae is thought to be straightforward but sometimes poses a challenge. Case presentation We present a case of a 54-year-old Caucasian man with a giant emphysematous bulla who underwent surgical resection. He had no smoking history and had previous pneumonia episodes. The surgery was free of complications, without air leaks, and he showed good ventilation of the lung. Discussion The main complications of bullae are pneumothorax, infection and hemorrhage. Pneumothorax is a serious complication in patients with compromised lung function. Therefore, it is very important to carefully distinguish bullae from pneumothorax to avoid iatrogenic pneumothorax in patients with bullous disease. Conclusion We emphasize how to differentiate between giant bullae and pneumothorax utilizing history, physical examination, and radiological studies, including computed tomography (CT) scan.

Lung neuroendocrine cells tumor (NET) classification and diagnosis, particularly for typical and atypical carcinoids, are complicated by a variable natural history and nonspecific symptoms. Mechanisms for the development and progression of well-differentiated lung NETs are still unclear. An accurate and timely diagnosis can ensure the implementation of appropriate treatment and impact on prognosis. One of the main unclear point is the definition of these cells’ composition. In fact, it is known that carcinoids are mainly constituted by neuroendocrine cells. Aim of our report is to show for the first time the presence of a high percentage of cancer stem cells (CSCs) in an atypical carcinoid. The ALDEFLUOR assay was used to identify and sort ALDH(high) and ALDH(low) human lung cancer cells following tissue digestion. SOX2 was additionally determined by immunohistochemistry. All specimens contained the 53.10% of ALDHhigh cells among all viable lung cancer cells, which indicates that more than half of the entire tumor cell population was composed by CSCs. As expected also in immunohistochemistry, about a half of the nuclei of the cells were positive for SOX2. We strongly support the hypothesis of the presence of cancer stem-neuroendocrine cells (CSCs-NETs) as subpopulation in these types of tumors.

Highlights • A multinodular goiter in an HIV-positive with lipodystrophy, buffalo hump and taurine neck. • Needle aspiration biopsy was difficult to use to determine the presence of lipodystrophy. • The goiter was with retrosternal engagement and the ovalization of the tracheal lumen. • Surgical treatment was necessary due to the presence of dyspnea during exercise. • Importance of the perioperative teamwork, in particular to the patient positioning., Background The authors present a case of multinodular goiter in an HIV-positive patient affected by lipodystrophy with particular accumulation of adipose tissue in the region of the neck and trunk. Case presentation The patient, a 53-year-old man, presented with multinodular struma with partial retrosternal engagement, as well as multiple thyroid nodules increasing in size; some of the nodules had suspicious characteristics on ultrasound. Needle aspiration biopsy was difficult to use to determine the presence of lipodystrophy; however, even in the absence of cytology, surgical treatment was necessary due to the presence of dyspnea during exercise, the dimension of the goiter with retrosternal engagement, and the ovalization of the tracheal lumen. The patient underwent total thyroidectomy by anterior cervicotomy with particular attention to patient positioning because of the buffalo hump and taurine neck. Histological examination was positive for adenomatous hyperplasia with outbreaks of papillary microcarcinoma. Conclusions The aim of this case report was to highlight the importance of the perioperative teamwork, with particular attention to patient positioning before surgery, as well as professional collaboration and experience among the operators.

Highlights • Renal cell carcinoma (RCC) is the most frequent type of renal tumor in adults. • RCC is able to metastasize through the blood system and lymphatic system. • Metastases from RCC to the bones are often of the osteolytic type. • The sternal metastatic site for RCC is a rare site and it often begins as pain., Background There are few papers published on sternal metastasis from renal cell carcinoma. The unifying element is the operability of the sternal metastasis if it is the only site of metastasis, on the operability of the primary site of the tumor and on the patient’s health conditions. Presentation of the case We present a case of a 66-years-old man undergone sternal resection for a large painful metastasis. He was previously undergone left nephrectomy for clear cells carcinoma. En bloc resection of the sternal manubrium and right clavicle was performed, a Gore-Tex mesh was placed. Histology confirmed metastasis of kidney clear cells carcinoma. Patient was discharged with no complications and no pain. Chest CT at six months follow up was negative for recurrence. Discussion and conclusion We highlighted the importance of surgery as possible first-line treatment in symptomatic large sternum metastasis. Therefore, prospective studies should be considered to confirm our strategy.

