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Enrico Ruffini
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MTE 17 - Neuroendocrine Tumor (Sign Up Required) (ID 566)
- Event: WCLC 2017
- Type: Meet the Expert
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 07:00 - 08:00, Room 418
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MTE 17.02 - Surgical Strategy for the Treatment of Neuroendocrine Tumors (ID 7799)
07:30 - 08:00 | Presenting Author(s): Enrico Ruffini
- Abstract
- Presentation
Abstract:
Neuroendocrine tumors (NETs) are a distinct subgroup of neoplasms arising from the neuroendocrine cells. Due to the peculiar morphological, immunohistochemical and molecular characteristics, NETs are usually classified as a separate group of tumors among solid malignancies. Thoracic NETs include the pulmonary and the thymic NET. Pulmonary NETs (PNETs) comprise well-differentiated neuroendocrine tumors (typical carcinoid), moderately-differentiated neuroendocrine tumors (atypical carcinoid), the latter two grouped as Bronchial Carcinoids (BCs); large cell neuroendocrine carcinoma (LCNEC) and small-cell lung carcinoma (SCLC). There are also two preneoplastic conditions, the Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) and the tumorlets whose role in the neuroendocrine carcinogenesis are yet to be fully clarified. PNETs represent about 25% of all lung cancers, most of them represented by SCLC. Thymic NETs (NeuroEndocrine Thymic Tumors, NETT) are considered as a subgroup of thymic carcinoma, although in most series they are classified separately, and are further classified as well-differentiated NETT (typical carcinoid), moderately-differentiated NETT (atypical carcinoid) and poorly-differentiated NETT (Large cell and small cell neuroendocrine carcinoma). NETTs are exceedingly rare and represent about 5% of all thymic tumors. The present lecture will focus on PNETs and NETTs, with a particular insight in the surgical management of these tumors. 1, Pulmonary NETs. The most recent TNM staging classifications of lung cancer (7[th] and 8[th] edition) suggest that PNETs should be staged similarly to Non-Small Cell Lung Cancer (NSCLC). Surgical indications largely depend on histology and stage. Bronchial carcinoids (BCs) represent about 10% of PNETs. The vast majority are typical carcinoids (TC, well-differentiated neuroendocrine tumors); they are usually located centrally in the lung parenchyma/airways (70%), and they are frequently confined to the lung without evidence of loco-regional or distant spread, which occur in about 5-10% of the cases. Atypical carcinoids (AT) share most of the characteristics of typical carcinoids, although they present a higher rate of mytoses and necrosis. They are more aggressive than TCs and they present with lymphnodal metastatic involvement in 30%-50% of the cases. LCNEC are usually diagnosed after resection, since a preoperative characterization on small biopsies is challenging. They are aggressive tumors, and more than 50% of the patients present with an advanced disease at diagnosis, for whom surgery is not indicated. As for SCLC, the vast majority of the patients present at an advanced stage, with hematogenous spread. The role of surgery in the treatment of PNETs is similar to what is currently employed for NSCLC. BCs are often amenable to surgery, due to the early stage at presentation. Anatomical resections (segmentectomy, lobectomy or more extended resections) offer the best outcome, while sublobar wedge resection should be avoided in fit patients, and should be reserved only for patients not amenable to anatomical resections. Parenchymal-sparing techniques (bronchial/vascular sleeve resection) should be employed whenever possible to avoid pneumonectomy in centrally-located tumors. Lymphadenectomy should be carried out according to the current guidelines (IASLC/ESTS), including a minimum of 6 nodes/stations of which 3 mediastinal including the subcarinal one. Endoscopic resection may have a role only in case of lobar/lung atelectasis to restore the bronchial patency before definite surgical resection Endobronchial resection is also employed with palliative intent in unresectable disease. Survival after resection of BCs is excellent, with more than 90% of the patients with typical carcinoids alive at 10 years, and 70% and 50% with atypical carcinoids alive at 5 and 10 years. The role of adjuvant therapy after complete resection of BCs is not fully determined and it is often discussed on an individual basis in a multidisciplinary