Lung Cancer Surgery in Octogenarians: Implications and Advantages of Artificial Intelligence in the Preoperative Assessment.

The general world population is aging and patients are often diagnosed with early-stage lung cancer at an advanced age. Several studies have shown that age is not itself a contraindication for lung cancer surgery, and therefore, more and more octogenarians with early-stage lung cancer are undergoing surgery with curative intent. However, octogenarians present some peculiarities that make surgical treatment more challenging, so an accurate preoperative selection is mandatory. In recent years, new artificial intelligence techniques have spread worldwide in the diagnosis, treatment, and therapy of lung cancer, with increasing clinical applications. However, there is still no evidence coming out from trials specifically designed to assess the potential of artificial intelligence in the preoperative evaluation of octogenarian patients. The aim of this narrative review is to investigate, through the analysis of the available international literature, the advantages and implications that these tools may have in the preoperative assessment of this particular category of frail patients. In fact, these tools could represent an important support in the decision-making process, especially in octogenarian patients in whom the diagnostic and therapeutic options are often questionable. However, these technologies are still developing, and a strict human-led process is mandatory.

A multicentric evaluation of pediatric lung transplantation in Italy.

BACKGROUND: Pediatric lung transplantation is performed in highly experienced centers due to the peculiar population characteristics. The literature is limited and not representative of individual countries' differences. The purpose of this study was to analyze the Italian experience. METHODS: A multicentric retrospective analysis was performed on 110 pediatric patients (<18 years old) who underwent lung transplantation from 1992 to 2019 at 9 Italian centers. Heart-lung transplantations and lung retransplantations were excluded. RESULTS: The population was composed of 44 male and 66 female patients, with a median age of 15 years. The most frequent indication was cystic fibrosis (83%). One quarter of patients were transplanted in an emergency setting. Median donors' Oto score and age were 1 and 15 years, respectively, with 43% of adult donors. In 17% of patients a graft reduction was performed. Postoperatively, the median duration of mechanical ventilation, intensive care unit, and in-hospital stay were 48 hours, 11 and 35 days, respectively. Thirty-day mortality was 6%, and 1-, 5-, and 10-year survival was 72%, 52%, and 33%, respectively. Risk factors for mortality were Oto score and recipients' body mass index. CONCLUSIONS: The outcomes of pediatric lung transplantation in Italy are comparable with current literature. Particular attention should be paid to the Oto score and recipient body mass index. Conversely, adult donors and graft reductions can be safely used to expand the donor pool.

A challenging upper digestive tract continuity restoration after recurrent esophago-colonic anastomosis complications.

BACKGROUND: Acute and chronic complications in esophago-colonic anastomosis have a significant impact in the postoperative course of patients with colonic transposition. Evidence about their management is poor and surgical treatment is mostly based on tailored approaches, so each new experience could be useful to improve knowledge about this peculiar condition. We report a unique case of an esophago-colonic resection and re-anastomosis without sternal approximation after recurrent anastomosis failure and strictures. CASE PRESENTATION: A 69-year-old woman was referred to our hospital for worsening dysphagia. The patient had undergone esophago-gastrectomy with right colon interposition 12 years prior due to caustic ingestion. The esophago-colonic anastomosis was initially complicated by an enterocutaneous fistula, which was treated with anastomosis resection and left colon transposition. This was then further complicated by dehiscence and sternal infection treated with resection of the distal portion of the sternum and a new colo-jejunal anastomosis. Finally, a chronic anastomotic stricture occurred, refractory to endoscopic dilatation and prothesis positioning. We planned a new colonic-esophageal resection and re-anastomosis. The main technical challenges were addressing the adhesions resulting from previous surgery and mobilizing an adequate length of the intestinal tract to allow conduit continuity restoration. Blood supply was assessed through Indocyanine Green Fluorescence. To avoid compression of the digestive conduit sternal margins were not re-approximated, and the transposed tube was covered and protected using both pectoralis major muscles flap. We decided to avoid the use of any prosthetic material to reduce the risk of infection. The patient was able to resume oral food intake on the 12th day postoperatively after a barium swallowing test showed an adequate conduit caliber. CONCLUSION: Esophago-colonic anastomosis complications represent a life-threatening condition. Therefore, reports and sharing of knowledge are important to improve expertise in management of these conditions.

