Virtual Library

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    E04 - Lung Cancer Pathology Classification (ID 4)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Pathology
    • Presentations: 4
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      E04.1 - Adenocarcinoma (ID 387)

      14:00 - 15:30  |  Author(s): M. Noguchi

      • Abstract
      • Presentation
      • Slides

      Abstract
      In 2011, an international multidisciplinary classification of adenocarcinoma was published (2011 IASLC classification) (1) (Table). Pathologists, oncologists, radiologists, and basic scientists in the field of lung cancer are involved in this project. The new concepts of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) in this classification are based on the multistep carcinogenesis of adenocarcinoma (2). Pulmonary adenocarcinoma develops to invasive adenocarcinoma through atypical adenomatous hyperplasia (AAH), AIS, and MIA. The diagnostic criteria for AIS and MIA were first defined in this new classification. AAH is a localized proliferation of mildly to moderately atypical cells lining involved alveoli and, sometimes, respiratory bronchioles. AAH is usually less than 5 mm in diameter and lacks any underlying interstitial inflammation or fibrosis. Before, AAH was detected as incidental findings in the adjacent lung parenchyma in resected lung adenocarcinoma, but recently it is found by thin-slice CT scan examination and shows characteristic ground glass opacity (GGO), similar to AIS. AAH shows positivity for TTF-1 antigen and is a preinvasive lesion of peripheral-type adenocarcinoma, especially the terminal respiratory unit (TRU) type (3). Adenocarcinoma with pure lepidic growth is a special subtype, because it mimics AAH, which is a preinvasive form of adenocarcinoma and has an extremely favorable prognosis. Among the pure lepidic adenocarcinomas, “adenocarcinoma in situ” is defined as localized small (< 3 cm) adenocarcinoma with growth restricted to neoplastic cells along preexisting alveolar structures (lepidic growth), lacking stromal, vascular, or pleural invasion. Differential diagnosis between AAH and AIS is sometimes very difficult. AIS corresponds to type A and B adenocarcinoma according to the 1995 Noguchi classification (4). AIS is usually nonmucinous but rarely may be mucinous. MIA is a small, solitary adenocarcinoma (< 3 cm), with a predominantly lepidic pattern and < 5 mm invasion in greatest dimension in any one focus. By definition, the invasive component is composed of histological subtypes other than the lepidic pattern (i.e. acinar, papillary, micropapillary, and/or solid) or tumor cells infiltrating myofibroblastic stroma (malignant stroma). MIA is excluded if the tumor invades lymphatics, blood vessels, or pleura, or contains tumor necrosis. If the tumor is larger than 2 cm, diagnosis should be done with caution, and the tumor needs to be extensively sampled, especially the solid component. On thin-slice CT examination, MIA reveals pure GGO or a partly solid appearance. MIA corresponds to type C’ adenocarcinoma according to the modified Noguchi classification (5). We believe that the 5-year survival of patients with localized resected MIA is more than 95%, but there are no actual data on the clinical outcome of MIA. In Japan, leading radiologists and pathologists have just started a joint project to clarify the natural history of MIA, supported by the Ministry of Health, Labor and Welfare. First, they are defining the radiological diagnostic criteria for MIA. Then, based on the criteria, they will follow up cases for more than 5 years. In the course of follow-up, the growing cases will be surgically resected and examined histologically. Finally we will understand the radiological and biological characteristics of MIA in more detail. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, micropapillary, and solid patterns. Among the subtypes, lepidic growth represents in situ growth or spreading of invasive adenocarcinoma and the region showing lepidic growth does not influence the patient’s outcome. Therefore, it is very important to report the percentage of the lepidic subtype in the invasive adenocarcinoma. In order to verify the utility of invasive adenocarcinoma classification, interobserver agreement (kappa value) of the diagnostic criteria was assessed (6). Eight Japanese pathologists used the 2011 IASLC classification to independently evaluate the histologic grade of 122 adenocarcinoma cases resected in the National Cancer Center Hospital (Tokyo). The mean (±SD) value of the kappa statistic for the 2011 IASLC classification was 0.46±0.09 (range: 0.24 to 0.61) and the value was not enough for practical use. But, if we modified the classification into low grade (lepidic, acinar, and papillary) and high grade (solid and micropapillary), the mean (±SD) value rose to 0.66±0.09 (range: 0.47 to 0.85) reaching the level of practical use (Figure). Therefore, the modified 2011 IASLC classification shows the clinical outcome of the invasive adenocarcinoma. References (1) Travis WD, Elisabeth B, Noguchi M, et al. International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thoracic Oncol 6:244-285, 2011. (2) Noguchi M. Stepwise progression of pulmonary adenocarcinoma. Clinical and molecular implications. Cancer Metastasis Rev 29:15-21, 2010. (3) Yatabe Y, Kosaka T, Takaashi T, et al. EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am J Surg Pathol 29:633-9, 2005. (4) Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 75:2844-2852, 1995. (5) Minami Y, Matsuno Y, Iijima T, et al. Prognistication of small-sized primary pulmonary adenocarcinomas by hitopathlogical and karyometric analyasis. Lung Cancer 48:339-348, 2005. (6) Nakazato Y, Maeshima AM, Ishikawa Y, et al. Interobserver agreement in the nuclear grading of primary pulmonary adenocarcinoma. J Thoracic Oncol 8:736-743, 2013

      IASLC/ATS/ERS Classification of Lung Adenocarcinoma
      Preinvasive lesions Atypical adenomatous hyperplasia (AAH) Adenocarcinoma in situ (<3cm formerly BAC)
      Minimally invasive adenocarcinoma (MIA) (<3cm lepidic predominant tumor with <5mm invasion)
      Invasive adenocarcinoma Lepidic predominant Acinar predominant Papillary predominant Micropapillary predominant Solid predominant with mucin production
      Variants (Invasive mucinous ad., Collid, Fetal, Enteric
      Figure 1Figure 2

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      E04.2 - Squamous Cell Carcinoma (ID 388)

      14:00 - 15:30  |  Author(s): A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Abstract
      Squamous cell carcinoma is one of the four common types of lung cancer, and is defined as a malignant epithelial tumour showing evidence of squamous differentiation in the form of keratinisation, intercellular bridging or both. The main purpose of a pathological classification is to produce clinically relevant subgroups, in addition being reproducible, thorough, dynamic, and globally applicable, and this talk summarises the current WHO classification and potential new parameters. Current morphological classification: Since the 1999 classification, the recognised variants have been being papillary, clear cell, small cell and basaloid. Pure primary basaloid carcinomas of the lung are rare and the current WHO (2004) classification classifies basaloid carcinomas as variants of large cell carcinoma when they lack evidence of squamous differentiation. When squamous differentiation is present, they are classified as basaloid variants of squamous cell carcinoma. Basaloid morphology has been shown to carry a poorer prognosis than poorly differentiated squamous cell carcinomas for stage I and II disease. Papillary squamous cell carcinomas tend to be endobronchial and most are staged as T1N0 with a 5‑year survival of over 60 percent, which may be due to early presentation at this location rather than the architectural pattern itself. With regard to small cell and clear cell variants, the last decade has seen virtually no publications. Indeed, the primary reason for recognising these variants is to avoid misdiagnosis as metastases or other subtypes of lung carcinoma. Therefore, with the exception of the basaloid variant that appears to carry a worse prognosis, especially given small cell and clear cell variants are cytological parameters, consideration should be given to their removal from the next WHO classification, as well as the papillary variant. Also, given the increased knowledge in relation to immunophenotyping, basaloid and basaloid variant of squamous cell carcinoma could potentially be collapsed into a single subgroup of squamous cell carcinoma. Potential new morphological subgroups: The last decade has seen publications suggesting an architectural classification termed "alveolar filling" pattern. One paper has shown 100% survival when this pattern is present, although the number of cases showing this as a pure pattern is very low, around 1-2%. A more recent paper has suggested that the percentage of alveolar filling (greater than 70%) was significantly associated with a better prognosis, arguing that in tumours less than 30 mm in maximum diameter, a minimally invasive category might be appropriate. Tumours with this predominance would likely be sufficiently frequent (near 25%) to be clinically useful, and more data are required to support its inclusion. Other histological parameters such as extent of background of lymphocytic infiltration and keratinisation do not seem to carry prognostic significance. Classification according to presentation and/or aetiological factors: Publications in the last decade have suggested that the frequency of peripheral squamous cell carcinomas is increasing, with a greater number of stage 1 patients having peripheral presentation, although there was no difference in survival in N0 disease when compared to central tumours in one paper (Funai K et al Am J Surg Pathol 2003:27;978-984) . Indeed, survival was better in N1 disease in central presenting tumours. The alveolar pattern of growth was seen within the peripheral group only. However, unlike adenocarcinomas where those that present peripherally may be never-smokers, nearly all peripheral squamous carcinomas appear to be either current or ex-smokers. The frequency of HPV being present in squamous cell carcinoma of the lung varies extensively in the literature. The same ‘high-risk’ subtypes of HPV for cervical carcinoma are found in invasive bronchial carcinomas. However, although data from oropharyngeal squamous cell carcinomas suggest HPV infection is associated with better prognosis, data in the lung are conflicting. There is also likely synergism between smoking and infection as the preferred site of entry for HPV is at squamo-columnar junctions, and the presence or absence of HPV is unlikely to be recommended as a parameter for subclassification. Pre-invasive lesions: Squamous lesions arising in the airways have been regarded as progenitors of squamous carcinoma for decades and basal cell hyperplasia and squamous metaplasia also likely represent earlier phases in the development of squamous carcinomas. The current WHO/IASLC classification tabulates methodology for such gradation, and the system is sufficiently reproducible for diagnostic usage. The sequence progresses from basal cell hyperplasia through squamous metaplasia and squamous dysplasia to carcinoma-in-situ. Immunohistochemistry and small biopsies: The past decade has seen increasing usage of immunohistochemistry to refine the diagnosis of non-small cell carcinoma, driven by the needs for more accurate subclassification in relation to chemotherapeutic agents. This is not part of the current (WHO 2004) classification, although is recommended for use in biopsies by the IASLC as well as the ATS and ERS in relation subclassifying biopsies hitherto called non-small cell carcinoma, not otherwise specified (NSCLC-NOS) (Travis et al. J. Thor. Oncol. 2011;6:244-85). Therefore, any biopsy with NSCLC showing keratinisation and/or intercellular bridges should be classified as squamous cell carcinoma and, in NSCLCs lacking these or other disciminating morphological features on biopsy, but showing immunohistochemical evidence of squamous differentiation (one or two of CK 5/6, P63, and P40 being the most commonly used antibodies for this purpose) should be classified as NSCLC, favouring squamous cell carcinoma on immunohistochemistry. Similar investigation should also be considered in resected large cell undifferentiated carcinomas. Molecular subtypes: There is a vast literature on the carcinogenesis of squamous carcinoma, in particular preinvasive lesions. However none have yet become part of pathology classification. In relation to targeted therapy for invasive squamous cell carcinoma, data are still primarily related to clinical trials, with low frequencies of identification. Therefore, although targets such as DDR2 show some promise, at present, there is insufficient data to warrant pathological classification of invasive squamous carcinoma in relation to specific genetic abnormalities. Conclusion: Unlike adenocarcinomas, there has not been much advance in the morphogical subtyping of squamous cell carcinoma. There has however been advance in immunophenotyping, especially in relation to NSCLC-NOS, and it is hoped that molecular classification may have a role to play in the next decade.

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      E04.3 - Large Cell and Sarcomatoid Carcinoma (ID 389)

      14:00 - 15:30  |  Author(s): K.M. Kerr

      • Abstract
      • Presentation
      • Slides

      Abstract
      Large cell and sarcomatoid carcinomas account for approximately 10% of all lung cancers. For all practical purposes, each of these diagnoses can only be made with accuracy in surgically resected cases since tumour definitions mandate a feature be excluded from or present in at least 10% of the whole lesion. Although features suggesting a large cell variant or sarcomatoid tumour may be recognised in a small biopsy or cytology sample, these diagnoses are inappropriate in such samples. Large cell carcinoma (LCC) is morphologically defined as comprising large undifferentiated tumour cells lacking any evidence of squamous, glandular or small cell carcinoma (SCLC). Epidemiologically these cases are no different from most other non-small cell carcinomas (NSCLC). They favour a more peripheral location in the lung and necrosis is common. Cells are generally large, with open nuclei, prominent nucleoli and abundant cytoplasm, but some cases show hyperchromatic, granular nuclei, inconspicuous nucleoli and less cytoplasm. In the classical case, the cells show no organisation, just sheets of cells with little intervening vascular stroma, but some cases show cellular stratification with more abundant fibrous stroma. Several variants of large cell carcinoma are described. Large cell neuroendocrine carcinoma (LCNEC) additionally requires demonstration of neuroendocrine differentiation, usually by immunohistochemistry. These are often large, necrotic tumours and share many epidemiological and molecular features with small cell lung carcinoma. Organoid morphology with trabeculae and rosettes are common. A significant proportion of LCNEC are combined with other tumour types in the same lesion, most often adenocarcinoma. These cases would more logically reside in a separate category with other NE tumours. The basaloid variant of LCC largely meets the above definition, but tends to have rather smaller cells, peripheral nuclear palisading around discrete nests/sheets of cells, frequent intercellular basement membrane material, like basaloid carcinomas at other sites. An infrequent and unusual form of small keratin pearl may be seen but basaloid carcinomas lack the larger cells with eosinophilic cytoplasm and intercellular bridges of squamous cell carcinomas (SCC). They share immunohistochemical features (p63, p40, CK5/6, desmocollin3) with SCC and could represent de-differentiated SCC. Defining basaloid carcinoma apart from SCC remains a controversial issue. Lymphoepithelioma-like lung carcinoma (LELC) comprises a syncytium of large undifferentiated cells with indistinct cell borders and a heavy lymphoplasmacytic infiltrate. Commoner in East Asian countries, this tumour is still rare and is closely associated with EBV genome. Distinction from other poorly differentiated carcinomas with a heavy immune cell infiltrate may be impossible in the absence of evidence of EBV infection and the latter should, perhaps, be incorporated into the tumour definition. Clear cell carcinoma of the lung features large cells with clear cytoplasm. This histological feature is, however, seen in a range of other NSCLC and as such, serves little useful purpose, apart from awareness of potential confusion with metastatic renal cell carcinoma. This would be better used as a descriptor rather than defining a separate tumour category. Large cell carcinoma with rhabdoid phenotype is rather ill-defined and extremely rare. A few cases reports or small series reflect the heterogeneity of so-called cases with no clear definition. One common impression is that of an aggressive tumour but again, this terminology is better used as a descriptor rather than defining a separate subtype. Emerging immunohistochemical and molecular data have questioned the nature of large cell carcinoma and our current classification. Many cases share a molecular and/or immunohistochemical phenotype with either squamous cell or adenocarcinoma, suggesting that they should be classified by their molecular profile, effectively deleting the LCC category. This approach has several problems including the following: (a) Not all cases can be so re-classified as squamous cell or adenocarcinoma, (b) these immune/molecular profiles are not specific for either diagnosis, and (c) the definition of these differentiated tumours is based on H&E morphology, not immune/molecular findings. Further confusion stems from the inappropriate use of the term ‘large cell carcinoma’ in the small biopsy/cytology setting. Any sample containing large undifferentiated cells lacking features of small cell carcinoma should be referred to as NSCLC, not otherwise specified (NOS) and not ‘large cell carcinoma’. Most of these cases, if resected, derived from differentiated adeno- or squamous cell carcinomas. The legitimate, recommended use of IHC to predict tumour subtype in small samples is neither validated nor justified in resected tumours under the current classification. However, it may be useful to characterise resected LCC cases by immunophenotype since this may correlate with some targetable mutations but it should not lead to a major change in diagnosis. Mutations of EGFR or KRAS are rarer than in adenocarcinoma but correlate with TTF1 positivity. Sarcomatoid carcinomas show pleomorphic, spindle or giant cells comprising at least 10% of the tumour. Usually all three cell types are seen. They account for 3-4% of resected tumours and are usually large, invasive, necrotic tumours. They are clinically aggressive and frequently chemorefractory, justifying their separation in our classification. Most lesions also show differentiated squamous cell or adenocarcinoma components. As for LCC, this diagnosis should not be made in the small biopsy/cytology setting but if these cell types are present in the sample they should be described in the report. Immunohistochemical and/or molecular studies are few. Most cases show an immunoprofile in the sarcomatoid component consistent with the differentiated tumour also present. Pure sarcomatoid cases may also show a ‘differentiation-associated’ immunoprofile but often it is inconclusive or IHC is negative. KRAS mutations have been consistently reported in a few case series. Carcinosarcoma is an exceptionally rare tumour, defined in the lung as a lesion showing carcinoma plus differentiated, heterologous sarcomatous elements, such as rhabdomyo, osteo or chondrosarcoma. Pulmonary Blastoma is a biphasic lesion combining primitive mesenchymal tumour and well-differentiated adenocarcinoma, the latter described as endometrioid or ‘fetal’ in pattern. Regarding the more typical cases of LCC, sarcomatoid and basaloid carcinoma, the molecular evidence supports the concept that these tumours may represent dedifferentiated carcinomas of the lung. How this emerging concept is reflected in our classification is a matter of ongoing debate.