Case Presentation A 72-year-old man underwent endoscopic resection of a 10-mm polypoid sessile lesion of the rectum. Histologic examination found a well-differentiated, low-grade (G1), neuroendocrine tumor. A thoracoabdominal CT scan was performed for staging purposes. The chest CT scan revealed a so-called cannonball-like distribution of multiple rounded nodules, with well-defined margins, ranging from 0.5 to 5 cm, scattered in both lungs (Figs 1A, 1B). The abdominal CT scan showed no abnormalities. A recent colonoscopy showed no evidence of malignancy. No prior chest imaging was available and the patient had never complained of respiratory symptoms. The patient was a former smoker, with a smoking history of 20 pack-years. He had a history of hypertension, mild stenosis of both carotid arteries, and benign prostatic hypertrophy. He reported the presence of long-standing multiple cutaneous hemangiomas on the trunk and face and a larger hemangiomatous lesion on his left lower limb, which was previously investigated by color Doppler ultrasound imaging. All these lesions were reported as unaltered and unchanged since early infancy.

Congenital cystic adenomatoid malformations are lung anomalies usually detected prenatally or in newborns and infants. Type 1 congenital cystic adenomatoid malformations appears as a multicystic lesion, with cysts up to 2 cm in diameter, or as a single large cyst. In the latter case, when detected in adults, the preoperative diagnosis is challenging because congenital cystic adenomatoid malformations can be confused with other more common lesions. We describe two cases of uniloculated type 1 congenital cystic adenomatoid malformation in adults. In both cases, the preoperative clinical diagnosis was missed and the patients were surgically treated with lung-sparing cyst resections.

Vacuum-Assisted Closure (VAC) in association to flap reconstruction is a well-established approach for treating complicated wounds. The authors present a case of soft-tissue breakdown with hardware exposure in a patient treated with modified Ravitch procedure for pectus excavatum. VAC therapy was applied in association to multiple debridement procedures and final flap closure. This was achieved without the need for hardware removal, thus maintaining adequate skeletal fixation. To our knowledge this approach has not yet been described into the literature after sternochondroplasty procedure. Aggressive debridement and VAC therapy before final closure may represent a new, conservative method for managing surgical complications after sternochondroplasty procedures.

Thymic epithelial tumors (TETs) are a heterogenous group of rare tumors, with a complex histopatological classification. Furthermore, the recent introduction of the first TNM staging system, that is scheduled to replace the Masaoka-Koga system, may create further difficulties in TET management, that remains challenging. Several guidelines for treatment of TETs are available and provide recommendations based mainly on non randomized trials and retrospective or limited series. Often the lack of evidence leads to formulation of indications based on expert opinions. As for other rare cancers it is crucial to create networks to coordinate the work among centres involved in treatment of these diseases in order to offer the best diagnostic and therapeutic tools. For this purpose, in 2014 a network named TYME (ThYmic MalignanciEs), was founded in Italy with the aim of improving care and research in TETs. In September 2017 a panel of multidisciplinary experts from TYME network and from other Italian centres strongly involved in TET diagnosis and treatment convened a first Italian Expert meeting together with representatives of association for patients affected by rare thoracic cancers Tu.To.R, to explore how these tumors are managed in the different centres of Italy compared to ESMO guidelines. In this paper we summarize the issues discussed during that meeting and we propose recommandations based on Masaoka Koga and the new TNM staging system.

Malattie della pleura e del mediastino e trapianto di polmoni.

Background: The prevention of recurrence after a first episode of primary spontaneous pneumothorax (PSP) remains a debated issue. The likelihood of recurrence based on the presence of blebs and bullae detected on high-resolution computed tomography (HRCT) imaging is controversial. Methods: We evaluated patients conservatively treated for PSP who underwent chest HRCT scan in a single-institution retrospective longitudinal study. Absolute risk values and positive and negative predictive values of recurrence based on HRCT findings were the primary end points. Results: We analyzed 176 patients. Ipsilateral and contralateral recurrence developed in 44.8% and 12% of patients, respectively. The risk of recurrence was significantly related to the presence of blebs or bullae, or both, at HRCT. The risk of ipsilateral recurrence for patients with or without blebs and bullae was 68.1% and 6,1%, respectively (positive predictive value, 68.1%; negative predictive value, 93,9%). The risk of contralateral pneumothorax for patients with or without blebs and bullae was 19% and 0%, respectively (positive predictive value, 19%; negative predictive value, 100%). The risk of ipsilateral recurrence was directly related to the dystrophic severity score: recurrence risk increased by up to 75% in patients with bilateral multiple lesions. Multivariate analysis showed that a positive HRCT was significantly related to ipsilateral recurrence. Conclusions: The presence of blebs and bullae at HRCT after a first episode of PSP is significantly related to the development of an ipsilateral recurrence or a contralateral episode of pneumothorax. Further studies are needed to validate the dystrophic severity score in the selection of patients for early surgical referral. © 2013 The Society of Thoracic Surgeons.

