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H. Nakayama



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    O13 - Limited Resections (ID 101)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Surgery
    • Presentations: 1
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      O13.01 - Limited Resection Trial for Pulmonary Ground-glass Opacity Nodules: Case Selection Based on High Resolution Computed Tomography: Interim Results (ID 1233)

      10:30 - 10:40  |  Author(s): H. Nakayama

      • Abstract
      • Presentation
      • Slides

      Background
      Japanese researchers have reported good correlation between radiologic and pathologic findings in early lung adenocarcinomas. For negative margin confirmation, we found a technique using lavage and cytological examination. The objective of this study is to confirm limited resection efficacy as radical surgery in patients with high-resolution (HR) computed tomography (CT) indicated minimally invasive lung cancer, and to confirm intraoperative cytology as a negative margin indicator and reliable margin non-recurrence predictor.

      Methods
      Enrollment required patients with a tumor ≤ 2 cm in diameter, diagnosed or suspected as a clinical T1N0M0 carcinoma in the lung periphery based on a CT scan. They had to have a HRCT scan indicating a sub-solid nodule with tumor disappearance ratio; TDR ≥ 0.5. (TDR = 1- DM/DL; DM: maximum tumor diameter on mediastinal settings, DL: maximum tumor diameter on lung settings). Patients with a malignancy history within the past 5 years or those unfit for lobectomy and systematic lymph node dissection were excluded. We performed a wedge or segmental resection. The used stapling cartridges were washed with 50 ml saline. Washing saline was centrifuged and sediment stained using Papanicolaou’s method and examined for cancer cells. If cytology was cancer positive, additional margin was resected, and cytologic examination repeated. If the second exam was positive, a routine lobectomy and systematic lymph node dissection was performed. Patients are followed up every 6 months by chest CT for the first 3 years, and annually thereafter for at least 5 years. The initial endpoint was 5-year local recurrence free survival rate, but we are now looking at 10-year rate.

      Results
      This prospective study started in November 2003, and 101 patients were enrolled as of November 2009. This was 4.5% of all resected lung cancer patients during this period, and 99 of them were eligible for analysis. There were 39 men and 60 women, aged 30-75, with an average 62 years. Tumor sizes ranged from 7 to 20 mm on high-resolution CT, averaging 15 mm. There were 11 Noguchi type A tumors, 54 type B tumors, 26 type C tumors, one type D tumor, one malignant lymphoma, one atypical adenomatous hyperplasia, one atypical cuboidal cell hyperplasia, one alveolar hyperplasia, and 3 inflammatory fibroses. All cancers showed no vessel invasion. Although no positive cytology results were obtained, pathologically positive margin was reported after surgery in one type C patient. He later underwent a routine lobectomy and systematic lymph node dissection. There was no clear correlation between tumor size, TDR, and Noguchi subtype. No mortality occurred, but one patient developed postoperative pneumothorax and pneumonia, and another hemorrhagic gastric ulcer. With a median follow-up period of 69 months, there have been no recurrences.

      Conclusion
      So far, HRCT scans appear to predict non- or minimally invasive GGO lung cancers with high reliability, warranting limited resection as curative surgery in this cohort. Intraoperative cytology reliably indicated negative margins and seems to predict freedom from local recurrence.

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    P2.09 - Poster Session 2 - Combined Modality (ID 213)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P2.09-016 - A feasibility study of neoadjuvant chemotherapy with cisplatin, pemetrexed and bevacizumab followed by surgery for nonsquamous non-small cell lung cancer (ID 2956)

      09:30 - 09:30  |  Author(s): H. Nakayama

      • Abstract

      Background
      Bevacizumab and pemetrexed/cisplatin improves the response and survival in patients with advanced or metastatic non-small cell lung cancer (NSCLC); however, the role of these medications in the setting of induction therapy for NSCLC is not well defined. The purpose of this study was to evaluate the feasibility of induction combination therapy with cisplatin, pemetrexed and bevacizumab followed by surgery in patients with clinical stage II/IIIA nonsquamous NSCLC.

      Methods
      Patients with clinical stage II/IIIA nonsquamous NSCLC were enrolled. The induction chemotherapy consisted of three cycles of cisplatin (75 mg/m[2]), pemetrexed (500 mg/m[2]) and bevacizumab (15 mg/kg) on Day 1, administered every 21 days. At least six weeks after the last administration of bevacizumab, the patients underwent surgical resection. The primary endpoint was the complete resection rate after the completion of three cycles of induction chemotherapy. The sample size was set at 30. The feasibility of the treatment was considered to be confirmed if the complete resection rate was 80% (24/30) or more.

      Results
      A total of six institutions in Japan participated in this trial. The study was initiated in June 2010, and patient enrollment was completed in November 2012. Thirty-one patients were recruited, 30 of which were eligible. The median age was 64 years (range: 54-71), and the male/female ratio was 17/13. The PS0/PS1 ratio was 29/1, the adenocarcinoma/large cell carcinoma ratio was 30/0 and the clinical stage IIA/IIB/IIIA ratio was 5/3/22. Grade 3 toxicities included neutropenia (7%), nausea (7%), appetite loss (13%), hypertension (23%) and pulmonary embolism (3%). There were no grade 4 events, and 27 (90%) patients completed three cycles at the full dose of chemotherapy. All but one patient exhibited radiologic tumor reduction based on the RECIST criteria. The objective responses to chemotherapy was CR in 0% of the patients, PR in 37%, SD in 50% and PD in 10% (due to new lesions). The disease control rate (CR+PR+SD) was 87%. Five patients dropped out from the study before surgery due to the patient’s decision in one patient, adverse events in three and disease progression in one. The complete resection rate after the completion of three cycles of induction chemotherapy was 83% (25/80). Therefore, the results met our criterion for feasibility.