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      E04.4 - Neuroendocrine Tumours (ID 390)

      14:00 - 15:30  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
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      Abstract
      TUMORLETS AND DIFFUSE IDIOPATHIC PULMONARY NE CELL HYPERPLASIA (DIPNECH) Tumorlets are defined as nodular proliferations of NE cells that measure less than 0.5 cm in greatest diameter. Tumorlets typically represent incidental histologic findings found in lung tissues with inflammatory and/or fibrotic lesions such as bronchiectasis, interstitial fibrosis, or infections. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) consists of widespread peripheral airway NE cell hyperplasia and/or multiple tumorlets. These patients are thought to represent a preinvasive lesion for carcinoid tumors because a subset of these patients has one or more carcinoid tumors.[1] DIPNECH may present as multiple pulmonary nodules often mistaken for metastatic cancer or as a form of interstitial lung disease with airway obstruction. Histologically DIPNECH is characterized by prominent NE cell hyperplasia and tumorlets. Some patients also have carcinoid tumors. Tumorlets may cause airway narrowing and/or obliteration. The surrounding lung parenchyma is generally normal.CARCINOID TUMORS Carcinoid tumors most commonly show an organoid growth pattern. The tumor cells show uniform cytologic features with a moderate amount of eosinophilic cytoplasm and finely granular nuclear chromatin. AC are separated from TC by the presence of mitoses between 2 and 10 per 2mm[2] area or the presence of necrosis. Necrosis is usually in the form small punctate foci. Other histologic features such as pleomorphism, vascular invasion and increased cellularity are not as helpful in separating TC from AC. Chromogranin, CD56 and synaptophysin are the most helpful NE immunohistochemical markers. A clear role for Ki-67 in separating TC from AC is not established. However, a low proliferation rate (≤5%) is typically seen in TC compared to AC where it is usually between 5 and 20%. Ki-67 is most useful in addressing the problem of over diagnosis of a high grade tumor in carcinoid tumors where diagnostic criteria are obscured in small crushed biopsies. In this setting a high proliferation rate (>59%) will be found in the high grade LCNEC or SCLC where TC or AC show a much lower proliferation rate.LARGE CELL NEUROENDOCRINE CARCINOMA LCNEC is a high grade NE carcinoma with cytologic features of a non-small cell carcinoma. It was classified as a variant of large cell carcinoma in the 2004 WHO classification.[1] LCNEC are diagnosed according to the following criteria: 1) NE morphology with organoid nesting, palisading or rosette-like structures, 2) high mitotic rate greater than 10 mitoses per 2 mm[2] (average 60-80 mitoses per 2 mm[2]), 3) non-small cell cytologic features including large cell size, low nuclear/cytoplasmic ratio, nucleoli, or vesicular chromatin, and 4) NE differentiation by immunohistochemistry with antibodies such as chromogranin, CD56 or synaptophysin or electron microscopy. The diagnosis of LCNEC is difficult to establish based on small biopsies or cytology. This is because the NE pattern is difficult to see morphologically in small tissue samples or cytology. Also NE differentiation can be difficult to demonstrate by immunohistochemistry in small pieces of tissue. For these reasons the diagnosis of LCNEC requires a surgical lung biopsy. When a LCNEC has components of adenocarcinoma, squamous cell carcinoma, giant cell carcinoma and/or spindle cell carcinoma it is called combined LCNEC. The most common component is adenocarcinoma, but squamous cell, giant cell or spindle cell carcinoma can also occur. If the second component is SCLC the tumor becomes a combined SCLC and LCNEC. NE differentiation must be demonstrated by immunohistochemistry or electron microscopy to diagnose LCNEC. NE immunohistochemical markers are usually best performed as a panel of chromogranin, CD56/NCAM, and synaptophysin. In 41-75% of cases, TTF-1 will be positive. The proliferation index by Ki-67 staining is very with staining of 50-100% of tumor cells .SMALL CELL CARCINOMA The diagnosis of SCLC is established based on small specimens such as bronchoscopic biopsies, fine needle aspirates, core biopsies, and cytology in most all cases, because of the presentation in advanced stages. Fortunately these specimens are diagnostic in most all cases. The diagnosis is based primarily based on light microscopy. Tumor cells appear round to fusiform, growing in sheets and nests. Necrosis is common and is often extensive. Tumor cell cytoplasm is scant and nuclear chromatin is finely granular. Tumor cell size is usually less than the diameter of three small resting lymphocytes. Nucleoli are inconspicuous or absent. A high mitotic rate averages 60-80 per 2 mm[2], however, mitoses can difficult to identify in small biopsy specimens. Combined SCLC is diagnosed when there is also a component of NSCLC such as adenocarcinoma, squamous cell carcinoma, large cell carcinoma, spindle cell carcinoma and giant cell carcinoma. In this setting each of the non-small cell components should be mentioned in the diagnosis. Combined SCLC can be seen in 25% of surgically resected tumors. At least 10% large cells should be present for the diagnosis of combined SCLC/large cell carcinoma; however, for the components of adenocarcinoma, squamous cell or spindle cell carcinoma the amount does not matter. Diagnostic challenges occur in the settings of crush artifact and surgically resected specimens. Crush artifact is common in small biopsy specimens. This can create a problem in separating SCLC from a variety of tumors including non-small cell lung cancer (NSCLC), lymphoma, carcinoid and chronic inflammation. Immunohistochemistry can be very helpful in this setting. In well fixed specimens such as resected specimens the tumor cells of SCLC appear larger than in small biopsies. This often results in over diagnosis of LCNEC. The most important special stain for the diagnosis of SCLC is a good quality H&E stain. However, a panel of immunohistochemical stains is often helpful in the diagnosis. The most common cause of problems in interpretation of biopsies for the diagnosis of SCLC result from sections that are too thick or poorly stained. If the histologic features are classic, it may not be needed. The stains that are useful for the diagnosis of SCLC include a pancytokeratin antibody such as AE1/AE3, CD56, chromogranin and synaptophysin, TTF-1 and Ki-67. If keratin is negative, In 70-80% of SCLC TTF-1 is positive. The main role of Ki-67 is to distinguish SCLC from carcinoids because the proliferation is very high (50-100%) in SCLC.

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    MO02 - General Thoracic and Minimally Invasive Surgery (ID 99)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Surgery
    • Presentations: 11
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      MO02.01 - Is Lower Zone Lymph Node Dissection always Mandatory in Patients with Lower Lobe Lung Cancer? (ID 1851)

      10:30 - 12:00  |  Author(s): H. Ueno, K. Suzuki, A. Hattori, T. Matsunaga, Y. Tsushima, K. Takamochi, S. Oh

      • Abstract
      • Presentation
      • Slides

      Background
      The recent UICC-IASLC classification defines lower zone lymph node metastasis, i.e., paraesophageal and pulmonary ligament lymph nodes metastasis, as p-N2 disease. Due to the relatively rare incidence of lower zone nodal involvement, however, controversies still surround regarding the clinical characteristics and the possible pathway for lower zone lymph node in patients with lower lobe lung cancer.

      Methods
      From 2009 to 2013, 257 consecutive patients underwent lobectomy with mediastinal lymph node dissection for lower lobe lung cancer. For all patients, thin-section CT scan was reviewed to investigate maximum tumor size, location and consolidation status. In a current study, radiologically “solid” tumor was defined as a tumor which constructed only by consolidation without ground glass opacity (GGO) lesions on thin-section CT scan. Several clinical factors were evaluated to identify significant predictive factors of lower zone lymph node metastasis using a multivariate analysis.

      Results
      Twenty (7.8%) patients revealed lower zone lymph node metastasis. Twelve were men and 8 were women. Patients ranged in age from 33 to 81 y, with an average of 63 y. Among them, tumors distributed especially in Segment (S) 10 (50%). All patients showed solid appearance on thin-section CT scan. A univariate analysis revealed that tumor location (S 10 or not) and solid tumors with more than 30mm in diameter were the significant predictors for lower zone lymph node metastasis (p=0.011, 0.033). Based on a multivariate analysis, these two factors were also shown to be independent predictors for lower zone nodal metastasis in patients with lower lobe lung cancer. (p=0.014, 0.034). Furthermore, the frequency of lower zone lymph node metastasis was approximately 24% for patients with solid tumors more than 30mm located in S10. On the other hand, lower zone lymph node metastasis was never seen in patients with c-T1a-b lower lobe lung cancer with GGO component.

      Conclusion
      Although lower zone lymph node metastasis is included in N2 disease, these incidences are extremely rare even in patients with lower lobe lung cancer except for those with radiologically large-sized solid tumor located in S10 field. Thus, selective dissection for lower zone lymph node could be an appropriate operative strategy in patients with small-sized lower lobe lung cancer especially with GGO predominance.

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      MO02.02 - Size decrease of ground-glass nodules should not be end of follow-up, but may be optimal timing of curative surgery (ID 2234)

      10:30 - 12:00  |  Author(s): H. Kaneda, T. Nakano, Y. Taniguchi, T. Saito, T. Konobu, Y. Saito

      • Abstract
      • Presentation
      • Slides

      Background
      As observed in colon carcinogenesis, recent reports support an atypical adenomatous hyperplasia (AAH)–adenocarcinoma sequence in lung carcinogenesis. Recent accumulating experiences based on pathologic–radiologic correlation show that most cases of AAH, adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and lepidic predominant adenocarcinoma can be detected by ground-glass nodules (GGNs)—the radiographic appearance of hazy lung opacity not associated with obscuration of underlying vessels. In this study, we retrospectively reviewed radiological and pathological characteristics of resected GGNs that were radiologically observed for at least 12 months before surgery, and discuss optimal timing of curative surgery.

      Methods
      We retrospectively reviewed clinical charts and chest computed tomography (CT) of patients on whom pulmonary resection was performed between January 2006 and March 2013 at the Kansai Medical University Hirakata Hospital. The definitions of pure GGNs and part-solid nodules were based on the tumor shadow disappearance rate. The histologic classification of adenocarcinoma followed the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma. We evaluated the radiologic findings, such as size change of whole tumor and appearance of solid component, and pathological findings. All statistical tests were performed with JMP software.

      Results
      A total of 568 patients underwent pulmonary resection during the study periods and 404 cases were adenocarcinoma (ADA), including 207 tumors with lepidic growth pattern. Total 32 GGNs of 31 patients were observed in chest CT before surgery for at least 12 months. Mean GGN size before surgery was 18.6 mm and mean follow-up period was 25.8 months. Pathological findings of 32 tumors were 6 AISs, 4 MIAs, 8 lepidic predominant ADA, 13 papillary predominant ADA, 1 acinar predominant ADA. On last CT before surgery, 15 lesions showed pure GGNs and 17 showed part-solid nodules. Thirteen of the 17 tumors showed slight size reduction of GGNs during the follow-up, mostly just before or just after appearance of solid component inside GGNs.

      Conclusion
      Some GGNs showed size reduction during the follow-up with chest CT. Even when mild collapse of the GGNs are observed, you should neither diagnose non-malignant tumors, such as inflammatory nodules, nor decide cessation of follow-up. And instead, we recommend rather careful follow-up in order to identify solid component inside the GGNs. If you confirm appearance of the solid component, the finding would be a sign of progression from AAH/AIS to invasive adenocarcinoma and may be optimal timing of pulmonary resection as curative treatment.

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      MO02.03 - Surgical intervention strategy for postoperative chylothorax after lung resection - clinical analysis of fifty patients who developed postoperative chylothorax (ID 3321)

      10:30 - 12:00  |  Author(s): S. Uchida, K. Suzuki, Y. Miyasaka, Y. Tsushima, K. Takamochi, S. Oh

      • Abstract
      • Presentation
      • Slides

      Background
      Chylothorax is a rare but well-known complication of general thoracic surgery. This study evaluated our treatment strategy for postoperative chylothorax and identified associated predictors.

      Methods
      We retrospectively reviewed 1235 patients who underwent lung resection and systematic mediastinal lymph node dissection for primary lung cancer at our department from January 2008 to September 2012. Postoperative chylothorax patients were analyzed. Chylothorax was diagnosed by the milky aspect of drainage fluid and confirmed by an elevated triglyceride level (>110 mg/dL) in the drainage fluid. We initially treated chylothorax patients conservatively with low fat diet (fat intake < 20 g/day). If this treatment was judged to be ineffective, we tried to do complete oral intake cessation or surgical intervention. Comparisons between conservative and surgical intervention groups were analyzed using Fisher’s exact test. Univariate and multivariate analysis of predictors for surgical intervention was performed using logistic regression analysis. Value of p<0.05 were considered statistically significant.

      Results
      Fifty patients (4.0%) developed postoperative chylothorax. There were 35 men and 15 women with a median age of 63 years (range 33 to 81 years). The operative procedures were pneumonectomy in 2 cases, bilobectomy in 5 cases, lobectomy in 32 cases, segmentectomy in 1 case, and sleeve lobectomy in 10 cases. Forty-one patients (82%) cured with conservative treatment. These patients continued a low fat diet for one month. The remaining 9 patients (8%) underwent surgical intervention at a median of 5.5 days after diagnosis (range 3 to 12 days). Postoperative chest tube drainage (ml/h) until first oral intake was significantly greater in the surgical intervention group than conservative group (37.4±15.7 ml/h vs. 24.7±9.7 ml/h; p=0.003). In multivariate analysis, postoperative chest tube drainage (ml/h) until first oral intake was significant predictor for the chylothorax patient required surgical intervention (p=0.012, Hazard Ratio 1.110, 95% Confidence Interval 1.024-1.205). Four patients (8%) had chest tube drainage exceeding 45 ml/h until first oral intake. Among them 3 patients (75%) required surgical intervention.

      Conclusion
      Postoperative chest tube drainage (ml/h) was independent predictor for surgical intervention in postoperative chylothorax patients. If postoperative chest tube drainage exceed 45 ml/h until first oral intake, we should suspect postoperative chylothorax and consider early surgical intervention.

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      MO02.04 - Safety and long term outcome of repeated lung resection for ipsilateral second primary lung cancer (ID 3048)

      10:30 - 12:00  |  Author(s): M. Tsuchida, K. Togashi, T. Watanabe, T. Hashimoto, T. Koike, S. Sato, T. Shirato

      • Abstract
      • Presentation
      • Slides

      Background
      Repeated lung resection for second primary lung cancer is indicated as an effective treatment in properly selected patients. Among repeated lung resections, surgery for ipsilateral lesion is a challenging modality for thoracic surgeons. We report our experience of repeated lung resection, especially focused on ipsilateral reoperation after anatomical major lung resection.

      Methods
      We retrospectively reviewed patients who had undergone a second lung resection for ipsilateral second primary lung cancer at the 3 institutions between 2000 and 2012. The diagnosis of the second primary lung cancer was based on the criteria from Martini. Variables analysis included clinical and pathologic data including age, sex, c-stage, surgical procedure, p-stage, histology, time interval between the two operations, operative findings, operative morbidity and mortality, as well as long term outcomes. Overall survival was calculated using the Kaplan-Meier method.

      Results
      There were 52 reoperations in 50 patients. Of the 50 patients, 35 were male and 15 were female. The median age at the time of a second operation was 69.9 years (range 51 to 85). The first lung resection was lobectomy in 48 patients and segmentectomy in 2 patients. According to the current TNM classification, p-stage of the first lung cancer was IA in 20, IB in 24, IIA in 3, IIB in 1, IIIA in 1, and IV in 1. The mean value of %vital capacity and forced expiratory capacity in one second /forced vital capacity obtained before the second surgery was 94.7% and 72.3% respectively. The second operation was wedge resection in 28, segmentectomy in 9, right middle lobectomy in 4, right upper lobectomy after lower lobectomy in one, and completion pneumonectomy in 7. The mean interval time between the two operations was 64 months (range, 15-156 months). During second surgery, vascular injury was occurred in 2 patients. Mean volume of blood loss during surgery was 354ml (range, 0 to 3440 ml), and blood transfusion was necessary in 6 patients. Intrapericaridial exposure of the main pulmonary artery was employed in 9 patients due to dense vascular adhesions. There was no operative death. Complications occurred in 9 patients (prolonged air leakage in 5, empyema in 2, heart failure in 1, and delirium in 1). One patient died of pneumonia 5 months after the second operation. Therefore morbidity and hospital mortality was 18% and 2%, respectively. Pathological diagnosis of the second primary lung cancer was adenocarcinoma in 41, squamous cell carcinoma in 9, and sarcoma in 1. P-stage of the second lung cancer was IA in 37, IB in 8, IIA in 1, IIB in 2, IIIA in 1, and IV in 1. The 5-year overall survival after the second operation was 67 %, and more favorable 5-year survival of 77% was observed in p-stage IA.

      Conclusion
      Most second primary lung cancer in this retrospective study was treated in p-stage I. Reoperations for a second primary lung cancer on the same side of the first surgery shows an acceptable morbidity and mortality rate, and provides favorable survival in selected patients with adequate physiologic pulmonary reserve.

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      MO02.05 - DISCUSSANT (ID 3919)

      10:30 - 12:00  |  Author(s): G.E. Darling

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO02.07 - Effect of Obesity on Peri-Operative Outcomes after Robotic-Assisted Pulmonary Lobectomy: Retrospecitve Analysis of 227 Consecutive Patients (ID 2440)

      10:30 - 12:00  |  Author(s): M.R. Thau, K.L. Rodriguez, T. Tanvetyanon, F.O. Velez-Cubian, W.W. Zhang, J. Fontaine, J.R. Garrett, C.C. Moodie, L.A. Robinson, E.M. Toloza

      • Abstract
      • Presentation
      • Slides

      Background
      Attention has increased over the safety and efficacy of robotic-assisted surgeries in recent years. With rates of obesity on the rise, the impact of excessive body weight on surgical outcomes comprises an important concern for administering care. Our purpose was to determine the relationship between preoperative body mass index (BMI) on perioperative complications following robotic-assisted pulmonary lobectomy for at a high-volume tertiary-care referral cancer center.

      Methods
      We retrospectively studied 227 consecutive patients who underwent robotic-assisted pulmonary lobectomy for known or suspected lung cancer. BMI was calculated as being equal to weight in kilograms divided by height in meters squared. We stratified BMI into 4 groups as defined by the World Health Organization (WHO): Underweight (BMI <18 kg/m2), Normal Weight (BMI 18-25 kg/m2), Overweight (BMI 25.01-30 kg/m2), and Obese (BMI >30 kg/m2). Perioperative complications from surgery to discharge from the hospital were assessed and included respiratory failure, hemothorax, pleural effusion, prolonged air leak, subcutaneous emphysema, aspiration, pneumonia, and hypoxia. Hospital length of stay and in-hospital operative mortality were also assessed. Of 227 total patients studied, there were 6 Underweight patients, 87 Normal Weight patients, 71 Overweight patients, and 63 Obese patients. Initially, with the Underweight group omitted due to small sample size, comparison of the remaining three BMI groups revealed that there were no significant increases in peri-operative complication rates, hospital length of stay, or in-hospital operative mortality among the 3 groups, although there were clear trends toward increased morbidity and mortality when patients had higher BMI. Therefore, we compared the peri-operative complication rates, hospital length of stay, and in-hospital operative mortality between Obese and Non-Obese patients.