tumour board setting. LCNEC are poor candidates for surgery, because of the loco-regional and distant spread at presentation. Anatomical resections, including extended resection to neighboring organs are needed in order to achieve a complete resection. Despite this, local recurrence and distant metastases are frequent after surgery. Adjuvant therapy (chemotherapy or chemoradiotherapy) is almost always needed after surgery for the disease control. SCLC has customarily been considered nonsurgical because of the high aggressiveness and the chemosensitivity of this neoplasm. However, in carefully selected patients with limited disease (T1-T2N0) surgery as part of a multidisciplinary protocol (chemoradiotherapy) may be proposed after a careful assessment of loco-regional (including mediastinal) and distant spread. 2, Thymic NETs. Thymic NETs (NETTs) are usually aggressive thymic tumors, very often presenting atypical features (atypical carcinoid). They express somatostatin receptors which may justify the use of Octreotide scintigraphy for the diagnosis and follow-up. About 30-40% have metastases at presentation and in some cases they are associated with endocrinopaties (Cushing syndrome, MEN-1 syndrome, etc). The staging system for NETTs has traditionally been the Masaoka system. The 7[th] edition of the TNM of thymic tumors included also the NETTs. As for other thymic malignancies, surgery is the treatment of choice for local and loco-regional disease (Stage I/II and selected Stage III). The resectability rate for NETTs is far lower than that of thymoma, ranging between 30% and 100% in most series. Complete (R0) resection is the most important prognostic factor. Median sternotomy and open surgical approaches are the optimal accesses for NETTs. The role of minimally-invasive techniques (MIT) in the treatment of NETT is extremely limited, due to the aggressive nature of the tumor. The role of induction and adjuvant treatments (radiotherapy or chemotherapy) has not been established yet, due to the rarity of the condition. 3, The collaborative effort. As for many rare diseases, also for NETs a collaborative, multi-Institutional, society-based effort is the single most important factor that can provide a real advancement in the research and management of this condition. The European Society of Thoracic Surgeons (ESTS) launched in 2012 a Neuroendocrine Tumors Working Group with the aim of collecting data from interested Institutions across the world. An amazing database collating more than 2100 patients has been designed which represents a tremendous opportunity for the study of these rare conditions. A number of studies have been published so far which constitute a solid backbone for the management of NETs.
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OA 16 - Treatment Strategies and Follow Up (ID 686)
- Event: WCLC 2017
- Type: Oral
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:Jun Nakajima, T. Demmy
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 315
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OA 16.02 - Risk of Recurrence in Stage I Adenocarcinoma of the Lung: A Multi-Institutional Study on Interaction with Type of Surgery and Type of Nodal Staging (ID 9304)
14:40 - 14:50 | Author(s): Enrico Ruffini
- Abstract
- Presentation
Background:
In last years, an increasing interest emerges on the role of sub-lobar resection and lobe-specific lymphnode dissection in the treatment of early stage lung cancer. The aim of our study was to define impact on Cumulative incidence of recurrence (CIR) of type of surgical resection and type of nodal staging. Furthermore, we evaluated the effect of interactions between the different kinds of procedure.
Method:
An analysis of 969 consecutive stage I pulmonary adenocarcinoma patients, operated in six Thoracic Surgery Institutions between 2001 and 2013, was conducted. Type of surgical resection included lobectomy and sub-lobar resection; pneumonectomy and bilobectomy were excluded from the analysis. Nodal staging procedures were classified in nodal sampling (NS), lobe-specific lymph node dissection (LS-ND) and systematic lymph node dissection (SND). Multivariable-adjusted comparisons for CIR was performed using Fine and Grey model, taking into account death by any cause as competing event. Test of interaction between type of surgical resection and type of nodal staging was carried out and results presented in a stratified way. Missing data were multiple-imputed, combined estimates were obtained from 5 imputed datasets.