Coaxial Drainage versus Standard Chest Tube after Pulmonary Lobectomy: A Randomized Controlled Study.

Chest tubes are routinely inserted after thoracic surgery procedures in different sizes and numbers. The aim of this study is to assess the efficacy of Smart Drain Coaxial drainage compared with two standard chest tubes in patients undergoing thoracotomy for pulmonary lobectomy. Ninety-eight patients (57 males and 41 females, mean age 68.3 ± 7.4 years) with lung cancer undergoing open pulmonary lobectomy were randomized in two groups: 50 received one upper 28-Fr and one lower 32-Fr standard chest tube (ST group) and 48 received one 28-Fr Smart Drain Coaxial tube (SDC group). Hospitalization, quantity of fluid output, air leaks, radiograph findings, pain control and costs were assessed. SDC group showed shorter hospitalization (7.3 vs. 6.1 days, p = 0.02), lower pain in postoperative day-1 (p = 0.02) and a lower use of analgesic drugs (p = 0.04). Pleural effusion drainage was lower in SDC group in the first postoperative day (median 400.0 ± 200.0 mL vs. 450.0 ± 193.8 mL, p = 0.04) and as a mean of first three PODs (median 325.0 ± 137.5 mL vs. 362.5 ± 96.7 mL, p = 0.01). No difference in terms of fluid retention, residual pleural space, subcutaneous emphysema and complications after chest tubes removal was found. In conclusion, Smart Drain Coaxial chest tube seems a feasible option after thoracotomy for pulmonary lobectomy. The SDC group showed a shorter hospitalization and decreased analgesic drugs use and, thus, a reduction of costs.

Prognostic impact of spread through air spaces in lung adenocarcinoma.

OBJECTIVE: Spread through air spaces (STAS) is a pattern of invasion present in some adenocarcinomas (ADC). The goal of this study was to assess the impact of STAS in patients treated with different types of surgical resections and on the clinical outcome in patients with ADC of different diameters and with different degrees of nodal involvement. METHODS: A total of 109 patients were reviewed. Complete surgical resection with systematic nodal dissection was achieved in all patients. The median follow-up was 65 months (3-90 months). RESULTS: STAS was observed in 70 cases (64.2%); 13 patients (18.5%) had lymph node involvement (N1 and N2). Overall survival and progression-free survival were higher in patients without STAS (P = 0.042; P = 0.027). The presence of STAS in tumours ≤2 cm was a predictor of worse progression-free survival following sublobar resection compared to major resections (P = 0.011). Sublobar resection of N0 STAS-positive tumours was associated with worse long-term survival compared to a major resection (P = 0.04). Statistical analyses showed that age >70 years and recurrence were independent variables for survival; smoking pack-years >20, sublobar resection and nodal involvement were independent variables for recurrence; and smoking pack-years >20 were independent variables for a history of cancer and pleural invasion for local recurrence. CONCLUSIONS: STAS seems to play a role in long-term survival, particularly for patients with N0 and tumours smaller than 2 cm. Further studies are necessary to validate this hypothesis.

METTL3-dependent MALAT1 delocalization drives c-Myc induction in thymic epithelial tumors.