      Results
      The results are shown in the following table:

      Surgical Complication Non-Obese BMI ≤30 Obese BMI >30 P-value
      N=162, n (%) N=65, n (%)
      Hypoxia or Respiratory failure 6 (3.7) 7 (10.8) 0.04*
      Hemothorax 3 (1.9) 2 (3.1) 0.57
      Effusion or Empyema 2 (1.2) 2 (3.1) 0.34
      Prolonged air leak 30 (18.5) 5 (7.7) 0.04*
      Subcutaneous emphysema 6 (3.7) 2 (3.1) 0.82
      Aspiration 4 (2.5) 2 (3.1) 0.79
      Pneumonia 17 (10.5) 8 (12.3) 0.69
      In-Hospital Operative Mortality 2 (1.2) 2 (3.1) 0.34
      Median Length of Stay (days+SEM) 5 + 0.3 4 + 0.6 0.54
      *statistically significant, p<0.05

      Conclusion
      Our study shows that obesity increases the risk of peri-operative hypoxia or respiratory failure but results in a lower risk of prolonged air leak after robotic-assisted pulmonary lobectomy. However, we found no significant difference in hospital length of stay or in-hospital mortality between obese and non-obese patients. Thus, our study suggests that robotic-assisted pulmonary lobectomy is feasible and safe in obese patients.

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      MO02.08 - The Feasibility of Single-incision Video-assisted Thoracoscopic Surgery in Major Pulmonary Resection (ID 1389)

      10:30 - 12:00  |  Author(s): H.K. Kim, K.H. Kang, Y.H. Choi

      • Abstract
      • Presentation
      • Slides

      Background
      We performed video-assisted thoracoscopic (VATS) lobectomy with one incision for the treatment of malignant or benign lung diseases, and have evaluated the feasibility and safety of this procedure.

      Methods
      Consecutive patients who underwent major pulmonary resection through VATS, using one incision from March 2012 to May 2013 were included in this study. The incision was placed at the 5th intercostal space in the mid-axillary line, approximately 3~5 cm long.

      Results
      A total of 60 patients (male 39, female 21; mean age 60.2 ± 12.53 years old, range 21~83) were included in this study. The preoperative diagnosis was malignant lung disease in 56 patients (93.3%) and benign lung disease in 4 patients (6.7%). Four patients (6.7%) needed a second port during surgery and conversion to thoracotomy was needed in two patients (3.3%). In 54 cases, which were completed by single-incision VATS, lobectomies were done in 50 patients, segmentectomy in 3, and sleeve lobectomy in 1. The resected lobes or segments were right upper in 15 patients, right middle in 3, right lower in 15, left upper in 10, and left lower in 11. In 50 cases, which were completed by a single-incision VATS lobectomy for primary lung cancer, the mean duration of the operation was 148.2 ± 45.29 minutes, and a total number of dissected lymph nodes per patient were 21.3 ± 10.08 (range, 5~55). The chest tube was removed on postoperative day 4.7 ± 1.8, and there was no occurrence of major perioperative morbidity and mortality.

      Conclusion
      Single-incision VATS lobectomy is applicable in the selected cases, and may obtain similar results with the conventional VATS lobectomy, through a certain period of learning curve.

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      MO02.09 - Needle scopic surgery for primary lung cancer: Reduced port surgery in thoracic surgery using fine scope and forceps (ID 1856)

      10:30 - 12:00  |  Author(s): M. Tajiri, T. Omori, Y. Ishikawa

      • Abstract
      • Presentation
      • Slides

      Background
      If a surgical approach is less invasive than a conventional method and can maintain a sufficient technical level equal to a conventional one, it will bring more benefits to patients. We have performed thoracoscopic anatomical segmentectomy and lobectomy for primary lung cancer for more than fifteen years. First we use and slide a 5mm-diameter scope through three or four ports. Then we start the needle scopic surgery(1 port+ 3 punctures method)using a 3mm-diameter scope, which we have used since September 2012. Now we would like to explain this operative procedure and effectiveness.

      Methods
      【Patients】Forty one patients underwent the needle scopic anatomical segmentectomy and lobectomy of the lung between September 2012 to May 2013. They had clinical stage IA or IB lung cancer. We compared the operation time, blood loss volume, post-operative creatinine phosphokinase (CK) and other peri-operative parameters of this method with those of the conventional method using a 5mm-diameter scope which were performed on 73 patients from January 2012 to August 2012. 【Operative procedure】1. We make a 2.5 to 3 cm length skin incision on the 4th or 6th intercostal space of the chest trunk and set the polyurethane-made retractor. We use it as the main port. 2. We puncture the skin with three 3mm-diameter trocars. Then we insert and slide a 3mm-diameter scope and fine forceps through them. We observe thoracic lumen and perform various manipulations using them. 3. Endostaplers, energy devices and electric cautery of which diameters are larger than 3mm go into the thoracic lumen through the main port. 4. Finally we set the chest tube within the main port incision at the end of surgery.

      Results
      We performed 8 segmentectomies and 33 lobectomies of the lung using this method in forty-one cases for the lung cancer. We dissected mediastinal nodes in all cases. We had no cases that were converted to the conventional method. However we elongated the incision of one puncture from 3 mm to 10mm in three cases in order to insert endostaplers for dissecting pulmonary veins and arteries. Mean operation time was 219±49 minutes. Mean blood loss volume was 20.5±28.4 ml. They were not significantly different from those of the conventional method. Post-operative peak titers of CK of this method were significantly lower than that of the conventional method. We had no severe intraoperative accidents or postoperative complications. All patients were smoothly discharged.

      Conclusion
      We were able to successfully perform the needle scopic surgery for lung cancer as well as conventional thoracoscopic surgery. Though some surgeons have tried the single port method for thoracic surgery as another less invasive surgery, we think the needle scopic method is more suitable for thoracic surgery. Because thoracic surgery needs observations and manipulations which are in the wider range of the inner space than that of the abdomen. This method would be the optimal and optional method if we appropriately select cases.

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      MO02.10 - Fluoroscopy-assisted thoracoscopic resection of pulmonary nodules after computed tomography-assisted bronchoscopic metallic coil marking (ID 1532)

      10:30 - 12:00  |  Author(s): T. Miyoshi, M. Aoyama, S. Inoue, N. Hino, M. Tsuyuguchi

      • Abstract
      • Presentation
      • Slides

      Background
      With advances in computed tomography (CT), small pulmonary lesions previously unseen on chest radiographs are being increasingly detected. Among lesions less than 10 mm in size, a considerable number of malignancies have been reported. To localize small and deeply situated pulmonary nodules during thoracoscopy with roentgenographic fluoroscopy, we developed a marking procedure that uses a metallic coil and a coin.

      Methods
      Thirty-two patients underwent video-assisted thoracoscopic surgery for removal of 33 pulmonary lesions. Fluoroscopy-assisted thoracoscopic surgery after CT-assisted bronchoscopic metallic coil marking was performed using an ultrathin bronchoscope under fluoroscopy viewing a coin on a patient’s chest wall. The coin was simulated a pulmonary lesion by the CT findings, and it was put on the patient's chest wall. During thoracoscopy, a C-arm-shaped roentgenographic fluoroscope was used to detect the radiopaque nodules. The nodule with coil markings was grasped with forceps and resected in partial resection or segmentectomy under fluoroscopic and thoracoscopic guidance.

      Results
      The marking procedure took 10 to 49 minutes from insertion to removal of the bronchoscope. There were no complications from the marking, and all 33 nodules were easily localized by means of thoracoscopy. The metallic coil showed the nodules on the fluoroscopic monitor, which aided in nodule manipulation. Nodules were completely resected under thoracoscopic guidance, in partial resection in 19 cases, in segmentectomy in 9 cases and lobectomy after partial resection in 4 cases. The pathologic diagnosis was primary adenocarcinoma in 16 patients, primary lung cancer except adenocarcinoma in 2 patients, pulmonary metastases in 11 patients, an atypical adenomatous hyperplasia in 1 patient, a hamartoma in 1 patient and a nontuberculous mycobacteriosis in 1 patient. One case of a bronchiolo-alveolar adenocarcinoma with an extensive two segments was performed a curative segmentectomy.

      Conclusion
      In this study, CT-guided transbronchial metallic coil marking with an ultrathin bronchoscope with a coin on a patient’s chest wall after CT-assisted stimulation was found to be feasible and safe. In our previous report, CT had been needed at least three times, but this method needed only twice CT scan. It might be a useful method not only for making a diagnosis but also for therapeutic resection in selected early lung cancers.

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      MO02.11 - Video-Assisted Thoracic Surgery, Hybrid, versus Open Thoracotomy for Stage I Non-Small Cell Lung Cancer - A Propensity Score Analysis Based on a Multi-institutional Registry (ID 3034)

      10:30 - 12:00  |  Author(s): J. He, C. Cao, T.D. Yan, Q. Wang, G. Jiang, W. Shao, L. Liu, D. Liu, Z. Wang, Z. Zhu, Q. Zhao, D. Wang

      • Abstract
      • Presentation
      • Slides

      Background
      We conducted a multi-institutional study comparing VATS lobectomy to Hybrid, and conventional open lobectomy for unmatched and propensity score-matched patients with stage I NSCLC in an attempt to stratify any potential differences in perioperative outcomes and long-term survival outcomes among the three procedures in patients with stage I NSCLC on a homogeneous well-balanced large population from multi-institutions.

      Methods
      Between January 2001 and December 2008 in eight institutions from the People’s Republic of China, a total of 2485 patients with stage I NSCLC who underwent lobectomy via c-VATS, Hybrid, or open thoracotomy were entered into the current multi-institutional registry. One thousand and fifty-six patients (42.5%) underwent c-VATS lobectomy, 273 patients (11.0%) underwent Hybrid lobectomy, and 1156 patients (46.5%) underwent open lobectomy. Of the patients who attempted to undergo c-VATS lobectomy, 65 were converted to assisted-VATS and 49 patients were converted to open lobectomy.

      Results
      After propensity-matching, c-VATS, Hybrid, and open lobectomy patients were similar in regards to age, gender, histological type and pathological TNM staging. Median operative time was 156.16±17.08 min in open lobectomy group, higher than in c-VATS lobectomy group (145.39±13.1 min) and Hybrid lobectomy group (148.86±11.62) before matching (P<0.001), after matching, it was 154.5±16.89 min, 145.41±12.17 min, and 148.81±11.63 min in open, c-VATS, and Hybrid lobectomy group, respectively (P<0.001). Transfusion occurred in 4 (12.9%) patients in c-VATS group and 6 (19.4%) patients in Hybrid group, both of them lower than in open lobectomy group of 21 (67.7%) patients (P=0.003). However, after matching, there was no statistical difference among three groups, 5 (41.7%) patients, 1 (8.3%) patients, and 6 (50.0%) patients in open, c-VATS, and Hybrid group, respectively (P=0.112). After selecting the propensity-matched patients, the 5-year survival of 78%, 74% and 76% in patients who underwent c-VATS, Hybrid, and open lobectomy, respectively. The perioperative mortality rate was 1.1% for the open group, 1.0% for the Hybrid group, and 0.8% for the VATS group. Two prognostic factors were independently associated with improved survival outcome in multivariate analysis: age < 60 (p = 0.01) and smoking history (p = 0.012). When comparing the three propensity-matched populations, patients who underwent c-VATS lobectomy had similar long-term survival outcomes to patients who underwent Hybrid or conventional thoracotomy (p = 0.770).

      Conclusion
      The present multi-institutional study represents the largest dataset evaluating surgical outcomes of patients who underwent c-VATS or Hybrid for NSCLC. VATS lobectomy for NSCLC was not associated with inferior long-term survival compared to Hybrid or conventional thoracotomy.

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      MO02.12 - DISCUSSANT (ID 3920)

      10:30 - 12:00  |  Author(s): M. Windsor

      • Abstract
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      Abstract not provided

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    MO22 - Advanced Disease and Outcomes (ID 103)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Surgery
    • Presentations: 12
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      MO22.01 - High procedure volume is strongly associated with improved survival after lung cancer surgery (ID 1704)

      10:30 - 12:00  |  Author(s): M. Luchtenborg, S.P. Riaz, V.H. Coupland, E. Lim, E. Jakobsen, M. Krasnik, R. Page, M. Lind, M.D. Peake, H. Moller

      • Abstract
      • Presentation
      • Slides

      Background
      Surgical resection is the first line treatment offered to patients with early stage non-small cell lung cancer (NSCLC) who are considered medically fit. Many studies have shown that patients undergoing surgery for lung cancer benefit from receiving treatment in hospitals where high numbers of lung cancer resections are carried out. This study explores the association between hospital volume and survival among all NSCLC patients diagnosed in England who underwent surgical resection and takes into account the differences in case selection and propensity to resect.

      Methods
      We analysed data on 134,293 patients with NSCLC diagnosed in England between 2004 and 2008 of whom 12,862 (9·6%) underwent surgical resection. Hospital volume was defined according to the number of patients with resected lung cancer in each hospital in each year of diagnosis. Cox proportional hazard regression analyses were used to assess the association between hospital volume and survival among resected patients. We calculated multivariable hazard ratios according to hospital volume, with adjustment for potential confounders (sex, age, socioeconomic deprivation, comorbidity and resection quintile). In addition, to account for the risk of death potentially varying between groups of patients treated within a given hospital, a shared frailty Cox model was used, with hospital as a random effect. The follow-up period was divided into three pre-defined periods: 0-30 days, 31-365 days and >365 days post-surgery.

      Results
      There was increased survival in hospitals performing more than 150 surgical resections compared with those carrying out less than 70 [HR 0·78 (95% CI 0·67-0·90), p~trend~ <0·01]. The association between hospital volume and survival was present in all three periods of follow-up, but the magnitude of the association was greatest in the period 0-30 days (HR for the 150+ hospital volume group compared with less than 70: 0·58, 95% CI 0·38-0·89) and smallest in the period after 365 days (HR 0·84, 95% CI 0·71-0·99).

      Conclusion
      High volume hospitals have higher resection rates, operate on patients who are older, have lower socioeconomic status, more comorbidities and despite that they achieve better survival, most notably in the early post-operative period.

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      MO22.02 - Resection rate, as a measure of the effectiveness of surgical treatment of lung cancer (ID 2428)

      10:30 - 12:00  |  Author(s): T.M. Orlowski, P. Rudzinski

      • Abstract
      • Presentation
      • Slides

      Background
      Surgery is the most effective way to treat lung cancer. There are significant differences between countries in the effectiveness of surgical treatment. The resection rate differe from 10 to over 20% in Europe

      Methods
      The National Registry of lung cancer in Poland comprises over 95% of patients with NSCLC treated with surgery. Resection rate (RR) is monitored for 20 years in Poland. Each year RR is calculated by the following formula: R R = (number of resected patients with NSCLC/ number of new cases) x 100 This ratio is calculated for each and even the smallest administrative area (16 provinces and 380 districts). To achieve such a result- the patient's place of residence is taken into account rather than a place where he had his surgery. This allows to determine how many of the patients in particular area have been diagnosed in certain stage of acceptance (mainly I and II) In year 2012, 3591 patients had surgery in Poland. The incidence of NSCLC this year was 22 348 new cases.

      Results
      The RR in Poland in 2012 was 16.1%. The difference in many provinces ranged from 10.2% - 22%. In few districts the RR was reported from 0% - 46%. 79% of patients were in stage I and II, 11.2% in IIIa, 2.7% in IIIb and and 1.9% in stage IV. Comparing to 2011, resection rate increased by 5%, and within five years - 16.8%. Since 2010 in the areas with the lowest RR a screening program with low-dose computed tomography was implemented. The RR increased from 1,2 to 22% in majority of districts (14/16)

      Conclusion
      1 Implementation of the resection rate allows to monitor the effectiveness of early diagnosis of lung cancer in different areas 2 Monitoring of the resection rate allows to improve the efficiency of diagnosis of lung cancer in areas where detection was low. 3. Regular evaluation of the RR supports the efforts to improve the results of surgical tratment of NSCLC

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      MO22.03 - Postoperative Rehabilitation and Follow-up - a randomized study. (ID 2422)

      10:30 - 12:00  |  Author(s): E. Jakobsen, O. Dan Joergensen, L. Ladegaard, S. Petersen, P. Mikkelsen, I. Aagaard, P. Licht

      • Abstract
      • Presentation
      • Slides

      Background
      The importance of postoperative follow-up and rehabilitation after lung cancer surgery remains a controversial topic. Previous studies have showed that follow-up programs did not influence survival but at that time there was little focus on the effects of rehabilitation. Introduction of new diagnostic procedures, improvements in treatment modalities and increasing awareness on quality of life after treatment has changed guidelines and recommendations for follow-up programs. There is little evidence for these recommendations which prompted us to conduct a randomized study to evaluate the effect of an intense follow-up program on survival and quality of life for patients undergoing surgery for lung cancer (NSCLC).

      Methods
      Between January 2003 and April 2008 a total 197 NSCLC patients were included in the study after undergoing surgical resection (wedge, lobectomy or pneumonectomy) through a posterolateral thoracotomy. Adjuvant chemotherapy was offered to stage Ib - IIIa. Postoperatively patients were randomized to either active rehabilitation and follow-up (POREFU, N=103) or passive follow-up (Standard, N=94). Patients in the POREFU group had intensive follow-up in the form of annual clinical evaluation, chest X-ray, chest CT, bronchoscopy and EBUS (Endobronchial Ultrasound) for 5 years. In the POREFU group patients were also evaluated by a nurse and a physiotherapist after 6 weeks, 6 months and at annual controls. When indicated, interventions were established to correct patient symptoms. Patients in the standard treatment group were offered a chest X-ray one year after surgery and a clinical examination by their family doctors upon request. Quality of life in both groups was assessed after 6 weeks, 6 months, 12 months and 2, 3, 4 and 5 years evaluating EORTC QLQ-C30/LC13. All survivors were followed for 5 years.

      Results
      Figure 1There was no significant difference in survival between the two groups (Kaplan Meier plot). There was a significant difference between the two groups in favour of active follow-up regarding Global health status as well as “Physical”, “Role” and “Emotional” functioning and POREFU patients had significant less pain and fatigue. There was no statistical significant improvement of other symptoms or functional issues.