Primary lung tumors arising in pulmonary sequestration is an exceptional event, usually consisting of common histologic types. On the other hand, malignant perivascular epithelioid cell (PEComatous) tumors with deposition of melanin pigment have never been reported in the lung so far. In this study, we report a challenging case of a 34-year-old man presented with recurrent hemoptysis and CT scan detection of a pulmonary mass at the left lower lobe, vascularized by aberrant communication with the left diaphragmatic artery. After surgical resection, we documented a malignant PEComatous tumor (characterized by TFE3 expression and high mitotic rate) that had arisen in the context of an extralobar sequestration.

Pulmonary sarcomatoid carcinoma (PSC) is a very rare subtype of non-small cell lung cancer (NSCLC). The aim of this study was to clarify the pathologic characteristics and long-term survival after surgical treatment in patients with PSC.From January 2003 to December 2013, we retrospectively reviewed the clinical findings, surgical notes, and pathologic and follow-up data from 148 consecutive patients who underwent curative resection for PSC in 5 institutions. The Kaplan-Meier method, log-rank test, and Cox regression analysis were used.Mean age and male to female ratio were 66.6 ± 9.9 years and 120:28, respectively. Surgical resection (pneumonectomy in 8 patients, bilobectomy in 132 patients, and sublobar resection in 8 patients) was complete in 142 cases (96%). At pathologic evaluation, 36 patients (24%) had stage I, 69 patients (47%) had stage II, 33 patients (22%) had stage III, and 10 patients (7%) had stage IV disease. A "biphasic tumor" (PSC with an NSCLC component) was observed in 77 patients (52%). We detected a high rate of vascular emboli in the surgical specimens (overall, 68%; 57% in pathologic stage I tumors), whereas lymphatic emboli were found in 30% of cases (5% of pathologic stage I tumors). Overall median and 5-year long-term survival (LTS) was 19 months and 12.6% (LTS, 16.3% in pathologic stage I), respectively. Distant recurrences frequently occurred after surgical treatment (81%), even in pathologic stage I tumors that underwent R0 resection (62%). Multivariable survival analysis identified R+ resection (hazard ratio [HR],12.3; 95% confidence interval [CI], 3.67-41.28; p0.0001), advanced pathologic stage (HR, 5.75; 95% CI, 2.55-12.98; p 0.0001), and the presence of vascular emboli (HR, 1.67; 95% CI, 1.05-2.67; p = 0.0327) as independent negative prognostic factors.PSCs have very aggressive behavior and high metastatic potential even in early stages. R+ resection, pathologic TNM status, and the presence of vascular emboli are independent prognostic factors.

IntroductionPrognostic evaluation of bronchioloalveolar carcinoma (BAC) from a homogenous population of Caucasian patients.MethodsRetrospective analysis of resected BAC reclassified according to the 2004 World Health Organization classification of lung tumors. Analyzed variables are clinicoradiologic presentation, histologic subtypes, stage, epidermal growth factor receptor (EGFR) and HER2/neu immunohistochemical expression, EGFR exons 18, 19, and 21 mutations, K-RAS exon 2 mutation. Univariate and multivariate analyses of survival were performed.ResultsOf 40 patients analyzed, EGFR and HER2/neu expression were detected in 72% and 20%, respectively. HER2/neu expression significantly characterized mucinous BAC (46% versus 7%; p = 0.014). EGFR mutations were identified in 17% (30% in nonmucinous BAC and none in mucinous BAC; p = 0.083). K-RAS mutations were found in 42.5% (92% in mucinous BAC versus 18% in other types; p < 0.0001). Early stages (IA+IB) nonmucinous BAC had excellent prognosis: 5 years overall survival of 91% (100% for stage IA). Sixty six percent (4 of 6) of patients with multifocal disease died (two mucinous BAC and one nonmucinous BAC with recurrent disease). Seventy one percent (5 of 7) of patients with pneumonic-like tumor (all mucinous BAC) died of recurrent/progressive disease. Stage (p = 0.004) and histologic classifications (p = 0.035) resulted as independent prognostic factors at multivariate analysis.ConclusionsEarly stage nonmucinous BAC has excellent prognosis, whereas mucinous BAC presents a poor prognosis. Locally advanced nonmucinous BAC has a poor prognosis: the diagnosis of nonmucinous BAC in large tumors should be interpreted with caution given the possible presence of invasive areas in incompletely sampled tumor. Coexpression of EGFR and HER2/neu in mucinous BAC could be considered for future trials on target therapies even in Caucasian population.