BACKGROUND: Thymic epithelial tumors (TETs) are rare neoplasms, originating from epithelial thymic cells. The oncogenic potential of these rare neoplasms is still largely undefined, and a deeper molecular characterization could result in a relevant advance in their management, greatly improving diagnosis, prognosis and treatment choice. Deregulation of N6-methyladenosine (m6A) RNA modification, catalyzed by the METTL3/METTL14 methyltransferase complex, is emerging as a relevant event in cell differentiation and carcinogenesis. Various studies have reported that altered expression of METTL3 is associated with an aggressive malignant phenotype and favors migration and invasiveness, but its role in Thymic Tumors remains unknown. RESULTS: In this study, we characterized that METTL3 contributes to Thymic Epithelial Tumor phenotype. We evidenced that METTL3 is overexpressed in tumor tissue compared to normal counterpart. Silencing of METTL3 expression in thymic carcinoma cells results in reduced cell proliferation and overall translation rate. Of note, METTL3 is responsible for the induction of c-MYC expression in TET cells. Specifically, high expression of c-MYC protein is enabled by lncRNA MALAT1, which is methylated and delocalized by METTL3. Interestingly, blocking of c-MYC by using JQ1 inhibitor cooperates with METTL3 depletion in the inhibition of proliferation and induction of cell death. CONCLUSION: This study highlighted METTL3 as a tumor promoter in Thymic tumors and c-MYC as a promising target to be exploited for the treatment of TET.

LINC00174 is a novel prognostic factor in thymic epithelial tumors involved in cell migration and lipid metabolism.

Long non-coding RNAs are emerging as new molecular players involved in many biological processes, such as proliferation, apoptosis, cell cycle, migration, and differentiation. Their aberrant expression has been reported in variety of diseases. The aim of this study is the identification and functional characterization of clinically relevant lncRNAs responsible for the inhibition of miR-145-5p, a key tumor suppressor in thymic epithelial tumors (TETs). Starting from gene expression analysis by microarray in a cohort of fresh frozen thymic tumors and normal tissues, we identified LINC00174 as upregulated in TET. Interestingly, LINC00174 expression is positively correlated with a 5-genes signature in TETs. Survival analyses, performed on the TCGA dataset, showed that LINC00174 and its associated 5-genes signature are prognostic in TETs. Specifically, we show that LINC00174 favors the expression of SYBU, FEM1B, and SCD5 genes by sponging miR-145-5p, a well-known tumor suppressor microRNA downregulated in a variety of tumors, included TETs. Functionally, LINC00174 impacts on cell migration and lipid metabolism. Specifically, SCD5, one of the LINC00174-associated genes, is implicated in the control of lipid metabolism and promotes thymic cancer cells migration. Our study highlights that LINC00174 and its associated gene signature are relevant prognostic indicators in TETs. Of note, we here show that a key controller of lipid metabolism, SCD5, augments the migration ability of TET cells, creating a link between lipids and motility, and highlighting these pathways as relevant targets for the development of novel therapeutic approaches for TET.

Comparison of preoperative scores predicting outcome in elderly undergoing lung malignancies resection.

BACKGROUND: Increased age of cancer patients is not an absolute contraindication to pulmonary resection. Different scores have been developed to determine the risk of morbidity and mortality. We have compared four scores in a series of elderly patients with primary or metastatic lung neoplasms who underwent pulmonary resection. METHODS: Data from 150 patients with an age equal or more than 75 years were reviewed. Mean age was 78.3 (range, 75-86) years. Based on medical history and preoperative tests 4 predicting scores were calculated. Statistical analysis was performed to identify which score correlates better with postoperative morbidity and mortality. RESULTS: Mortality at 30 days was observed in 3 patients (2%). Postoperative morbidity was observed in 38 patients (25.3%). Univariate analysis showed that risk factors significantly predicting the onset of postoperative complications were type of resection (P=0.02), American Society of Anesthesiology (ASA) score (P<0.001) and Glasgow Prognostic Score (GPS) (P=0.02). At multivariate analysis smoking and type of resection were significant prognostic factors for both overall and pulmonary morbidity; the ASA score and GPS showed an impact only on overall morbidity. The Cox regression showed significant results for GPS greater than zero and cancer-related death. Age above 80 years was not a negative prognostic factor. A significant difference in terms of 1-year survival was noted in ASA I-II vs. ASA III-IV (90% vs. 78%; P=0.022) and GPS 0 vs. GPS 1 or 2 (90% vs. 77%; P=0.02). CONCLUSIONS: Prognostic scores are useful to predict postoperative morbidity and mortality and GPS seems to correlate better with them.

Inflammatory Myofibroblastic Tumor After Lung Transplant-A Rare and Aggressive Complication: A Case Report.