      Conclusion
      This randomized trial shows that a follow-up program with an additional focus on rehabilitation and intervention towards reported symptoms in patients operated for NSCLC significantly improves quality of life but has no effect on overall survival.

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      MO22.04 - Standardising the Management of Patients Following Lung Resection: Does It Improve Outcome? (ID 2114)

      10:30 - 12:00  |  Author(s): A.J. Sharkey, J. Coad, R. Owen-Smith, A. Cale, M. Chaudhry, S. Griffin, M. Loubani, M. Cowen

      • Abstract
      • Presentation
      • Slides

      Background
      There is marked variation in the management of Thoracic surgical patients post-operatively, both between individual surgeons and surgical centres. This lack of standardisation can lead to staff and patient dissatisfaction, and differing outcomes for patients. In 2012 we introduced a more standardised approach to the management of patients undergoing Thoracic surgery under the care of one consultant (Consultant A). This was based on the ‘fast-track’ protocol published in 2001 by Cerfolio et al. We aimed to determine whether this approach to patient management has affected patient outcome.

      Methods
      Data for all patients undergoing lung resection at a single centre from April 2012 to March 2013 were collected. The patients were split into two groups, those under the care of Consultant A (group A), and those under the care of the remaining 4 consultants (group B). Group A were managed according to the new standardised pathway which included; stopping the routine use of suction unless clinically required, chest drain removal with cessation of an air leak and drainage below 400mls in 24 hours, and epidural catheter removal on post-operative day 2. Those in group B were managed according to the instructions of the operating Consultant, or the surgical registrars covering the ward. Pre-operative, operative and post-operative data were collected and analysed. Patients were then propensity matched using operation and age.

      Results
      Two hundred and thirty one patients were identified. Overall mean length of stay for all patients in group A was 5.65 days (SD±4.68), and in group B; 9.97 days (SD±12.06), p<0.001. Of these patients 94 were suitable for propensity matching. There were no significant differences found in the proportion of patients with benign versus malignant pathology, the number with primary lung cancer, or in the stage of the resected primary lung cancer. In-hospital mortality for both groups was one patient (2.13%). There was a lower number of drains inserted peri-operatively in group A patients (p<0.001). Mean time to drain removal (all drains) was 3.42 days (SD±6.35) for group A and 4.24 days (SD±3.08) for group B, p=0.026. Mean length of stay for group A was 6.00 days (SD± 4.86) and for group B 10.33 days (SD±19.29), p=0.042.

      Conclusion
      Standardising care following surgery has been shown to improve patient safety, and both patient and staff satisfaction. We have found that reducing variation, and following a validated management pathway, significantly reduces the time to chest drain removal and in-hospital length of stay for patients undergoing lung resection for any pathology. We are currently analysing the various elements of the pathway to determine which specific factors impact patient outcome. Further work is required to determine the effect these differences have on patient reported outcome measures, including overall satisfaction.

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      MO22.05 - Surgery in octogenarians with early stage non-small cell lung cancer: A SEER database analysis (ID 2923)

      10:30 - 12:00  |  Author(s): A.K. Ganti, V. Shostrom, A. Marr, K.M. Islam, R.P. Lackner, K. Trujillo, A. Kessinger

      • Abstract
      • Presentation
      • Slides

      Background
      Surgical resection is the standard of care for patients with early stage non-small cell lung cancer (NSCLC). However outcomes in older patients, especially octogenarians, following resection have not been studied in detail. This analysis was undertaken to evaluate the variations in patterns of care over time and outcomes following resection in octogenarians with early stage NSCLC.

      Methods
      Patients 80 years of age and older diagnosed with clinical stages I and II NSCLC, between 1988 and 2007, were identified from the SEER database. Data abstracted included age at diagnosis, stage, gender, race, histology, year of diagnosis and cause of death. The type of surgical resection was not available for a majority of patients and hence was not considered. Overall survival was estimated as the time from the date of diagnosis to death, or date of last contact (if censored). Factors associated with survival were assessed using regression analysis based on the Cox proportional hazards model. Temporal trends in survival were compared using log-rank test. Lung cancer specific survival (LCSS) was also estimated in these patients and temporal trends were compared using log-rank tests.

      Results
      Six hundred and forty-nine patients ≥80 years of age, who underwent surgical resection for stages I and II NSCLC, were identified. The majority of these patients had stage I disease (n=549), were white (n=586) and had an adenocarcinoma (n=325). Females comprised 50.6% of stage I, but only 37% of stage II patients. Factors associated with worse overall survival on multivariate analysis in this cohort were: increasing age [Hazard ratio (HR) - 1.08; 95% CI - 1.03, 1.12], male gender (HR - 1.33; 95% CI - 1.07, 1.65), stage II (HR - 2.21; 95% CI - 1.71, 2.87) and squamous histology (HR - 1.36; 95% CI - 1.07, 1.74). The percentage of patients undergoing surgery increased over time. Of the patients who underwent surgery 8.6% were diagnosed between 1988-1992, 16% between 1993-1997, 24.2% between 1998-2002 and 51.2% between 2002-2007. Despite this the median survival was not significantly different over these time periods. Median survivals for the four different time periods were as follows: 1988-1992 – 3.9 years; 1993-1997 – 3.2 years; 1998-2002 – 3.8 years; 2002-2007 – 3.3 years (p = 0.09). These are comparable to those reported previously in younger patients (ages 65-75 years) (5.92 years - stage I, 2.6 years - stage II). Similarly lung cancer specific survival was not significantly different between the different time points. Median LCSS for the four time periods were 9.2 years, 6.8 years, 7.9 years, and not reached, respectively (p = 0.51).

      Conclusion
      Among octogenarians who had surgical resection for lung cancer, increasing age, male gender, higher stage and squamous histology were associated with worse survival. Despite an increased incidence of surgical resection for octogenarians, outcomes remained unchanged between 1988 and 2007. Octogenarians, when carefully selected, are capable of experiencing a similar advantage provided by surgical resection of early stage non small cell lung cancer as younger patients.

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      MO22.06 - DISCUSSANT (ID 3927)

      10:30 - 12:00  |  Author(s): S. Knight

      • Abstract
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      Abstract not provided

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      MO22.07 - Local treatment of oligometastatic recurrence after surgery for non-small cell lung cancer. (ID 932)

      10:30 - 12:00  |  Author(s): T. Yano, T. Okamoto, A. Haro, S. Fukuyama, D. Kawano, Y. Morodomi, T. Yoshida, M. Kohno, Y. Maehara

      • Abstract
      • Presentation
      • Slides

      Background
      We previously reported a retrospective study indicating the prognostic impact of local treatment of postoperative oligometastases in patients with non-small cell lung cancer (NSCLC) (Yano T et al. J Surg Oncol 2010;102:852-855). However, previous studies have not been sufficient to determine the therapeutic significance of local treatment for postoperative oligometastases since the conclusions were based on retrospectively collected data and the assessment of overall survival. In the present study, we prospectively observed postoperative oligometastatic patients and investigated the effects of local treatment on progression-free survival (PFS).

      Methods
      Using a prospectively maintained database of patients with completely resected NSCLC treated between October 2007 and December 2011, we identified 52 consecutive patients with postoperative recurrence. Of these patients, 31 suffering from distant metastases alone without primary site recurrence were included in this study. In order to exclude cases of second primary carcinoma of the lungs, the criteria of Martini and Melamed, modified by Antakli et al., were used to differentiate between second primary lung cancer and pulmonary metastasis. According to the definition of ‘oligometastases’ as limited recurrence potentially controlled with local treatment, 17 patients had oligometastatic disease. The number of metastases was less than four.

      Results
      The oligometastatic sites included the lungs in five patients, the brain in four patients, bone in four patients, the lungs and brain in two patients, the adrenal glands in one patient and soft tissue in one patient. Fifteen of the 17 patients first received local treatment. Three patients (lung, adrenal gland, soft tissue) underwent surgical resection, and the remaining 12 patients received radiotherapy. The median PFS was 33 months in the oligometastatic patients who received local treatment. There were seven patients with a PFS of longer than two years. The metastatic sites in these patients varied, and the number of lesions in three patients was two or three. On the other hand, the two remaining patients first received a systemic chemotherapy of their own selection. The PFS of these two patients was five and 15 months, respectively.

      Conclusion
      Both our previous retrospective study and the present study favor a choice of local treatment in patients with postoperative oligometastatic NSCLC.

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      MO22.08 - Surgical Resection of Stage IIIA-N2 non-small cell lung cancer: Should we still talk about the futile thoracotomy? (ID 825)

      10:30 - 12:00  |  Author(s): O. Mercier, E. Fadel, M. De Perrot, T. Pierard, S. Mussot, D. Fabre, F. Leroy Ladurie, B. Besse, C. Le Pechoux, T. Le Chevalier, P. Dartevelle

      • Abstract
      • Presentation
      • Slides

      Background
      Stage IIIA-N2 non-small cell lung cancer (NSCLC) is currently mainly managed with chemotherapy and radiation therapy with limited outcome. Whether surgical resection should be offered to patients with resectable IIIA-N2 NSCLC as part of a multi-modality approach with adjuvant or neoadjuvant treatment remains unclear. We sought to determine the long-term result of resected IIIA-N2 NSCLC in a single institution.

      Methods
      We reviewed the charts from a consecutive series of 263 patients with a mean age of 62 years (range, 37-68) undergoing lung resection and complete en bloc lymph node dissection for IIIA-N2 NSCLC from 01/2000 to 12/2011. Clinical N2 (cN2) patients were diagnosed preoperatively on chest CT scan and/or PET scan and were histologically proven by mediastinoscopy or EBUS. Patients with cN2 with a single site of mediastinal disease were occasionally treated with surgery upfront followed by adjuvant chemotherapy with or without radiation (cN2 adj, n=70). The remaining patients with cN2 disease were treated with neoadjuvant therapy followed by surgery (cN2 neoadj, n=55). Minimal N2 patients were diagnosed postoperatively on final pathology report and received adjuvant therapy (mN2, n=138).

      Results
      Lung resection was a pneumonectomy in 75 patients and a lobectomy in 188 patients with a post-operative mortality of 1.3% and 3.1%, respectively. Adjuvant chemo- or chemoradiation therapy was administered in 181 patients. The overall 5-year survival was 43.6%, with no significant difference between the type of lung resection (pneumonectomy: 38.9% vs. lobectomy: 45.5%, p=0.18) or the number of mediastinal lymph node site involvement (1 site 44.8% vs. 37,7% for multiple sites, p=0.9). Long-term survival tended to be better for mN2 compared to cN2 (5-year survival of 50.4% vs. 35.9%, respectively; p=0.08). However, survival for cN2 was similar between neoadjuvant and adjuvant therapy (5-year survival of 30.3% vs. 40.2%, respectively; p=0.53). The number of mediastinal lymph node site involvement did not impact survival in patients with cN2 disease (1 site 37.6% vs 27.6% for multiple sites, p=0.59).

      Conclusion
      Surgery for Stage IIIA-N2 NSCLC achieved good long-term survival when combined with chemotherapy or chemo-radiation therapy in well selected patients. Long-term survival was similar in patients with clinical N2 disease whether they received adjuvant or neoadjuvant therapy. Surgery should be considered as part of a multimodality treatment for patients with stage III-N2 NSCLC.

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      MO22.09 - Thoracoscopic half carina resection and bronchial sleeve resection for central lung cancer (ID 2083)

      10:30 - 12:00  |  Author(s): X. Xu, H. Chen, W. Yin, W. Shao, X. Xiong, J. Huang, J. He

      • Abstract
      • Presentation
      • Slides

      Background
      The objectives of this study were to report the surgical techniques and clinical outcome of thoracoscopic half carina resection and thoracoscopic bronchial sleeve resection for central lung cancer.

      Methods
      Between January 2011 and November 2012, 675 patients with lung cancer underwent radical surgery by thoracoscopy, 49 (7.3%) underwent bronchial sleeve resection. Among 49 patients, 20 (41%) received thoracoscopic bronchial sleeve lobectomy. Perioperative variables and postoperative outcomes of these cases were analyzed to evaluate the technical feasibility and safety of this operation.

      Results
      In one patient, right upper lung sleeve resection was combined with half-carinal resection and reconstruction. In another, right medial lung sleeve resection was combined with lower right dorsal segment resection. The average time of surgery was 239 min (range, 142-330 min, 239±51 min), and the average time of airway reconstruction was 44 min (range, 22-75 min, 44±17 min). The intraoperative blood loss averaged 207 ml (range, 80-550 ml, 207±96 min). The median postoperative hospital stay was 10 days (interquartile range, 8-12 days). Postoperatively, extubation was achieved in the recovery room without further need for mechanical ventilation. None of the patients developed anastomotic leak. Perioperative mortality was not observed.

      Conclusion
      Thoracoscopic bronchial sleeve resection can be considered a feasible and safe operation for selected patients with central lung cancer. The complicated anastomosis technique of half carina resection was feasible.

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      MO22.10 - Surgery after Concurrent Chemo-Radiation with 55 Gy in 20 Fractions over four weeks with full dose Platinum and Vinorelbine (ID 3447)

      10:30 - 12:00  |  Author(s): J. Maguire, J. Littler, V. Kelly

      • Abstract
      • Presentation
      • Slides

      Background
      Concurrent chemo-radiation is the standard of care for patients with inoperable stage III NSCLC and good performance status. Following concurrent chemo-radiation some patients may have operable disease, and surgery may be considered to improve the prospects of cure for patients with negative mediastinal nodes and evidence of residual activity in the primary tumour. Surgery is usually not considered for patients who have received radiation doses higher than 45 Gy in 2 Gy daily fractions because of the perceived risk of post operative complications.

      Methods
      Our standard concurrent chemo-radiotherapy regimen comprises 55 Gy in 20 fractions of 2.75 Gy per day, given over four weeks with cisplatinum 20 mg/m[2] given with radiotherapy fractions 1-4 and 16-19, and vinorelbine 15 mg/m[2 ]IV (40 mg/m[2] orally for patients without dysphagia) with fractions 1, 6, 15 and 20. Twenty-two patients at the Liverpool Heart and Chest Hospital have undergone thoracotomy with a view to resection of residual tumour after completion of this concurrent chemo-radiotherapy schedule.

      Results
      Resection of residual disease was achieved in 21 out of 22 cases. In one patient, resection was not possible due to dense fibrosis and adhesions at the tumour site. Five patients underwent pneumonectomy, 15 lobectomy and one underwent wedge resection. There was one death in the 30 days following surgery and one patient developed a fistula at 4 months. Histological examination of resection specimens confirmed complete histological response in 14 out of 21 cases (66%). Median survival for was 93.8 months, with 5 year survival of 58.8% and 27.6% of patients surviving 10 years from start of treatment.

      Conclusion
      Surgical resection is feasible after concurrent chemo-radiation to a dose of 55 Gy in 20 fractions over 4 weeks. The remarkably high complete histological response rate in this series confirms the effectiveness of a strategy to minimise accelerated repopulation by using hypofractionated radiotherapy with cisplatinum and vinorelbine over four weeks.

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      MO22.11 - Prospective Study of Surgery with Curative Intent and Intraoperative Photodynamic Therapy to Achieve Long-term Pleural Control and Improve Overall Survival for Patients with Non-small Cell Lung Cancer with Pleural Dissemination (ID 3141)

      10:30 - 12:00  |  Author(s): C.B. Simone, K.M. McKay, M.J. Culligan, D. Sterman, E. Alley, T.M. Busch, E. Glatstein, S.M. Hahn, K.A. Cengel, J. Friedberg

      • Abstract
      • Presentation
      • Slides

      Background
      Non-small cell lung cancer (NSCLC) with pleural spread carries a dismal prognosis of 6-9 months median survival. Standard treatment is palliative chemotherapy. Surgery typically has no role, with studies showing no overall survival (OS) benefit and high rates of local recurrence of up to 90% due to microscopic residual disease following resection. This study investigated the use of surgery with the intent of achieving a gross total resection and intraoperative photodynamic therapy (PDT) to target microscopic residual disease for patients with NSCLC with pleural metastasis to improve local control and OS.

      Methods
      All patients with NSCLC with pleural metastasis treated with definitive surgery and PDT (porfimer sodium, 24hr drug-light interval, 630nm, 30-60J/cm[2]) from 1997-2012 on either of two IRB-approved prospective clinical trials were assessed. Progression-free survival (PFS) and OS were defined as the time from surgery to recurrence and death, respectively, or to last contact. Pleural control was defined as absence of ipsilateral pleural disease after surgery, whereas locoregional control was defined as absence of lung parenchymal or intrathoracic nodal disease.

      Results
      34 consecutive patients were assessed, all with ECOG performance status 0-1. The cohort was 50% male, predominantly Caucasian (85%), and a median of 55yrs at the time of surgery (range, 35-73yrs). Most had adenocarcinoma (79%), clinical N2 nodal metastasis (64%), and received neoadjuvant chemotherapy (94%) and/or radiotherapy (12%). Over half (56%) underwent pneumonectomy, whereas 38% received a lesser anatomic resection. Two patients were found intraoperatively to have unresectable disease due to pericardial effusion (n=1) or trans-diaphragmatic extension (n=1). Pathologic staging was pT4N0 (24%) or pT4N2 (76%). Four patients (3/19 pneumonectomy, 1/13 lung-sparing) suffered peri-operative mortality (day 11-98), with one death attributable to PDT (ARDS, day 11). Following surgery/PDT, 59% of patients received mediastinal radiotherapy (median 50.4Gy/1.8Gy) and 50% received chemotherapy. Pleural recurrence rates and OS were similar for patients undergoing pneumonectomy or other procedures (p>0.05 for both). Cohort median OS was 21.4 months (0.4-161.1 months), and survival rates were 59% at 1yr and 41% at 2yrs. Median overall PFS was 7.5 months, with numerous patients achieving durable disease-free intervals (mean PFS 18.4 months). Median pleural PFS was 13.6 months, with pleural recurrences occurring in only 32%. Overall, 79% experienced recurrence or unresectable disease progression, and distant failure was most commonly observed (53%).