Result:Multivariable-adjusted Fine and Grey model for Comulative Incidence of Recurrence (take into account age, gender, smoking habit, side of intervention, pTNM stage, vascular invasion, pTNM stage, predominant histologic pattern and histologic grade)(Results of test of interaction presented in a stratified way)
Median follow-up was 63 months. Eight-hundred forty-six (87%) patients were submitted to lobectomy, while 123(13%) to sub-lobar resection. Four-hundred fifty-five (47%) patients received SND, 98(10%) LS-ND and 416(43%) NS. Two-hundred forty-seven (26%) patients developed a local/distant recurrence with a 5-year CIR of 24%. Multivariable-adjusted comparisons showed an independent negative effect of sub-lobar resection(HR 1.52;95%CI:1.07-2.17), LS-ND(HR 1.74;95%CI:1.16-2.6) and NS(HR 1.49;95%CI:1.12-1.98) on CIR(Table). Test of interaction showed an homogeneity of results among subgroups.Sub-lobar resection vs. Lobectomy HR (95%CI) P INTERACTION P-value Overall 1.52 (1.07 to 2.17) 0.02 0.268 SND 1.98 (1.14 to 3.42) LS-ND 1.87 (0.94 to 3.74) NS 1.08 (0.61 to 1.93) LS-ND vs SND HR (95%CI) P INTERACTION P-value Overall 1.74 (1.16 to 2.6) 0.007 0.903 Lobectomy 1.66 (1.03 to 2.69) Sub-lobar resection 1.58 (0.75 to 3.32) NS vs. SND HR (95%CI) P INTERACTION P-value Overall 1.49 (1.12 to 1.98) 0.007 0.131 Lobectomy 1.61 (1.18 to 2.19) Sub-lobar resection 0.88 (0.43 to 1.82)
Conclusion:
In our series, lobectomy and systematic lymph node dissection confirmed to be the optimal strategy to achieve a favorable prognosis in stage I adenocarcinoma of the lung. The real value of sub-lobar resection and less aggressive nodal staging should be assessed by randomized clinical trial before being integrated in clinical practice.
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P2.09 - Mesothelioma (ID 710)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.09-003 - Dissecting the Immune Environment in Malignant Pleural Mesothelioma: Results from a Prospective Assessment (ID 8256)
09:30 - 09:30 | Author(s): Enrico Ruffini
- Abstract
Background:
Malignant pleural mesothelioma (MPM) cells grow in the context of immune cells, either infiltrating the tumor or present in the associated pleural effusion. Specific immune cell subsets and immune-checkpoints on T-lymphocytes infiltrating the tumor have been proposed as possible prognostic factors (Uiije, DOI:10.1080/2162402X.2015.1009285; Awad, DOI:10.1158/2326-6066.CIR-16-0171) and therapeutic targets (Marcq, DOI:10.1080/2162402X.2016.1261241; Khanna, DOI: 10.1016/j.jtho.2016.07.033). The immune cells infiltrating MPM are however dynamically exchanged with those present in the pleural fluid (Lievense, DOI: 10.1016/j.lungcan.2016.04.015). The heterogeneity of tumor bulk, ranging from terminally differentiated cells to tumor-initiating cells (TIC), makes the interactions between tumor and immune cells even more jeopardized. Our study is the first that analyzes at the same time the immune-phenotype of MPM cells, immune cells infiltrating the tumor and present in the matched pleural fluid, to obtain a comprehensive signature of MPM immune-environment and precise indications for personalized immunotherapy-based interventions.
Method:
From June 2015 to June 2017, we collected 120 pleural fluids and biopsies from patients that undergone diagnostic thoracoscopy: 34 samples were diagnosed as MPM (25 epithelioid, 5 sarcomatoid, 4 biphasic MPM), 56 samples were reactive non neoplastic pleuritis, 30 samples were pleural localization of lung adenocarcinoma or other tumors. Cells of pleural fluids were analyzed by cell sorting and flow cytometry. Biopsies were cut and digested, and cell populations were analyzed as well. We isolated, expanded and analyzed the TIC-component from 5 epithelioid and 5 sarcomatoid MPM.
Result:
MPM significantly differed from non neoplastic pleuritis for the increased number of CD3[+]CD8[+]T-lymphocytes in pleural essudate coupled with the reduction of this population within the tumor (p<0.001). M2/M1-macrophages ratio was also higher (p<0.02). The increased number of T-regulatory cells and granulocytic/monocytic myeloid-derived suppressor cells in both pleural fluid and tumor significantly (p<0.005) differentiated MPM from non neoplastic pleuritis and other malignancies. Either CD3[+]CD8[+]or CD3[+]CD4[+]T-lymphocytes present in pleural fluid and infiltrating the tumor had higher expression of PD-1, LAG-3, TIM-3 immune-checkpoints (p< 0.02), coupled with increased expression of PD-1L, LAG-3, TIM-3 and GAL-9 on matched MPM (p<0.05) compared to non neoplastic pleuritis. Interestingly, immune-checkpoints were down-regulated in TIC, suggesting that immune-checkpoint inhibitors may be poorly effective against this MPM component.
Conclusion:
Our study identified an immune-signature that discriminates MPM from pleuritis secondary to other tumors or non malignant diseases. Such immune-signature will help to refine prognostic factors and define a precision immunotherapy for MPM.