INTRODUCTION: Malignant diseases are well-known complications after lung transplantation (LT). Among these, inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with a not well-known and often aggressive biological behavior. MATERIAL AND METHODS: We hereby describe 2 cases of cystic fibrosis patients who underwent bilateral sequential LT (BSLT) complicated by IMT. RESULTS: A 26-year-old man presented a right endobronchial lesion 6 months after BSLT. Two consecutive fiber bronchoscopic biopsies showed granulation tissue. For the persistent lesion growth, the patient underwent a transthoracic biopsy showing histologic diagnosis of IMT. Therefore, he underwent to right pneumonectomy that was unfortunately complicated after 6 months with a late bronchopleural fistula and empyema with exitus 6 months later. A 31-year-old woman 1 year after BSLT presented with a left voluminous pleural-parenchymal lesion; the histologic examination after biopsy revealed an IMT. She underwent a removal of the lesion with a macroscopic R0 resection. Histologic, immunophenotypic, and cytogenetic examinations showed a strong overexpression of anaplastic lymphoma kinase requiring biological adjuvant therapies; however, the patient refused it. Four years later, she presented a recurrence treated with debulking procedure and adjuvant radiotherapy. At last follow-up, the patient was alive with stable disease and optimal graft function. CONCLUSIONS: Although IMT is a rare complication after lung transplant, to obtain a careful diagnosis, an early and aggressive treatment is mandatory.

Early clear cell "sugar" lung cancer management: A case report and a brief literature review.

A clear cell tumor is a histological entity that rarely originates outside of the kidney. We describe a rare case of a clear cell tumor of the lung, also known as "sugar cancer," that occurred in a 74 year-old male patient, and perform a brief literature review. This report highlights the importance of an adequate disease management team, including surgeons, oncologists, and pathologists, to identify the best therapeutic approach to improve survival rates and the quality of life of patients affected by this rare disease.

Visual analysis versus quantitative CT analysis of interlobar fissure integrity in selecting emphysematous patients for endobronchial valve treatment.

OBJECTIVES: The aim of this study is to compare the accuracy of the standard visual scoring of computed tomography (CT) scans with a cloud-based quantitative CT analysis that uses the StratX software, to measure collateral ventilation and, thus, predict lobar atelectasis after valve treatment. METHODS: This is a retrospective, multicentre study of patients who had previously undergone valve treatment for severe heterogeneous emphysema and whose required fissure integrity ≥90% had been qualitatively scored by visual assessment of CT scans. For this study, all preprocedural CT scans were retrospectively analysed using the StratX software to provide quantitative scores of fissure integrity. The diagnostic accuracies of the visual and quantitative scores for predicting a target lobe volume reduction (TLVR) of ≥350 ml were calculated and statistically compared, as this level of volume reduction can be achieved only with sound fissure integrity. The clinical outcome of TLVR was also evaluated according to the minimal clinically important difference criteria. RESULTS: Eighty-three patients were included in the analysis. Of them, 65 of 83 (78%) patients presented with TLVR ≥350 ml. Visual scoring correctly identified the absence of collateral ventilation in 65 of 83 (78%) cases but failed in 18 of 83 (22%) cases. Of these 18 patients, quantitative analysis showed that 16 of 18 (89%) patients did not present completeness of the fissure. The diagnostic accuracy of the quantitative analysis was better than that of the visual analysis (96.4% vs 78.3%; P = 0.0003). Only patients having TLVR ≥350 ml met or exceeded the minimal clinically important difference criteria. CONCLUSIONS: The quantitative analysis using the StratX software contributed a more objective and efficient evaluation of collateral ventilation that would have improved the selection of emphysematous patients for endobronchial valve treatment in the study population.

Do Repeated Operations for Recurrent Colorectal Lung Metastases Result in Improved Survival?