      Conclusion
      This study demonstrates that surgery and intraoperative PDT can achieve durable local control and prolonged survival for NSCLC patients with pleural dissemination. Compared with current standard treatment, which offers a median survival of 6-9 months from pleural metastasis diagnosis, our cohort lived a median of 24.7 months from pleural diagnosis and 21.4 months from surgery/PDT. This study also demonstrates that surgery/PDT can be performed with acceptable morbidity. Distant recurrence was the most common failure, indicating need for improved adjuvant systemic therapy. These results are sufficiently encouraging to warrant further study and suggest that stage IVA NSCLC patients with pleural dissemination, good performance statuses, disease limited to one hemithorax, and of the mind to be aggressive about their disease could be considered for this investigational treatment approach.

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      MO22.12 - DISCUSSANT (ID 3928)

      10:30 - 12:00  |  Author(s): B.E. Louie

      • Abstract
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      Abstract not provided

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    MS13 - Statistics of Personalised Medicine (ID 30)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Statistics
    • Presentations: 4
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      MS13.1 - A Review of Randomised Trials in Lung Cancer (ID 516)

      14:00 - 15:30  |  Author(s): R. Stephens

      • Abstract
      • Presentation
      • Slides

      Abstract
      There is a long and distinguished history of clinical trials investigating the treatment of lung cancer dating back to the 1950’s. One of the first such trials to be published looked at the use of nitrogen mustard and DON (6-diazo-5-oxo-L-norleucine) in patients with various cancers including bronchogenic carcinoma[1], and probably the first published randomized trial specifically for lung cancer patients compared surgery and supervoltage radiotherapy[2]. Continued progress in treatment relies on randomized clinical trials and meta-analyses, and a review was undertaken in 2003 to assess the quality and quantity of all published randomized lung cancer treatment trials[3]. This showed that, of nearly 1000 trials, only 4 accrued more than 1000 patients, and that clinicians (and patients) could only rely on a few meta-analyses to guide treatment decision making. The review called for greater global collaboration to design and run large trials to improve the survival rates and quality of life of lung cancer patients. Ten years on, an update and extension of the 2003 review has been undertaken, to see what changes have occurred, what patterns have emerged, and whether the data will help the design of future trials. The Cochrane Library was used as the e-library, as it contains some abstracts from major meetings, as Song et al[4] estimate that up to 50% of all trials are not fully published. In addition to sample size, information was collected regarding the histological subgroup studied, the treatment modality investigated, the trial design, the outcome and the country of affiliation of the first author. A search of ‘(lung OR bronchus) AND (cancer OR carcinoma)’ in Sept 2012 produced 7130 reports (5218 full papers and 1912 meeting abstracts) classified by the Cochrane Library as ‘trials’. However, as the inclusion of meeting abstracts was found to be inconsistent, the results presented here are based only on the full publications. A total of 1792 randomized clinical trials of lung cancer were identified, of which 1677 included the sample size in the title or abstract, 49 did not, and in the remaining 66 the abstract could be accessed. An analysis of the 1677 trials with sample size stated showed that: There was an increasing number of randomized trials, mainly due to an increasing number of randomized phase II trials[5] Only 20 trials included >1000 patients, and 48% had less than 100. The median sample size has remained unchanged for 40 years (~100 patients) although the median sample size for those designated as randomized phase III trials has increased from ~200 to ~400 patients over the last 10 years In nearly half of the trials the primary research question addressed chemotherapy, 15% supportive care, 8% radiotherapy and only 1% surgery Of those that indicated the histology, trials of NSCLC cancer accounted for 73% The country producing the most trials (397) was the USA, but China is now the second country, and published the most trials over the last 10 years. Although there are limitations of this review (it is necessarily several years out of date, is only looking at the title and abstract of trials on the Cochrane Library, is complicated by multiple reporting of trials, etc), its strengths are the longitudinal overview and comprehensive inclusion criteria which substantially extend the results reported by Subramanian et al[6] who compared ongoing trials of medical treatment for NSCLC in 2012 with those in 2009. The need to improve the quantity and quality of trials in lung cancer has been highlighted for more than 20 years[7-10 ]as trials have not been sufficiently large, or poorly designed, or unnecessarily duplicated previous work[11-12]. In contrast, well designed trials make best use of researchers’ time, funders’ money and patients’ goodwill[13], and may inform future work. The results of the current review suggest that greater global collaboration is still required to run large trials that will produce reliable results and influence practice worldwide. Updated and more detailed results will be presented. References 1. Krantz S, et al for the Veterans Administration Cancer Chemotherapy Study Group. A Clinical Study of the Comparative Effect of Nitrogen Mustard and DON in Patients With Bronchogenic Carcinoma, Hodgkin's Disease, Lymphosarcoma, and Melanoma. JNCI 1959, 22, 433-9 2. Morrison R. The treatment of carcinoma of the bronchus. A clinical trial to compare surgery and supervoltage radiotherapy. Lancet 1963, 1, 683-4 3. Stephens R. The need for a world strategy for clinical trials. Lung Ca 2003, 41 (suppl 3), S96 (abs E-77) 4. Song F, et al. Dissemination and publication of research findings: an updated review of related biases. Health technology Assessment 2010, 14, No. 8 5. Turrisi AT. Creeping phase II-ism and the Medical Pharmaceutical Complex: Weapons of Mass Distraction in the War against Lung Cancer. JCO 2005, 23, 4827-9 6. Subramanian J, et al. Review of Ongoing Clinical Trials in NSCLC - a status report from the CinicalTrials.gov Web Site. J Thorac Oncol 2013, 8, 860-5 7. Nicolucci A, et al. Quality, evolution, and clinical implications of randomized, controlled trials on the treatment of lung cancer. A lost opportunity for meta-analysis. JAMA 1989, 262, 2101-7 8. Brundage MD, Mackillop WJ. Locally advanced non-small cell lung cancer: Do we know the questions? A survey of randomized trials from 1966-1993. J Clin Epidemiol 1996, 49, 183-92 9. Breathnach OS, et al. Twenty-two Years of Phase III trials for Patients With Advanced Non-Small Cell Lung Cancer: Sobering Results. J Clin Oncol 2001, 19, 1734-42 10. Macbeth F, et al. An open letter to all members of the IASLC. Lung Cancer 2004, 45, 119-20 11. Chalmers I. The lethal consequences of failing to make full use of all relevant evidence about the effects of medical treatments: the importance of systematic reviews. Rothwell P, ed. Treating individuals: from randomised trials to personalised medicine. London: Lancet, 2007: 37-58. 12. Young C, Horton R. Putting clinical trials into context. Lancet 2005, 366, 107-8 13. Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Lancet 2009, 374, 86-9

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      MS13.2 - Clinical Trial Designs for Biomarker Driven Therapies in Advanced Disease (ID 517)

      14:00 - 15:30  |  Author(s): R. Herbst

      • Abstract
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      Abstract not provided

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      MS13.3 - Clinical Trial Designs for Biomarker Driven Therapies in Early Disease (Adjuvant) (ID 518)

      14:00 - 15:30  |  Author(s): G. Scagliotti

      • Abstract
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      Abstract not provided

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      MS13.4 - The Future of RCTs in the Molecular Era? (ID 519)

      14:00 - 15:30  |  Author(s): D. Gandara

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS22 - The Mediastinum 2013 (ID 39)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 4
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      MS22.1 - The Anatomy of the Mediastinum / CT Imaging (ID 562)

      14:00 - 15:30  |  Author(s): N. Kurimoto

      • Abstract
      • Presentation
      • Slides

      Abstract
      Overview of ultrasound imaging of the right and left bronchi using the radial probe The positional relationship between the peribronchial organs in EBUS images taken from the trachea corresponds to those in a reversed CT image (CT scans are cross-sectional images looking from the caudal direction). EBUS images taken distal to the bifurcation of the left and right main bronchi, however, are cross-sectional images of planes perpendicular to the long axis of the bronchus, and therefore have different positional relationship between the peribronchial organs to the CT images. To fully understand EBUS, it is essential to understand the positional relationship between the peribronchial organs during visualisation while the probe is being pulled out. 1. Right bronchi 1) Right lower lobe bronchi When the balloon is inflated in the right basal bronchus, the inferior pulmonary vein (V6) passes on the dorsal side of the bronchus, whereas anterior to the bronchus the pulmonary artery divides into A8, A9 and A10 positioned between 9 o’clock and 2 o’clock. As the probe is pulled back, A8, A9 and A10 meet at the 12 o’clock direction and the direction of the pulmonary artery changes gradually to the 3 o’clock direction. When the probe is pulled further back, it approaches the bifurcation of B6. Pulling the probe back further, the opening of the middle lobe bronchus, indicated by reflection of the ultrasound pulse, appears at 12 o’clock. The pulmonary artery has gradually moved round to the 2 o’clock position. 2) From the right intermediate bronchus to the right main bronchus As the probe is pulled from the distal intermediate bronchus to a point immediately below the origin of the upper lobe bronchus, the pulmonary artery crosses the bronchus from the right to the left. In the central section of the intermediate bronchus, the superior pulmonary vein can sometimes be seen anterior to the pulmonary artery. When the probe is pulled further back, the origin of the upper lobe bronchus is indicated by reflection of the ultrasound pulse at 3 o’clock. Pulling the probe back further, A1+3, originating from the pulmonary trunk, can be seen crossing horizontally anterior to the right main bronchus. Retracting the probe further, the origin of the left main bronchus at the carina is indicated by reflection of the ultrasound pulse at 9 o’clock. 2. Left bronchi 1) Left lower lobe bronchi When the balloon is inflated in the left basal bronchus, the inferior pulmonary vein (V6) passes on the dorsal side of the bronchus, whereas the A8, A9 and A10 branches of the pulmonary artery meet at 9 o’clock. As the probe is pulled back, it approaches the bifurcation of B6. Pulling the probe back further, the opening of the upper lobe bronchus, indicated by reflection of the ultrasound pulse, appears at 11 o’clock. The pulmonary artery is located below the origin of the upper lobe bronchus. 2) Left main bronchus The distal section of the left main bronchus is characterised by the left pulmonary artery at 10 o’clock, the descending aorta at 7 o’clock, and the left atrium from 1 o’clock to 3 o’clock. As we enter the central section of the left main bronchus, the left atrium disappears, and the oesophagus appears at 6 o’clock. The subcarinal (#7) lymph node is often visible medial to the oesophagus. Ultrasound imaging of mediastinal and hilar lymph nodes for EBUS-TBNA by the Convex Bronchoscope #7 LN: Subcarinal lymph node For approaching #7 LN, the convex bronchoscope is inserted into right main bronchus. While scanning at 9 o’clock direction, we can confirm the largest area of the #7 LN. While rotating right handed and scanning at 11 o’clock direction, we can watch the right main pulmonary artery. 11R LN: right intralobar lymph node (between right lower lobe bronchus and right middle lobe bronchus) For approaching #11R LN, the convex bronchoscope is inserted into right basal bronchus. While scanning at 12 o’clock direction, we can confirm the largest area of the #11R LN. While rotating right handed and scanning at 3 o’clock direction, we can watch the right pulmonary artery. 11R LN: right intralobar lymph node (between right intermediate trunk and right upper lobe bronchus) For approaching #11R LN, the convex bronchoscope is inserted into right intermediate trunk. On the bronchoscopic findings, right upper bronchus is locates at 12 o’clock direction from the intermediate trunk. While scanning at 12 o’clock direction, we can confirm the largest area of the #11R LN. While rotating left handed and scanning at 9 o’clock direction, we can watch the right main pulmonary artery. 11L LN: left intralobar lymph node For approaching #11R LN, the convex bronchoscope is inserted into left basal bronchus. On the bronchoscopic findings, left upper lobe bronchus is locates at 12 o’clock direction from left lower lobe bronchus. While scanning at 12 o’clock direction, we can confirm the largest area of the #11L LN. While rotating left handed and scanning at 10 o’clock direction, we can watch the right pulmonary artery. 4L LN For approaching #4L LN, the convex bronchoscope is inserted to the distal site of the trachea. On the bronchoscopic findings, the left side of the trachea is locates at 12 o’clock direction. While scanning at 12 o’clock direction, we can confirm the largest area of the #4L LN. While pushing the scope to distal site about 1-2cm, we can watch the left main pulmonary artery. While pushing the scope to proximal site about 1-2cm, we can watch aortic arch. 4R LN For approaching #4R LN, the convex bronchoscope is inserted to the distal site of the trachea. On the bronchoscopic findings, the membranous portion of the trachea is locates at 6 o’clock direction. While scanning at 2 o’clock direction, we can confirm the largest area of the #4R LN. While scanning 4R LN, we can watch superior vena cava (SVC) just below. While pushing the scope to proximal site about 1-2cm, we can watch aortic arch #4R LN.

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      MS22.2 - Further Staging Using Imaging - PET, MRI and PET/CT (ID 563)

      14:00 - 15:30  |  Author(s): E. Hsiao

      • Abstract
      • Presentation
      • Slides

      Abstract
      PET and PET/CT FDG PET scans have shown high sensitivity and specificity in detecting mediastinal nodal involvement. It works by detecting increased accumulation of F-18 fluorodeoxyglucose (FDG) in the neoplastic cells which have a deranged glucose metabolism. FDG undergoes similar uptake and metabolic pathway glucose molecules. The accumulation of positron emitting F-18 isotope can then be used to localise these hypermetabolic neoplastic tissue. Both 2003 and 2007 guidelines of the American College of Chest Physicians (ACCP) endorsed the use of PET imaging as a non-invasive staging tool for non-small cell lung cancer[1, 2]. FDG PET scan has become the standard of care in staging primary lung cancer. It is recognised as the most accurate non-invasive tool in the staging of lung cancer. It is also widely accepted that PET scanning improves detection of distant metastatic disease as well as unsuspected N2 or N3 disease particularly in the high-risk patients. Therefore, several series have shown that the use of PET imaging reduces unnecessary or futile surgical resection. Traditionally, a standard uptake value (SUVmax) of 2.5 or above is used as a threshold for malignancy, but this was initially based on the uptake of peripheral lung masses with diameter >2cm. Whether this can be applied to mediastinal nodes is questionable. The special resolution of a current generation PET scanner is approximately 7mm. Nonetheless, small or non-enlarged lymph nodes with highly aggressive tumour metastasis may be detected based on the higher intensity of uptake compared to the background. While FDG PET is clinically useful, it is an imperfect technique. The meta-analysis carried out by Silvestri et al [3]in the third edition of ACCP guideline demonstrated that the median sensitivity and specificity for detecting mediastinal metastases were 80% and 88% respectively. The findings demonstrate that PET is more accurate than CT scanning (median sensitivity 55% and median specificity 81%) [3]. However, it is important to know that neither technique is perfect. Interestingly, an increasing number of recent studies were performed using integrated PET/CT scanner. The meta-analysis by the ACCP showed a median sensitivity of 62% and median specificity of 90%[3]. The specificity is slightly higher although the sensitivity is lower. The reason for this observation remains unclear. Nonetheless, PET/CT hybrid cameras have superseded the role of stand alone PET scanners in nowadays. False negative results are more often seen with adenocarcinoma in situ, well-differentiated invasive adenocarcinoma, and typical carcinoid tumours. Small volume or micrometastasis can also be missed due to the finite spatial resolution of PET and perhaps by all imaging techniques. Studies have demonstrated that PET scanning is less sensitive for lymph nodes measuring <7-10mm diameter, and micrometastases have been detected in non enlarged lymph nodes without abnormal FDG uptake by invasive sampling[4]. Furthermore, in the presence of a central FDG avid lung cancer, N1 disease can be missed by FDG PET imaging in up to 25% of cases[5]. In the evolution of a peripheral T1A lesion particularly if the density of the nodule is ground glass or sub-solid. It is well known that these types of neoplasms have low incidence of mediastinal metastasis though the risk is not nil. It is important that the interpretation of a negative PET scan to be combined with clinical judgement as well as the pre-test likelihood of mediastinal metastasis. Furthermore the local availability and expertise in invasive biopsy procedures are also important factors. False positive findings are often due to infection or inflammation. Common causes include sarcoidosis, silicosis, reactive changes, fungal or mycobacterial infections. In summary, it is important to confirm N2 and N3 disease with tissue sampling to avoid delay or missing potentially curative surgery. In the presence of negative of PET and CT findings in the mediastinum, that the decision to operate or to have invasive tissue sampling requires careful consideration and clinical judgement. Combined with invasive mediastinal staging techniques Transbronchial biopsy has shown a median sensitivity of 78% and specificity of 100% in a systemic review. The sensitivity has been reported to be high in patients with positive CT or PET/CT findings. Occasional false positive results have been reported to be approximately 7%. The median negative predictive value in this systemic review is 77%. Endobronchial ultrasound with needle aspiration can achieve a median negative predicted value of 91%. This is further improved with combined EBUS and EUS which have a median negative predictive value is 96%[3]. For most patients undergoing PET/CT staging, the need of invasive mediastinal staging is not eliminated. It is important to confirm the presence of N2 or N3 disease in patients without evidence of metastatic disease to avoid withholding potentially curative surgery. FDG PET/CT can guide needle biopsy as to which nodal stations are considered high risk. Targeting lymph nodes with a higher pretest probability further decreases the inherent false negative rate of needle biopsy. The location of FDG avid nodal stations is important as to which technique will be most appropriate. For example, the identification of an FDG supraclavicular node (N3) can lead to ultrasound guided percutaneous biopsy. An FDG avid aortopulmonary lymph node may be sampled by using Chamberlain procedure, CT guided fine needle aspiration, or extended cervical mediastinoscopy. In cases with enlarged mediastinal lymph node with negative PET, confirmation by invasive techniques is also advised, as up to 21% of these can still have nodal involvement[4, 6]. There are two exceptions to the rule. First, it is known that in a patient with a peripheral T1 tumour (<3 cm), negative FDG uptake and no enlarged lymph node in the mediastinum carries a high negative predicted value with false negative rate being only 4%[3]. Therefore invasive staging is not recommended in these patients given the similar negative predicted value in a combined EBUS and EUS needle biopsy. Secondly, in lung cancer patients with infiltrative mediastinal mass on CT or PET/CT either from overt T4 disease or bulky nodal disease would not require invasive mediastinal staging. MRI and emerging Techniques MR imaging has mainly been used to evaluate non-small cell lung carcinoma when there is possible involvement of superior sulcus or brachial plexus. It is currently not a routine clinical tool in mediastinal nodal staging. New studies albeit with relatively smaller patient sample size have shown that MRI can detect nodal metastasis particularly using STIR and diffusion weighted imaging (DWI) [7, 8]. Several studies have shown comparable efficacy in relation to the PET/CT staging techniques[9]. Diffusion weighted imaging detect random thermal motion of water molecules, known as Brownian motion. Tissues with restricted diffusion will have a lower apparent diffusion coefficient (ADC) values. Hypercellular density, larger cellular nuclei and dense tumour cell membranes are known to cause restricted diffusion in malignant tissue. A study has confirmed the negative relationship between the SUV on FDG PET/CT scans and the lower ADC values on MRI[10]. Furthermore, MRI has the ability to differentiate tumour tissue from vasculature and mediastinal fat. It is therefore potentially useful to delineate direct tumour invasion of the mediastinum, chest wall, diaphragm or spinal column. More research is required in this field of MR mediastinal staging. The latest development in PET/MR imaging technique [11]using hybrid scanner will provide a fertile ground for future research in the use of non-invasive mediastinal staging. References 1. Silvestri, G.A., M.K. Gould, M.L. Margolis, et al., Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest, 2007. 132(3 Suppl): p. 178S-201S. 2. Physicians, A.C.o.C. and H.a.S.P. Committee, Diagnosis and management of lung cancer: ACCP evidence-based guidelines. American College of Chest Physicians. Chest, 2003. 123(1 Suppl): p. D-G, 1S-337S. 3. Silvestri, G.A., A.V. Gonzalez, M.A. Jantz, et al., Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, 2013. 143(5 Suppl): p. e211S-250S. 4. de Langen, A.J., P. Raijmakers, I. Riphagen, et al., The size of mediastinal lymph nodes and its relation with metastatic involvement: a meta-analysis. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 2006. 29(1): p. 26-29. 5. Pozo-Rodríguez, F., J.L. Martín de Nicolás, M.A. Sánchez-Nistal, et al., Accuracy of helical computed tomography and [18F] fluorodeoxyglucose positron emission tomography for identifying lymph node mediastinal metastases in potentially resectable non-small-cell lung cancer. J Clin Oncol, 2005. 23(33): p. 8348-8356. 6. De Leyn, P., D. Lardinois, P.E. Van Schil, et al., ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 2007. 32(1): p. 1-8. 7. Usuda, K., X.-T. Zhao, M. Sagawa, et al., Diffusion-weighted imaging is superior to positron emission tomography in the detection and nodal assessment of lung cancers. Ann Thorac Surg, 2011. 91(6): p. 1689-1695. 8. Ohno, Y., H. Koyama, M. Nogami, et al., STIR turbo SE MR imaging vs. coregistered FDG-PET/CT: quantitative and qualitative assessment of N-stage in non-small-cell lung cancer patients. J Magn Reson Imaging, 2007. 26(4): p. 1071-1080. 9. Pauls, S., S.A. Schmidt, M.S. Juchems, et al., Diffusion-weighted MR imaging in comparison to integrated [¹⁸F]-FDG PET/CT for N-staging in patients with lung cancer. European Journal of Radiology, 2012. 81(1): p. 178-182. 10. Heusch, P., C. Buchbender, J. Köhler, et al., Correlation of the Apparent Diffusion Coefficient (ADC) with the Standardized Uptake Value (SUV) in Hybrid 18F-FDG PET/MRI in Non-Small Cell Lung Cancer (NSCLC) Lesions: Initial Results. Rofo, 2013. 11. Kohan, A.A., J.A. Kolthammer, J.L. Vercher-Conejero, et al., N staging of lung cancer patients with PET/MRI using a three-segment model attenuation correction algorithm: Initial experience. Eur Radiol, 2013.

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      MS22.3 - Minimally Invasive and Endoscopic Options (ID 564)

      14:00 - 15:30  |  Author(s): D. Gompelmann

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      Abstract not provided

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      MS22.4 - Surgical Techniques for Definitive Staging (ID 565)

      14:00 - 15:30  |  Author(s): U. Pastorino

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      Abstract not provided

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    O10 - Stereotactic Ablative Body Radiotherapy (ID 104)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 8
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      O10.01 - Exploring the optimal biologically effective dose of stereotactic body radiation therapy for Stage I non-small-cell lung cancer - An update (ID 3030)

      16:15 - 17:45  |  Author(s): J. Wang, B. Li, J. Zhang

      • Abstract
      • Presentation
      • Slides

      Background
      To investigate the relationship between the different levels of biologically effective dose (BED) and the outcome of stereotactic body radiation therapy (SBRT) for Stage I non–small-cell lung cancer (NSCLC).

      Methods
      Eligible studies were identified on Medline, Embase and the Cochrane Library from January 2001 to March 2013. According to the quartile of included studies, BED was divided into four dose groups: low (<100Gy), medium (100–112.3Gy), medium to high (112.3–135Gy), high (>135Gy). To obtain pooled estimates of overall survival (OS), local control rate (LCR), cancer-specific survival(CSS), regional failure rate(RFR), distant failure rate (DFR),data were combined in a random effect model. The difference in pooled estimate among BED groups was assessed with the Pearson chi-squared test. The meta-regression model was used to explore the relationship between the characteristics of the studies and the prognostic index.

      Results
      Fifty-nine observational studies with a total of 5,562 patients were included in the meta-analysis. Pooled estimates of 2-year and 3-year OS in the medium BED (79%, 71%) group were higher than in the low (64%, 57%) or medium to high BED (69%, 57%) or high groups (66%, 56%), respectively (p<0.001, p<0.001, p<0.001,respectively). Pooled estimates of 2-year LCR in the medium BED (89%) group was lower than in medium to high BED (94%)or high groups (94%), respectively (p=0.003,0.009 respectively). While no significant differences were observed between each two of four different levels of BED and the 3-year RFR.

      Conclusion
      Based on the meta-analysis, a statistically significant OS benefit at 2 and 3 years can be demonstrated in the treatment of Stage I NSCLC with the delivery of medium BED compared with low, medium to high BED or high BED. The medium BED (range, 100–112.3Gy) for SBRT may currently be more beneficial and reasonable in Stage I NSCLC.

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      O10.02 - Radiation Therapy Oncology Group (RTOG) protocol 0915: A randomized phase II study comparing 2 Stereotactic Body Radiation Therapy (SBRT) schedules for medically inoperable patients (pts) with stage I peripheral Non-Small Cell Lung Cancer. (ID 68)

      16:15 - 17:45  |  Author(s): G. Videtic, C. Hu, A. Singh, J. Chang, W. Parker, K. Olivier, S. Schild, R. Komaki, J. Urbanic, H. Choy

      • Abstract
      • Presentation
      • Slides

      Background
      To select the most favorable treatment regimen based on the rate of grade 3 or higher protocol-specified adverse events (psAEs) at 1 year.

      Methods
      Pts with documented baseline medical conditions precluding lobectomy and biopsy-proven peripheral (greater than 2 cm from the central bronchial tree) T1/T2, N0 (clinically node negative by PET), M0 tumors were eligible. Patients (pts) were randomized to receive either 34 Gy in one fraction (arm 1) or 48 Gy in 4 consecutive once-daily fractions (arm 2). Rigorous central accreditation and quality assurance assessments were used to assure pts were treated according to protocol guidelines. The study was designed to detect whether psAEs rate>17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included primary tumor control (PC) rate, 1-year overall survival (OS), progression-free survival (PFS). The regimen selection criteria were based on pre-specified rules of psAEs and PC for each arm. Formal comparisons were not performed.

      Results
      The study opened in September 2009 and closed in March 2011 after accruing a total of 94 pts. Median follow up was 20.6 months. Of 86 evaluable pts, 41 were in arm 1 and 45 in arm 2. Baseline pt and tumor characteristics were balanced between both arms. 4 (9.8%) pts on arm 1 (95% CI: 2.7-23.1%; p=0.151) and 6 (13.3%) pts on arm 2 (95% CI: 5.1-26.8%; p=0.337) experienced psAEs. 39 (95.1%) pts on arm 1 and 45 (100%) pts on arm 2 received planned SBRT treatment. Contouring compliance indicated 100% and 95.6% of targets and 89.5% and 82.2% of normal tissue structures were outlined per protocol/minor deviations, for arms 1 and 2, respectively. OS at 1 year was 85.4% (95% CI: 70.3-93.1%) for arm 1 pts and 91.1% (95% CI: 78.0-96.6%) for arm 2. PFS at 1 year was 78.0% (95% CI: 62.1-87.9%) for arm 1 and 84.4% (95% CI: 70.1-92.3%) for arm 2. The PC rates at 1 year were 97.1% (95% CI: 85.1-99.9%) for arm 1 and 97.6% (95% CI: 87.1-99.9%) for arm 2.

      Conclusion
      At one year, 34 Gy in one fraction met pre-specified criteria with respect to adverse events and primary control, and therefore is selected as the experimental arm for a planned phase III trial. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from NCI.

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      O10.03 - Safety of Endobronchial Implantation of Electromagnetic Fiducials for Real-time Tracking of Lung Tumors during Radiotherapy (ID 2040)

      16:15 - 17:45  |  Author(s): D.A. Nader

      • Abstract
      • Presentation
      • Slides

      Background
      Lung tumor control has improved with advances in radiotherapy delivery (RT). Respiratory motion inders improvements. An Anchored Beacon® transponder (Varian Medical Systems, Palo Alto, CA) can track lung tumors in real time during RT. This study evaluates the safety of these bronchoscopically implanted transponders in 50 lung tumor patients undergoing RT

      Methods
      Each patient underwent implantation of 3 anchored transponders in the lung. A delivery catheter was inserted into the bronchoscope and using fluoroscopic guidance +/- radial endobronchial ultrsound (EBUS) and/or electromagnetic guidance (superDimension): the catheter was positioned in a 2-2.5 mm diameter airway, within 3 cm of the tumor. The transponder was deployed by depressing a plunger within the delivery catheter. The catheter was then withdrawn. CT's were acquired before RT and every 1-2 weeks during treatment. Transponder positions were measured.

      Results
      50 patients (28 female/ 22 male) with median age 64 had transponders inplanted. Follow-up ranged from 0- 15.5 months (median 9.2). Positional stability of the Anchored transponders over the course of RT was confirmed. Inter-transponder distance from serial CT scans have been evaluated in 47 of 49 patients who underwent RT. Inter-transponder distances were stable over the course of radiation therapy for 140/141 (99%) of Anchored transponders. 2 Anchored transponders migrated, one after completion of RT. Safety: 2 patients (4%) sustained pneumothorax with insertion. Each resolved within one day with chest tube placement and withdrwal. One patient sustained a cardiac arrest prior to bronchoscopy for implantation. 2/147 (1%) sustained migration. Patient A coughed one transponder. which was placed in too large and proximal airway. Patient B was found the have the transponder migrating to the pleural space associated with a suppurative lung infection 3 months post-treatment.

      Conclusion
      Bronchoscopic implantation of Anchored transponders can be performed with few complications. Anchored transponders are positonally stable in the lung with a 99% retention rate. There are multiple advantages to real-time localization and tracking of lung tumors. The Anchored transponder demonstrated a high safety profile and significantly low migration.

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      O10.04 - DISCUSSANT (ID 3929)

      16:15 - 17:45  |  Author(s): U. Ricardi

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      Abstract not provided

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      O10.05 - Blinded assessment of radiological changes after stereotactic ablative radiotherapy for early-stage lung cancer: local recurrences versus fibrosis. (ID 1416)

      16:15 - 17:45  |  Author(s): S. Senthi, K. Huang, D. Palma, A. Warner, B. Slotman, S. Senan

      • Abstract
      • Presentation
      • Slides

      Background
      Stereotactic ablative radiotherapy (SABR) is now a guideline-recommended treatment for early-stage lung cancer (ES-NSCLC), achieving 5-year local control rates of approximately 10%. The timely detection of local recurrence (LR) and early salvage following SABR is impaired by fibrotic changes, which occur commonly. Seven high-risk CT features (HRFs) that suggest LR include; enlarging opacity, cranio-caudal growth, sequential enlarging opacity, enlarging opacity after 12 months, bulging margin, loss of linear margin and loss of air bronchograms. We validated these, performing blinded clinician assessment in patients with and without LR.

      Methods
      ES-NSCLC patients treated with SABR, who developed pathology-proven LR (n=12), were matched 1:2 to patients without clinical LR (n=24), based on tumor location, SABR fractionation, PTV size and follow-up duration. Three radiation oncologists assessed serial follow-up CT images for HRFs, while blinded to outcomes. The sensitivity and specificity of HRFs and combinations of these were determined.

      Results
      The median follow-up was 24 months (range 6-67) and both cohorts were well matched. All HRFs were significantly associated with LR (p≤0.002), Table 1. The best individual predictor of LR was opacity enlargement after 12 months (100% sensitivity, 83% specificity), however this was detected slowest, at a median 22 months. The earliest HRF detected was cranio-caudal growth detected at a median 13 months. The HRFs enlarging opacity and cranio-caudal growth were each detected at least 3 months prior to the actual diagnosis of LR 42% of the time. The odds of LR increased 4-fold for each additional HRF detected (p<0.001). The sensitivity and specificity of detecting multiple HRFs is shown in Table 2, with ≥3 HRFs being the best predictor of LR (sensitivity 92%, specificity 92%). Figure 1 Figure 2

      Conclusion
      LR following SABR can be accurately predicted by the presence of HRFs on surveillance CT scans. This approach may reduce unnecessary confirmatory procedures, and facilitate earlier salvage treatment.

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      O10.06 - Inter-Rater Reliability of the Categorization of Late Radiographic Changes after Lung Stereotactic Body Radiation Therapy (SBRT) (ID 1901)

      16:15 - 17:45  |  Author(s): S. Faruqi, M. Giuliani, H. Raziee, M.L. Yap, H. Roberts, L. Le, A. Brade, B.C.J. Cho, A. Sun, A. Bezjak, A. Hope

      • Abstract
      • Presentation
      • Slides

      Background
      Radiographic changes following lung SBRT have been previously categorized into 4 groups: modified conventional pattern (A), mass-like fibrosis (B), scar-like fibrosis (C) and no evidence of increased density (D) (Dahele et al.).The purpose of this study was to assess the inter-rater reliability of this categorization in patients with early stage non-small cell lung cancer.

      Methods
      79 patients treated with SBRT for early stage NSCLC at a single institution who had a minimum follow-up of 6 months were included in this study. Serial post-treatment CT images were presented to expert clinicians (up to 6) familiar with post-SBRT radiographic changes and were scored by each individual in a blinded fashion according to the published categorization of A, B, C or D. The proportion of patients categorized as A, B, C or D at each interval was determined. Krippendorff's alpha (KA) was used to establish inter-rater reliability at each time point. A leave-one-out analysis was performed at each time point on each rater to determine the sensitivity of the KA score to an individual rater. To explore if a training effect existed the KA of the first and last 20 patients scored by the raters was determined.

      Results
      There were 351 ratings on 67 patients at 12mo, 250 ratings on 49 patients at 24mo, 169ratings on 31 patients at 36mo and 80 ratings on 14 patients at 48mo. The proportion of patients scored in each category of A,B,C &D is reported in Table 1. Table 1: Scale Category by Time-Point

      A (Modified-Conventional) B (Mass-like Fibrosis) C (Scar-like Fibrosis) D (No Evidence of Increased Density)
      6 months 43% 9% 6% 42%
      12 months 50% 16% 11% 23%
      18 months 46% 18% 16% 20%
      24 months 46% 22% 17% 15%
      36 months 40% 24% 21% 15%
      48 months 29% 24% 31% 16%
      Category A was the most common at all time points except 48 months when category C was the most common. KA was 0.28, 0.27, 0.18 and 0.27 at 12, 24, 36 and 48 months respectively. The range of KA in the leave-one-out analysis was 0.25-0.31, 0.24-0.27, 0.15-0.22 and 0.24-0.31 at 12, 24, 36 and 48 months respectively. The KA of the first 20 patients vs the last 20 patients was 0.34 vs 0.47 at 12 months.

      Conclusion
      The predominant pattern of post SBRT radiographic changes evolves over time. In this study categorization of late post-SBRT radiographic changes has moderate inter-rater agreement. There is a suggestion of a training effect with more experience. However, categorization of late radiographic changes following SBRT is challenging and may require specific training.

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      O10.07 - Dose-response analysis of radiation induced rib fractures after SBRT for NSCLC (ID 2690)

      16:15 - 17:45  |  Author(s): B. Stam, A. Scheenstra, J. Belderbos, H. Peulen, J. Nijkamp, J.J. Sonke

      • Abstract
      • Presentation
      • Slides

      Background
      Symptomatic rib fractures occur in approximately 5% of patients treated with SBRT for early stage NSCLC. Only in small patient cohorts has the dose-effect relation of radiation induced rib fractures been determined. Recent developments in automatic rib segmentation allow determining the dose-effect relation in a large patient cohort, which is the aim of this study.

      Methods
      From 2006-2012 453 patients with early stage NSCLC were treated with SBRT (3x18 Gy). Follow-up (FU) consisted of a physical examination and a CT scan 4 months after treatment and every 6 months up to two years and yearly thereafter. For the first 101 patients with FU>6 months, all ribs were automatically segmented using 15 atlases of manually delineated ribcages. A non-rigid registration followed by a multi-level label fusion produced for each patient a set of ribs. The physical dose distributions were NTD (Normalized Total Dose) corrected with α/β=3 Gy. Cox proportional hazard regression analysis, which takes into account the time to event with patient as random intercept, was used to find the optimal dose parameter. Evaluated were the dose received by x% of the rib D~x~ (x ranged 1-30%) and equivalent uniform dose (EUD) (volume effect 1/n ranged 0.1-60). The Lyman-Kutcher-Burman (LKB) model based on this optimal dose parameter was used to model the dose-effect relationship. Using maximum-likelihood estimation, parameters were median toxic dose (TD~50~), steepness parameter m and 1/n were optimized.