BACKGROUND: Lung metastases occur in 10% to 20% of patients with colorectal cancer (CRC). Lung metastatic pathways of CRC are poorly known, and the optimal management for recurrent lung metastases remains uncertain. METHODS: Long-term oncologic outcomes of 203 patients with CRC lung metastases who underwent metastasectomy were investigated in this multicenter retrospective study. Ninety-two patients (45.3%) with tumor relapse underwent repeated metastasectomy and 11 (5.4%) received a third metastasectomy for a second relapse. Demographic and clinical data, including histologic grade of primary tumor, presence of CRC liver metastases, type of primary tumor resection, number, size, location, and resection type of pulmonary metastases, were evaluated. Overall survival (OS) and disease-free survival were analyzed. Cox regression model was performed to identify variables that influenced OS. RESULTS: One hundred seventy-three patients (85.2%) received a wedge resection, 21 (10.3%) underwent pulmonary lobectomy, and 9 (4.4%) underwent other procedures (pneumonectomy, bilobectomy). The mean follow-up was 39 months (range: 7 to 154 months). One-, 3-, and 5-year global OS from CRC diagnosis was 99%, 80%, and 60%, respectively, and 97%, 60%, and 34% from the first metastasectomy, respectively. Log-rank test between OS (one versus repeated metastasectomy) did not show significant differences (p = 0.659). Cox regression model showed that nodal status (hazard ratio [HR] 17.7, p = 0.008) and administration of adjuvant chemotherapy (HR 0.33, p = 0.026) are risk and protective factors, respectively, for OS. CONCLUSIONS: Repeated pulmonary metastasectomy should be offered to patients with metastatic CRC because there are no differences in terms of OS between patients undergoing single and repeated metastasectomy. Adjuvant chemotherapy should be suggested in case of metastatic CRC.

Vena cava anomalies in thoracic surgery.

BACKGROUND: Vena cava anomalies are a rare group of anatomical variations due to an incorrect development of the superior or inferior vena cava during fetal life. They generally show no clinical relevance and the diagnosis is done due to the association with congenital heart diseases in most of cases. However, preoperative identification of these anomalies is mandatory for surgeons to proper surgical planning. If not recognized, lethal complications may occur, as already reported in literature. CASE PRESENTATION: We report a case series of three different unidentified vena cava anomalies in patients undergoing lung resection. These unrecognized anomalies led to minor complications in two cases and required an accurate intraoperative evaluation in another. A careful retrospective evaluation of preoperative radiological images showed the anomalies. CONCLUSIONS: A careful evaluation of the vena cava anatomy at pre-operative imaging is mandatory for thoracic surgeons to properly plan the surgery and avoid complications.

Bronchoscopic treatment of emphysema: an update.

Chronic obstructive pulmonary disease (COPD) is the major causes of disability and mortality. The efficacy of maximal medical treatment, although effective at the early stages of the disease, becomes limited when extensive alveolar destruction is the main cause of respiratory failure. At this stage of the disease more aggressive options, when feasible, should be considered. Lung transplantation and lung volume reduction surgery (LVRS) are currently available for a selected group of patients. Endoscopic alternatives to LVRS have progressively gained acceptance and are currently employed in patients with COPD. They promote lung deflation searching the same outcome as LVRS in terms of respiratory mechanics, ameliorating the distressing symptom of chronic dyspnea by decreasing the physiological dead space.

Pulmonary metastasectomy in uterine malignancies: outcome and prognostic factors.

BACKGROUND: This retrospective study is designed to evaluate factors affecting survival in a population of patients receiving pulmonary metastasectomy after gynecologic cancers. METHODS: Nineteen patients with isolated lung metastases (one or two) were surgically treated with R0 resection. Four of them underwent lobectomies. RESULTS: Six patients (31.6%) received adjuvant therapy and 11 (58%) experienced recurrences after metastasectomy. Five- and ten-year survival were 40.9% and 31.4%, respectively. Five-year survival in patients receiving adjuvant therapy was 52.4%. At multivariate analysis factors negatively influencing survival were a disease-free interval (DFI) of less than 24 months and recurrence after pulmonary metastasectomy. CONCLUSIONS: Pulmonary resection for metastatic gynecologic cancer is feasible and effective; adequate selection of patients is mandatory to achieve satisfactory results and long-term survival.

Multimodality treatment of stage II thymic tumours.