      Results
      In 354 patients with FU>6 months (median 22 months), 38 patients(11%) were diagnosed with a total of 49 rib fractures, symptomatic (grade 2) for 9 patients(2.5%). Included in the dosimetric analysis were 2410 ribs (14 ribs outside field-of-view). 26 ribs in 15 patients(15%) were fractured, symptomatic for 4 patients(4%). In the univariate analysis, all dose parameters significantly correlate with rib fracture (p-values<0.001). Hazard ratios (95%CI) for the parameters with highest log likelihood: D~1~=1.022 (1.017-1.027) and EUD~0.033~=1.021 (1.016-1.026). Multivariate analysis identified EUD as the predictor with the highest log-likelihood and was used in the LKB model. The optimal LKB parameters to predict rib fracture in this dataset were (95% CI): TD~50~=395.5 Gy (244.3-555.1), m=0.348 (0.311-0.384) and 1/n=32.3 (4.82-inf). The risk of rib fracture was <5% in case the NTD-corrected EUD<170 Gy.Figure 1

      Conclusion
      In this subgroup of NSCLC patients treated with 3x18Gy, the risk of rib fracture was significantly correlated to the dose, and was <5% in case the biological dose is kept under 170 Gy.

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      O10.08 - DISCUSSANT (ID 3930)

      16:15 - 17:45  |  Author(s): S. Senan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    O12 - Lung Cancer Biology II (ID 87)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Biology
    • Presentations: 8
    • +

      O12.01 - Prospective isolation of human lung stem/progenitor cells and their role in the initiation of lung cancer (ID 1716)

      10:30 - 12:00  |  Author(s): C.E. Weeden, K. Viitaniemi, G. Ramm, J. Ciciulla, I. Bertoncello, M. Asselin-Labat

      • Abstract
      • Presentation
      • Slides

      Background
      Cells of origin of cancers acquire the first genetic aberration(s) that lead to tumourigenesis. An understanding of the cell of origin in different subtypes of lung cancer could allow earlier detection of malignancies and more effective treatment. Stem or progenitor cells are likely tumour initiating cells due to both their longevity, allowing for accumulation of genetic lesions, and their capacity for renewal. This study aims to isolate human lung progenitor subpopulations based on their differential expression of cell surface markers to evaluate their role as the cell of origin of the different subtypes of lung cancer.

      Methods
      Single cell suspensions were generated from adjacent normal tissue of patients undergoing lung cancer resection. Epithelial cells were immediately separated based on their expression of cell surface markers by fluorescence activated cell sorting (FACS). The progenitor cell capacity of epithelial cell subsets was then assessed using an in vitro colony forming assay. Subsets with progenitor activity were analysed for their expression of differentiated lung cell markers both before and after colony formation.

      Results
      We have identified a sort strategy that allows for enrichment of basal cells, Clara cells, type I and II pneumocytes from fresh human lung tissue as shown by qPCR and electron microscopy data. The basal cell and type II pneumocyte subpopulations consistently formed colonies in vitro - cell types that have previously shown progenitor activity in the mouse lung. The Clara cell and type I cell compartment did not consistently form colonies. Basal and type II cells formed phenotypically distinct colonies when cultured in a three-dimension matrix that expressed different lung specific markers (p63, SP-C…) as shown by RT-PCR analysis and immunofluorescence staining.

      Conclusion
      This study has demonstrated the prospective isolation of four epithelial cell subsets from fresh human lung tissue for the first time and confirmed the progenitor activity of basal cells and type II cells in the human lung. We are currently comparing the genetic profile of these human lung progenitor cells with the genetic profile of molecular subtypes of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) using next generation sequencing. Future studies aim to transform lung progenitor cells with genetic alterations common in NSCLC and SCLC to further establish their role as cells of origin of these cancers.

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      O12.02 - Pathway Analysis of Gene Expression Profiles that Distinguish Persistent from Regressive Bronchial Dysplasia Indicate Synergistic Role for Polo-Like Kinase 1 (PLK1) and Epoxide Hydrolase 3 (EPHX3) in Malignant Progression. (ID 3334)

      10:30 - 12:00  |  Author(s): D.T. Merrick, M.G. Edwards, W. Franklin, M. Sugita, Y. Miller, M. Friedman, L. Dwyer-Nield, M. Tennis, K. Choo, G. Hickey, T. Kennedy, A. Van Bokhoven, L. Heasley, F.R. Hirsch, P.A. Bunn, M. Geraci, R.L. Keith, R. Nemenoff

      • Abstract
      • Presentation
      • Slides

      Background
      160,000 Americans die from lung cancer annually and the prognosis for invasive lung cancer is poor. Prevention of cancer represents an approach with high potential for significant reduction in mortality. Bronchial dysplasia (BD) is a precursor lesion of squamous cell carcinoma (SCC) of the lung, and persistent BDs represent a high risk subset of these lesions. Genomic instability is an important process underlying malignant progression. Gene expression microarray analyses were used to identify potential mediators of genomic instability in persistent BD and study their activity in these high risk lesions. Two genes, PLK1, which abrogates G2-M checkpoint DNA damage repair, and EPHX3, which converts tobacco smoke derived pro-carcinogens to mutagens, were selected for further analysis.

      Methods
      Sixty-three frozen baseline biopsies were classified into persistent/progressive BD, regressive BD , progressive non-dysplasia and stable non-dysplasia groups according to the presence or absence of BD on follow-up biopsies. H&E staining was performed on frozen sections to confirm histology, and RNA was harvested for global gene expression microarray analysis. Intergroup comparisons employed ANOVA statistical analysis with a false discovery rate of 10% to identify differentially expressed genes associated with persistence and gene expression alterations related to baseline histology used Spearman correlation coefficient cutoff of r= +/- 0.5. A pathway analysis (Ingenuity) using the persistence related genelist was performed to identify active pathways associated with persistence of BD. Validational studies were performed by quantitative RT-PCR in cell lines established from persistent and regressive bronchial sites. Inhibitors of persistence associated enzymes were used in tissue culture based assays of cellular proliferation.

      Results
      Gene expression analyses support the unique biological nature of persistent BD. Intergroup comparisons showed significant numbers of differentially expressed genes only in the comparisons of persistent BD with regressive BD (318 genes) or stable non-dysplasia (6254 genes). 831 genes showed differential expression associated with increasing baseline dysplastic grade regardless of outcome. While approximately half of these genes also differentiated persistent from regressive BD, the presence of numerous persistence related genes that are independent of histology further substantiates the unique high risk nature of persistent BD. A pathway analysis revealed “mitotic roles of PLKs” as having the most significant association with persistence. Quantitative RT-PCR using cultures of 8 persistent BD and 6 regressive BD validated increased expression in persistent BD of PLK1 (2.77X, p=0.002) and EPHX3 (2.36X, p=0.081). Using a classification of dysplastic specimens as high or low expressers of PLK1 and/or EPHX3 (high > mean), we found a significant direct relationship with increased level of outcome diagnosis score: low expression of both genes (2.58); high expression of only one gene (3.60); and high expression of both (5.06). The baseline diagnosis did not differ between groups. Culture of the SCC cell line H2009 with EPHX inhibitor revealed a non-significant trend toward decreased proliferation (80.4% vs untreated).

      Conclusion
      Gene expression data confirms the biologically distinct nature of persistent BD. PLK1 and EPHX3 overexpression demonstrate a cooperative effect in respect to increased outcome histology suggesting a potential role for these enzymes in persistence/progression of BD via promotion of genomic instability.

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      O12.03 - Pseudogenes as miRNA sponges in non-small cell lung cancer (ID 3455)

      10:30 - 12:00  |  Author(s): G.L. Stewart, K.S. Enfield, S. Lam, W.L. Lam

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer is the most common cause of cancer death worldwide, with a five-year survival of less than 15%. This poor therapeutic outcome is largely due to complex molecular backgrounds as well as typically late stage at diagnosis, with most patients presenting with unresectable local tumours or metastatic disease. While mutations of driver genes is a well known mechanism of tumorigenesis, approximately half of all non-small cell lung cancer (NSCLC) tumours harbour no known actionable oncogenic drivers, emphasizing the need to explore alternative mechanisms. New sequencing technologies have allowed investigation of previously unexplored areas of the genome and revealed that several classes of non coding RNAs (ncRNAs), those with no protein product, are involved in tumourigenesis, emphasizing the need for further exploration and study. MicroRNAs (miRNAs) have emerged as major players in lung carcinogenesis, displaying both oncogenic and tumor suppressive functions through translational inhibition of genes containing miRNA target sequences. Pseudogenes are non-coding relatives of protein-coding genes that contain a high degree of sequence similarity with their parent genes, thus sharing many of the same miRNA target sequences. As a result, when overexpressed, a pseudogene can function as a miRNA "decoy" protecting its parent gene from miRNA-mediated translational inhibition. DNA copy number (CN) alterations (gain of oncogenes/loss of tumour suppressors), is a major molecular mechanism driving cancer. Like protein coding genes, CN alterations can influence ncRNA expression levels, and several pseudogenes have been reported to be deregulated at the CN level in other cancer types. We hypothesize that pseudogenes of lung cancer-related genes are deregulated at the CN level in NSCLC.

      Methods
      Global CN profiles for 83 lung adenocarcinomas, and 12 squamous cell carcinomas, as well as paired adjacent non-malignant tissues were generated on the Affymetrix SNP 6.0 array. Frequencies of DNA CN alterations were assessed at candidate pseudogene loci (gain>2.3 copies, loss<1.7 copies). Candidate pseudogenes (1) have a parent gene that has been previously reported to play a role in cancer biology, (2) are expressed in human tissue, and (3) share at least one conserved miRNA binding site with its parent gene.

      Results
      Several pseudogenes for OCT4 (octamer-binding transcription factor 4), an early embryonic transcription factor, were found to be frequently gained (46.9-34.9%), and could protect OCT4 from miRNA-mediated translational inhibition. Additionally, pseudogenes for E2F3 (E2F Transcription Factor 3), a potent cell cycle regulator, as well as those for the well known lung cancer oncogene BRAF, were found to have high frequencies of CN alteration (36.1%, and 19.2%, respectively). These high frequencies of alteration suggest that these pseudogenes play an important role in NSCLC.

      Conclusion
      These results suggest that pseudogenes are clonally selected for at the DNA level, and pseudogene-mediated protection of oncogenic transcripts from miRNA-mediated translational inhibition may represent a novel mechanism of oncogenicity in NSCLC. Analyses of pseudogene expression and corresponding parent gene protein level in cell models will yield insight into how this class of ncRNA affects tumourigenesis, potentially leading to improvements in early detection, diagnosis, and treatment.

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      O12.04 - DISCUSSANT (ID 3896)

      10:30 - 12:00  |  Author(s): K. Sutherland

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      O12.05 - Defining the role of ZEB1 in the pathogenesis of non-small cell lung cancer (NSCLC) using immortalized human bronchial epithelial cells (HBECs) (ID 1139)

      10:30 - 12:00  |  Author(s): J.E. Larsen, J.K. Osborne, A. Augustyn, J.P. Sullivan, M. Sato, L. Girard, A.F. Gazdar, J.D. Minna

      • Abstract
      • Presentation
      • Slides

      Background
      To study the role of common lung cancer mutations in transforming lung epithelial cells in an appropriate cellular context we used cdk4/hTERT-immortalized normal HBECs. We developed an isogenic series of HBECs by introducing genetic manipulations representing common lung cancer mutations (such as p53, KRAS[V12], cMYC, and LKB1). This defined in vitro system allows characterization of specific tumorigenic contributions as well as identification of acquired changes, likely representing tumor acquired vulnerabilities and novel therapeutic targets (Mol Cancer Res 2013). One acquired change observed with oncogenic transformation of HBECs is a spontaneous epithelial-to-mesenchymal transition (EMT), an important biologic process in cancer. This study sought to characterize the role of EMT in driving tumorigenesis in HBECs and, in turn, lung cancer to identify novel therapeutic targets.

      Methods
      Genetic manipulations were introduced into cell lines using siRNA/shRNA or over-expression constructs. Tumorigenicity was measured using in vitro (anchorage-dependent and -independent colony formation, proliferation, migration and transwell Matrigel invasion assays) and in vivo (subcutaneous or intravenous injection into NOD/SCID mice) methods. Genome-wide mRNA expression data from five independent datasets was obtained either in-house using Illumina HumanHT-12v4 BeadChips or from publicly available databases.

      Results
      Analysis of EMT-promoting transcription factors in our isogenic series of oncogenically-manipulated HBECs found ZEB1 expression highly correlated with mesenchymal-like HBECs. Functional studies confirmed ZEB1 was a significant driver of tumorigenic phenotypes in both oncogenic HBECs and human lung cancer cell lines where loss of ZEB1 resulted in decreased colony formation, migration and invasion in vitro and subcutaneous tumor growth and intravenous colonization in vivo. A set of ZEB1-associated genes was identified from analyzing five independent mRNA microarray datasets comprising both cell lines and lung adenocarcinomas. From this gene set we found ZEB1 directly represses ESRP1 by binding to its promoter, which leads to increased mesenchymal splicing of the ESRP1 target CD44. The mesenchymal isoform of CD44, CD44s, conferred a CD44[hi] flow cytometry profile which, in turn, could be used to select for a highly tumorigenic subpopulation in partially transformed HBECs. To identify candidate ZEB1-activated targets we screened ZEB1-upregulated genes in a siRNA invasion assay. Several genes including PMP22 and CD70 could phenocopy ZEB1 where siRNA-mediated loss of expression led to decreased invasiveness in multiple NSCLC cell lines. CD70 (also called TNFSF7, tumor necrosis factor ligand superfamily member 7) may represent a prime therapeutic target for anti-metastatic growth in lung cancer. The ligand for CD27, it is involved in immune regulation, upregulated in some cancers and is being studied as a potential target for antibody therapeutics. Importantly, an anti-CD70 monoclonal antibody inhibited invasion of NSCLC cell lines comparably to siCD70 and siZEB1.

      Conclusion
      We demonstrate in vitro models of defined oncogenic HBEC transformation provide an invaluable tool to study lung cancer progression where EMT is an important mediator. ZEB1 is spontaneously expressed with malignant transformation of HBECs and is a significant driver of oncogenic progression in both HBECs and NSCLC cells. Identification of CD70 and PMP22 as downstream targets of ZEB1 may represent novel therapeutic targets for lung cancer.

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      O12.06 - Hedgehog/Gli Promotes Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (ID 2091)

      10:30 - 12:00  |  Author(s): H. Li, D. Yue, T.H. Tseng, D.M. Jablons, T. Cheng, B. He, M.J. Mann

      • Abstract
      • Presentation
      • Slides

      Background
      A majority of non-small cell lung cancer (NSCLC) patients are diagnosed with metastatic phenotypes. Epithelial-to-Mesenchymal Transition (EMT), characterized by loss of epithelial markers, such as E-cadherin, is suggested to be involved in the metastatic process. In addition, aberrant activation of the Hedgehog-Gli(Hh/Gli) signaling pathway is implicated in various cancers, including NSCLC. We hypothesize that the Hh/Gli signaling pathway may regulate EMT in NSCLC, and inhibition of Hh/Gli pathway may provide a novel strategy to treat NSCLC and prevent metastasis.

      Methods
      Tumor tissues of 324 NSCLC patients were analyzed by immunohistochemistry for Gli and E-cadherin expression. Mechanistic studies were carried out in four NSCLC cell lines, A549, H1666, H2170 and H1703. Our lab has developed a novel small molecule Gli inhibitor (Gli-I )that effectively suppresses lung cancer in vitro and in vivo. Gli-I and a Smoothened inhibitor vismodegib were applied to suppress Hh/Gli signaling, while Hh protein was utilized to stimulate the pathway. Upon different treatments, EMT phenotypes were evaluated by wound healing assays and 3D cell invasion assays. Expression of EMT markers was measured by immunofluorescent staining and western blot at protein levels, as well as quantitative RT-PCR at mRNA levels.

      Results
      Our results demonstrated elevated Gli expression in 78% of NSCLC patient tissues. Gli expression was reversely correlated with E-Cadherin in patient tissues and culture cell lines. Inhibition of Hh signaling reduced cell migration and invasion, while stimulation of Hh signaling promoted EMT phenotypes. Specifically, Gli-I significantly suppressed cell proliferation, migration and invasion more effectively than vismodegib. Furthermore, mechanistic studied showed Hh/Gli signaling may regulate EMT through suppressing E-Cadherin.

      Conclusion
      Our results suggested that SHh/Gli signaling promotes cell proliferation and EMT, leading to NSCLC cell invasion and metastasis. Inhibition of Hh/Gli signaling by a novel Gli inhibitor Gli-I suppresses cell proliferation and invasion. Our novel Gli inhibitor holds the promise to provide an effective therapeutics to treat NSCLC and prevent metastasis.

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      O12.07 - Pulmonary fibroblasts increase EMT signaling and decrease sensitivity to chemotherapy in non-small cell lung cancer cells via TGF-beta and IL-6 signaling (ID 265)

      10:30 - 12:00  |  Author(s): Y. Shintani, A. Abulaiti, T. Kimura, S. Funaki, T. Nakagiri, M. Inoue, N. Sawabata, M. Minami, E. Morii, M. Okumura

      • Abstract
      • Presentation
      • Slides

      Background
      The tumor microenvironment is a key factor in tumor progression. A specific subset of stromal cells, termed cancer associated fibroblasts (CAFs), modulate the behavior of adjacent cancer cells by secreting various growth factors and cytokines. The purpose of this study was to clarify the roles of transforming growth factor (TGF)-β and interleukin (IL)-6 in the communication between CAFs and non-small-cell lung cancer (NSCLC) cells.

      Methods
      Fibroblasts obtained during surgical exploration were co-cultured with human lung adenocarcinoma cell lines. We defined fibroblasts obtained from tumors as CAFs and those from normal lung tissue as lung normal fibroblasts (LNFs). Immunohistochemistry was used to examine the fibroblast distribution, as well as TGF-β and IL-6 expression in 60 tumor specimens obtained from patients with NSCLC after undergoing induction chemotherapy or chemoradiotherapy (ITx).

      Results
      The expression levels of myofibroblast markers were higher in CAFs than LNFs after 5 passages in the absence of continuing interaction with carcinoma cells, and we used at least 2 pairs of those CAFs and LNFs in the following experiments. Conditioned medium (CM) from both types of fibroblasts induced epithelial mesenchymal transition (EMT) and acquisition of cancer stemness in lung cancer cells (A549 and NCI-H358), indicating it to be biologically active. Phenotypic changes of cancer cells by CM from CAFs were greater than those induced by CM from LNFs. These CAF-induced changes were inhibited by addition of the TGF-β inhibitor SB431542 or IL-6 receptor neutralizing antibody (IL6-R-Ab). The concentrations of TGF-β1 and IL-6 were higher in CM from CAFs as compared to that from LNFs. Subcutaneous co-injection of lung cancer cells and CAFs in mice enhanced tumor growth when compared with cancer cells alone, which was attenuated by administration of SB431542 or IL-6R-Ab. These findings suggested that CAFs may be more activated in our experimental system as compared to LNFs, and stimulate tumor progression via TGF-β and IL-6 signaling. In addition, decreased expression of epithelial markers and upregulation of mesenchymal markers were detected in surgically resected specimens after ITx as compared with biopsy specimens obtained before treatment. The disease-free survival rate of patients with EMT marker-positive tumors was significantly lower than that of those with EMT marker-negative tumors, indicating that EMT changes are associated with insensitivity to ITx. Furthermore, an increased diffuse distribution pattern of SMA-positive activated fibroblasts was significantly correlated with the expression of EMT markers. Also, though SMA-stained fibroblasts expressed IL-6 in the surgical specimens, TGF-β was expressed in cancer cells as well as CAFs after ITx. Together, our results suggest that tumor stromatic tissues including CAFs increase in response to ITx, while CAFs secrete TGF-β and IL-6, inducing EMT in cancer cells.

      Conclusion
      The TGF-β and IL-6 axis induces EMT and stimulates tumor progression, while TGF-β and IL-6 may play roles to contribute to communication between CAFs and NSCLC cells for tumor progression. Targeting CAFs as a therapeutic strategy against cancer is an intriguing concept that would benefit from further study.

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      O12.08 - DISCUSSANT (ID 3897)

      10:30 - 12:00  |  Author(s): J. Minna

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    O20 - Staging and Advanced Disease (ID 102)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Surgery
    • Presentations: 8
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      O20.01 - Transcervical Extended Mediastinal Lymphadenectomy (TEMLA) is Superior to PET/CT for Restaging of the Mediastinum after Neoadjuvant Therapy for Non-Small Cell Lung Cancer (NSCLC) (ID 358)

      16:15 - 17:45  |  Author(s): S. Yendamuri, A. Battoo, I. Dinga-Madou, C. Nwogu, E. Dexter, M. Hennon, A. Picone, T. Demmy

      • Abstract
      • Presentation
      • Slides

      Background
      Accurate staging of the mediastinum is critical in therapeutic decision making in NSCLC. PET/CT has emerged as an important modality for staging of treatment-naïve NSCLC, but like endobronchial ultrasound and conventional mediastinoscopy typically is inaccurate following neoadjuvant therapy. We sought to determine the accuracy of TEMLA in staging NSCLC after induction therapy.

      Methods
      A retrospective chart review looking at clinical stage assessed by PET -CT and TEMLA, pathologic stage, lymph node yield and clinical characteristics was performed. Accuracy of staging by TEMLA and PET-CT was compared.

      Results
      71 of 100 consecutive patients that underwent TEMLA had it for restaging after neoadjuvant therapy; 65 of these patients were also restaged by PET-CT. Clinical characteristics of these 65 patients are presented (Table 1). TEMLA was completed successfully on 63 (96.9%) patients and was associated with permanent recurrent laryngeal nerve injury in 2 (3%) patients. On average, 17 lymph nodes were obtained per TEMLA. Concomitant anatomic resections were completed in 58 (89.2%) of patients. 12 and 3 (18.5% and 4.6%) patients were classified as having N2 and N3 disease on final pathology. Compared to PET-CT, TEMLA more accurately classified these patients (95.4% vs. 80.0%; P<0.05). The sensitivity, specificity, positive predictive value and negative predictive value of PET/CT and TEMLA for detection of N2 disease are 50.0%, 86.8%, 46.1%, 88.5% and 75%, 100%, 100%, 94.6% respectively (Table 2). Of the 3 patients inaccurately classified by TEMLA, only 1 patient had N2 disease in TEMLA-accessible nodes. Figure 1

      Table 2: Patient numbers according to nodal status.
      Path + Path - PET + PET -
      TEMLA + 9 0 4 5
      TEMLA - 3 53 9 47
      PET + 6 7
      PET - 6 46

      Conclusion
      TEMLA is superior to PET/CT for restaging of the mediastinum after induction therapy. Since TEMLA showed little added morbidity despite central tumor and treatment effects, consideration should be given for its widespread adoption for mediastinal re-staging of NSCLC after neoadjuvant therapy.

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      O20.02 - A novel nodal classification for resected non-small cell lung cancer: comparison between location-based and number-based systems (ID 881)

      16:15 - 17:45  |  Author(s): J. Ichinose, T. Murakawa, H. Hino, C. Konoeda, Y. Inoue, K. Kitano, K. Nagayama, J. Nitadori, M. Anraku, J. Nakajima

      • Abstract
      • Presentation
      • Slides

      Background
      The current UICC/WHO nodal classification system is based on the location of metastatic lymph nodes, while some studies have revealed that the number or ratio of metastatic lymph nodes may work as more effective prognostic indicators. The Japan Lung Cancer Society proposed a new tumor site-based classification for mediastinal nodal metastases according to the tumor-bearing lobe. This study aimed to compare the prognostic power of location-based and number-based classification systems and elucidate the optimal classification.

      Methods
      Of 511 patients with non-small cell lung cancer (NSCLC) who underwent lung lobectomy and complete hilar and mediastinal lymph node dissection with curative intent at our institute between 1998 and 2009, 119 with confirmed lymph node metastases were retrospectively analyzed. Ten classifications were compared using a log-rank test. Four classifications were location-based: the current system, the tumor site-based classification, the classification based on presence or absence of clinical N2 disease, and the classification based on presence or absence of non-skip N2 disease. The other 6 classifications were number-based: the classifications based on the number or ratio of metastatic lymph nodes, the classifications based on that of metastatic stations, and the classifications based on that of metastatic mediastinal lymph nodes.

      Results
      Compared with the current system [hazard ratio (HR), 1.4; p = 0.29], the tumor site-based classification (HR, 2.8; p = 3.0E-4), the classification based on the number of metastatic lymph nodes (HR, 2.8; p = 1.7E-4), and the classification based on the number of metastatic mediastinal lymph nodes (HR, 2.3; p = 3.3E-3) were considered to be stronger predictors of overall survival. Similar results were obtained in terms of disease-free survival (current system: HR, 1.6; p = 0.047; tumor site-based classification: HR, 2.7; p = 2.3E-5; number of metastatic lymph nodes, HR, 2.3; p = 4.0E-4; number of metastatic mediastinal lymph nodes: HR, 2.4; p = 1.4E-4). A combination of the tumor site-based classification with the classification based on the number of metastatic lymph nodes (p = 9.0E-4) or the classification based on the number of metastatic mediastinal lymph nodes (p = 9.5E-4) further increased predictive efficiency.

      Conclusion
      The tumor site-based classification as well as the classifications based on the number of metastatic lymph nodes and the number of metastatic mediastinal lymph nodes was more predictive of surgical outcomes compared with the current nodal system. The results need to be further validated in a new set of patients. Figure 1

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      O20.03 - Lobe-specific lymphadenectomy protocol for non-small cell lung cancer presenting as a solitary pulmonary nodule (ID 1763)

      16:15 - 17:45  |  Author(s): X. Yang, Z. Zhao

      • Abstract
      • Presentation
      • Slides

      Background
      We sought to establish an acceptable lobe-specific mediastinal lymphadenectomy protocol for non-small cell lung cancer (NSCLC) presenting as solitary pulmonary nodules (SPN) .

      Methods
      We retrospectively analyzed 415 patients pathologically diagnosed as NSCLC undergone lobectomy, bilobectomy or pneumonectomy with systematic lymphadenectomy from March 2004 to June 2011 in our hospital. All of the patients enrolled were considered SPN preoperatively. Information about primary tumor location, lymph node metastasis, and other baseline data were collected. Stepwise logistic regressions using N1 and lobe-specific regional mediastinal lymph nodes’ conditions as covariates were used to figure out the key lymph node station that indicated non-regional mediastinal lymph nodes metastases (NRM).

      Results
      As for the location of the primary tumor, 121 cases were in right upper lung (RUL), 42 in right middle lung (RML), 77 in right lower lung (RLL), 107 in left upper lung (LUL), and 68 in left lower lung (LLL). Stepwise regression showed that #2(OR (odds ratio) = 28.250, 95%CI (confidence interval): 1.756-454.422, P=0.018), N1 (OR=24.000, 95%CI: 3.346-172.121, P=0.002) and N1 (OR=21.667, 95%CI: 3.266-143.736, P=0.001) was the key lymph node station for RUL, LUL and RLL, respectively. None of the covariates show statistical significant for LLL.Patients with tumors >2 cm rarely had NRM without primary regional mediastinal involvement. Figure 1 Figure. Malignant cells’ residue when the key station shows negative metastasis

      Conclusion
      With rigid consideration, lobe-specific lymphadenectomy is feasible in practice. This protocol could be established when the lobe-specific key nodes show negative under intraoperative frozen section, especially for those NSCLCs presented as SPN smaller than 2 cm preoperatively. Table. Protocols for lobe-specific mediastinal lymphadenectomy for SPN

      Tumor locations
      RUL LUL RLL LLL RML
      Superior mediastinum^4 ○[b]
      Inferior mediastinum ○[a] ○[b]
      Note: ◎: Complete regional lymphadenectomy is warranted; ○: Lymph nodes dissection could be omitted considerably. [a]: when #2 shows negative in intraoperative frozen section; [b]: when #10, 11 shows negative in intraoperative frozen section; ^4: #1-4 in RUL, #4-7 in LUL

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      O20.04 - DISCUSSANT (ID 3925)

      16:15 - 17:45  |  Author(s): P. De Leyn

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      O20.05 - Prognosis and outcome after surgical resection of solitary brain metastasis in 82 NSCLC patients: a single institution experience (ID 302)

      16:15 - 17:45  |  Author(s): O. Pikin, K. Konstantin, V. Glushko, A. Zaytzev, A. Amiraliev, D. Vursol, A. Kartoveshenko

      • Abstract
      • Presentation
      • Slides

      Background
      The brain is one of the most frequent sites of distant metastasis in patients with lung cancer. Surgical resection of isolated brain metastases in NSCLC patients is not widely accepted and still a matter of debate. The study was aimed to evaluate the long-term results and prognosis after surgical resection of primary tumor and solitary brain metastasis in NSCLC patients.

      Methods
      In this retrospective study, the data of 82 patients who underwent lung resection for primary NSCLC and brain metastasectomy for solitary metastasis between 1991 and 2011 in our clinic were analyzed. There were 68 (82,9%) males and 14 (17,1%) females, median age – 59,6 years. The most common histologic type of lung cancer was adenocarcinoma (70,7%). Synchronous brain metastasis was detected in 21 (25,6%), metachronous – in 61 (74,4%) patients. The primary lung cancer was completely resected in all cases. Surgery included pneumonectomy – in 7 (8,5%), lobectomy – in 69 (85,4%) and wedge resection – in 5 (6,1%) patients. In all cases of synchronous brain metastasis, except one, we performed brain metastasectomy first followed by lung surgery in 4-6 weeks interval. Simultaneous lung resection and brain metastasectomy was performed only in one patient. Surgery in patients with metachronous brain metastasis depended on the time of detection and varied from 4 to 38 months.

      Results
      Postoperative complications were registered in 10 (12,2%) patients, mortality rate was 3,7% (3 patients). Overall 1, 3 and 5-year survival after brain metastasectomy was 52,0%, 29,0% and 25,6% respectively with median survival 18,6 months. The most important prognostic factors were N-status of primary lung cancer and synchronous or metachronous diagnosis of brain metastasis. Three and 5-year survival after brain metastasectomy in patients with N0 status was significantly better than in N+ patients: 56,8% and 34,8% versus 21,4% and 6,5% respectively (p<0,01). Median survival was 19,8 months in N0 group and only 12,4 months in patients with positive lymph nodes. Five-year survival in patients with metachronous brain metastases was 19,8% versus 10,0% in synchronous group (p<0,05). Eight patients are alive free of recurrence, 10 patients – with recurrence in the brain and 64 (78,0%) patients died of disease progression in the brain or other distant sites.

      Conclusion
      Surgery in NSCLC patients with operable solitary brain metastasis is justified especially in N0 cases and metachronous disease. Surgical resection improves long-term results and quality of life in patients with operable brain lung cancer metastasis.

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      O20.06 - Surgical techniques and results of reconstruction of the pulmonary artery for patients with central non-small cell lung cancer (ID 110)

      16:15 - 17:45  |  Author(s): Q. Ma, D. Liu, Y. Guo, B. Shi, Z. Song, Y. Tian, B. Ge, X. Wang, T.A. D'Amico

      • Abstract
      • Presentation
      • Slides

      Background
      It is difficult to achieve a margin-negative resection (R0) for non-small cell lung cancer (NSCLC) patients with infiltration of the pulmonary artery. We report our experience with reconstruction of the pulmonary artery with regard to long-term survival.

      Methods
      Clinical records of 118 patients with NSCLC who underwent partial or circumferential pulmonary artery resection during a 21-year period were reviewed retrospectively. Technical outcomes and survival were analyzed.

      Results
      We performed 22 pulmonary artery sleeve resections, 51 reconstructions by autologous pericardial patch, 36 tangential resections, 3 left main pulmonary artery (PA) angioplasties during pneumonectomy without cardiopulmonary bypass, and 6 by only preserving the 1[st] branch of pulmonary arterial trunk. In 41 patients, bronchial sleeve resection was associated; in 7 cases, superior vena cava reconstruction was also required. Thirty-one patients received induction therapy. Thirteen patients had stage IB disease, 41 stage II, 53 IIIA, and 11 IIIB. Ninety-three patients had squamous cell carcinoma, 22 adenocarcinoma, 2 mixed and 1 large cell carcinoma. Negative bronchial and vascular margins were achieved in all. 5 positive bronchial margins were due to limited lung function. The analysis of 118 cases yielded follow-up data in 94 cases. The mean follow-up was 70 months (range 1-156 months). There was no in hospital death, and the overall 5-year survival was 50.2%. Five-year survival for stages Iand II, versus IIIwere 63.9% versus 37.0% (p=0.0059). Multivariate analysis yielded non-squamous cell carcinoma, stage IIIand patch pulmonary arterioplasty as negative prognosis factors. PA reconstruction associated with bronchial sleeve resection was the positive prognostic factor.´

      Conclusion
      Pulmonary artery resection and reconstruction is feasible and safe, with favorable long-term survival. Our results support this technique as an effective alternative to selected patients with infiltration of the pulmonary artery, such as stage Iand IIand those who proved down-staged from stage III. Accurate preoperative evaluation, precise and suitable surgical techniques are crucial to achieve good results. Only preserving the anterior and apical pulmonary arteries reconstruction of the main pulmonary artery by using the artery conduit technique without cardiopulmonary bypass in association with left pneumonectomy can be performed successfully. Postoperative anticoagulation is unnecessary.

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      O20.07 - Local therapy for limited distant metastasis in patients with completely resected NSCLC (ID 1262)

      16:15 - 17:45  |  Author(s): H. Matsuguma, R. Nakahara, H. Suzuki, T. Sugiyama, K. Inoue, T. Kasai, Y. Kamiyama, S. Katano, K. Mori, K. Yokoi

      • Abstract
      • Presentation
      • Slides

      Background
      In general, distant metastasis is regarded as an incurable systemic disease. Therefore, local therapies including metastasectomy or radiotherapy are rarely applied, and the treatment goals are disease control using chemotherapy or palliation. There are, however, several reports in which local therapy can contribute to long-term survival in patients with metastatic disease, especially for brain metastasis or adrenal metastasis in patients with NSCLC.

      Methods
      Between 1986 and 2009, among 1548 patients who underwent surgical resection for NSCLC in our institution, we identified 405 patients who experienced recurrence after R0 resection, without history of other malignancy, and detailed recurrence information available. We investigated the recurrent mode, number of metastatic focus and organ, treatment for metastasis, and prognosis.

      Results
      Among 405 patients, 245 patients had distant metastasis without local recurrence, 115 had local recurrence, and 45 had both local and distant metastasis. We focused on the 245 patients with distant metastasis without local recurrence, including 215 patients who had only single organ metastasis and 93 patients who had only solitary metastasis. The treatments for distant metastasis and the 5-year survival rates were shown in the Table 1. The number of organ involved and metastatic focus were significantly associated with prolonged survival. Local therapy were mainly applied for limited metastases, and associated with higher survival rates. The number of patients and the 5-year survival rates according to the metastatic organ in patients with solitary metastasis are shown in Table 2. Other metastatic organ included soft tissue in 3 patients, kidney in 3, and trachea, intestine, and abdominal lymph node in 1.Finally, 6 patients survived more than 5 years with disease-free status; these included 2 brains, 2 lungs, 1 bone, and 1 subcutaneous metastasis.

      Table 1
      Multiple organ Single organ Multiple Single
      Treatment Number of pts 5y OS (%) Number of pts 5y OS (%) Number of pts 5y OS (%) Number of pts 5y OS (%)
      BSC 8 0 48 6.4 43 7.1 5 0
      Chemo Tx 3 0 32 16.3 30 17.7 2 0
      Radio Tx 19 5.7 101 11.8 43 0 58 21.4
      Surgery 0 - 34 38.0 6 66.7 28 33.4
      Total 30 3.5 215 15.2 122 8.9 93 23.3
      Table 2
      Organ Number of pts 5y OS (%)
      Brain 36 19.2
      Bone 24 16.7
      Lung 18 32.4
      Adrenal gland 6 0
      Other 9 55.6

      Conclusion
      Prolonged survival can be achieved using local therapy in patients with limited distant metastasis irrespective of metastatic organ.

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      O20.08 - DISCUSSANT (ID 3926)

      16:15 - 17:45  |  Author(s): E. Vallieres

      • Abstract
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      Abstract not provided

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