BACKGROUND: Complete resection for stage II thymic tumors can be easily accomplished even if the capsula and adjacent mediastinal tissue are macroscopically involved; however, also at this stage, recurrence may occur, particularly for B2, B3 and thymic carcinoma. The criteria for the administration of adjuvant therapy remain controversial and it is unclear whether patients at this stage may benefit from it. We reviewed a series of patients at this stage receiving adjuvant chemo-radiotherapy (chemo-RT) based on histology. METHODS: Eighty-eight consecutive patients with stage II thymic tumors were reviewed; 59 patients (67%) with B thymoma or thymic carcinoma received adjuvant treatment with mediastinal irradiation (40-55 Gy), chemotherapy (CH) (PAC regimen) or a combination of both. RESULTS: Complete resection was achieved in all patients. Fifty-four patients (61%) received post-operative chemo-RT, 2 (2%) patients received adjuvant CH only and 3 (3%) post-operative RT only; they all had B2, B3 histology or thymic carcinoma. The median follow up was 107±83 months. 5-year and 10-year survival were 96%±2% and 83.4%±5%. Recurrence was observed in 5 patients (5.7%). Disease-free 5 and 10-year survival was 94%±2% and 92%±3% respectively. Five patients (5.7%) had recurrence. CONCLUSIONS: The administration of adjuvant chemo-RT to patients with stage II type B thymoma and thymic carcinoma contributes to reduce the recurrence rate and to increase long-term survival.

IL-18 receptor marks functional CD8+ T cells in non-small cell lung cancer.

IL-18 is an inflammasome-related cytokine, member of the IL-1 family, produced by a wide range of cells in response to signals by several pathogen- or damage-associated molecular patterns. It can be highly represented in tumor patients, but its relevance in human cancer development is not clear. In this study, we provide evidence that IL-18 is principally expressed in tumor cells and, in concert with other conventional Th1 cell-driven cytokines, has a pivotal role in establishing a pro-inflammatory milieu in the tumor microenvironment of human non-small cell lung cancer (NSCLC). Interestingly, the analysis of tumor-infiltrating CD8+ T cell populations showed that (i) the relative IL-18 receptor (IL-18R) is significantly more expressed by the minority of cells with a functional phenotype (T-bet+Eomes+), than by the majority of those with the dysfunctional phenotype T-bet-Eomes+ generally resident within tumors; (ii) as a consequence, the former are significantly more responsive than the latter to IL-18 stimulus in terms of IFNγ production ex vivo; (iii) PD-1 expression does not discriminate these two populations. These data indicate that IL-18R may represent a biomarker of the minority of functional tumor-infiltrating CD8+ T cells in adenocarcinoma NSCLC patients. In addition, our results lead to envisage the possible therapeutic usage of IL-18 in NSCLC, even in combination with other checkpoint inhibitor approaches.

Blockade of Stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells.

Poor prognosis in lung cancer has been attributed to the presence of lung cancer stem cells (CSCs) which resist chemotherapy and cause disease recurrence. Hence, the strong need to identify mechanisms of chemoresistance and to develop new combination therapies. We have previously shown that Stearoyl-CoA-desaturase 1 (SCD1), the enzyme responsible for the conversion of saturated to monounsaturated fatty acids is upregulated in 3D lung cancer spheroids and is an upstream activator of key proliferation pathways ß-catenin and YAP/TAZ. Here we first show that SCD1 expression, either alone or in combination with a variety of CSCs markers, correlates with poor prognosis in adenocarcinoma (ADC) of the lung. Treatment of lung ADC cell cultures with cisplatin enhances the formation of larger 3D tumor spheroids and upregulates CSCs markers. In contrast, co-treatment with cisplatin and the SCD1 inhibitor MF-438 reverts upregulation of CSCs markers, strongly synergizes in the inhibition of 3D spheroids formation and induces CSCs apoptosis. Mechanistically, SCD1 inhibition activates endoplasmic reticulum stress response and enhances autophagy. These data all together support the use of combination therapy with SCD1 inhibitors to achieve better control of lung cancer.