      Conclusion
      Induction chemotherapy using a combination of cisplatin, pemetrexed and bevacizumab in patients with resectable clinical stage II/IIIA nonsquamous NSCLC is therefore considered to be a feasible treatment modality. Figure 1

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 2
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      P2.18-019 - Clinicopathological features in non-small cell lung cancer patients with EGFR and KRAS mutations. (ID 2985)

      09:30 - 09:30  |  Author(s): H. Nakayama

      • Abstract

      Background
      Some of molecular pathways have been shown to have prognostic impact in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations predict the effect of EGFR tyrosine kinase inhibitors. KRAS is also critical oncogene, and it has been reported that KRAS pathway might interact with EGFR. But, the role of KRAS in NSCLC is unclear. We investigated the relationship between EGFR and KRAS mutation status and clinicopathological features in NSCLC.

      Methods
      A total of 383 consecutive patients with NSCLC underwent complete resection from 2006 to 2008 were examined retrospectively. The expression of EGFR and KRAS were evaluated by tissue microarray.

      Results
      The mutations of EGFR and KRAS were detected in 181/383 (47.3%) and 32/383 (8.4%) patients, respectively. On analysis of EGFR mutations, female were 107/181 (59.1%) and 51/202 (25.2%), adenocarcinoma were 177/181 (97.8%) and 123/202 (60.9%), no vascular invasion were 147/181 (81.2%) and 110/202 (54.5%), and non-smoker were 99/181 (54.7%) and 41/202 (20.3%) patients in EGFR mutation and wild type patients, respectively. As a result, EGFR mutation was found more frequently in female, adenocarcinoma, no vascular invasion, and non-smoker. The number of patients with pathological T1a were 49/181 (27.0%) and 42/202 (20.8%), T1b were 63/181 (34.8%) and 41/202 (20.3%) in EGFR mutation and wild type patients, respectively. Moreover, average tumor diameter was smaller in patients with EGFR mutation (2.68 cm±0.92) than wild type (3.34cm±1.70) (P<0.001). There were no differences in clinicopathological characteristics between exon19 and 21 EGFR mutations. In contrast, there were no significant differences between KRAS mutation and gender, histopathological type, vascular invasion and.smoking. Although KRAS status was not correlated with pathological T factors, average tumor diameter was larger in patients with KRAS mutation (3.49 cm±2.00) than wild type (2.98 cm±1.35) (P<0.001).

      Conclusion
      Our results suggest that EGFR mutation may suppress vascular invasion, and tumor growth, on the other hand, KRAS mutation may correlate with activation of tumor growth.

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      P2.18-020 - Appropriateness Evaluation of Handling Method for the Small Lung Adenocarcinoma in the Frozen Section Diagnosis by Radiological-Pathological Correlation (ID 3007)

      09:30 - 09:30  |  Author(s): H. Nakayama

      • Abstract

      Background
      The frozen section diagnosis is often performed in the sublobar resection of lung tumor. As no standard of preparation method for the frozen section is proposed, its methodology differs depending on institutions. In this study, we examine appropriateness of our preparation method for a resected specimen with a small adenocarcinoma by comparing between radiological and pathological tumor size.

      Methods
      We retrospectively reviewed the records of 59 resected lung specimens for the frozen section diagnoses (54 wedges and 5 segmentectomies) of lung adenocarcninomas from January to December 2008. After the specimen was well inflated with saline using injector, the pathologist cut it into segments with a width of 3-5mm and immersed them in saline. Taking the segment with maximum diameter of tumor as a sample, the pathological tumor sizes were measured (I) macroscopically by using metal straight ruler, (II) microscopically on the frozen section, and (III) microscopically on the permanent paraffin section. For obtaining the stereoscopic tumor size (Ⅱ and Ⅲ), we used a stereoscopic image analysis software, Leica Application Suite (Leica Microsystems; Tokyo, Japan). CT tumor size was measured by using 1-2mm thin-section CT (X-Vigor/Real or Aquillion, Toshiba Medical Systems, Tokyo, Japan). We obtained the tumor shadow disappearance rate (TDR) by comparing tumor size on the lung and mediastinal window image, to classify 59 cases into two groups according to TDR; TDR≧50% defined as the air-containing type (Group A, n=44) and TDR＜50% as the solid-containing type (Group S, n=15). We also calculated the diremption rate (DR%) between the pathological and the CT tumor size (DR% = |CT tumor size － each pathological tumor size|/CT tumor size×100(%)) and compared Group A and Group S.

      Results
      Mean CT tumor size and its standard deviation(SD) were 18.36±5.23mm, and mean pathological tumor sizes and SD of Ⅰ, Ⅱ, and Ⅲ were 17.17±6.12, 14.29±3.66, and 14.23±4.38mm, respectively. Mean CT tumor size was statistically larger than that of Ⅱ and Ⅲ (p<0.001 using Paired t-test). All the three pathological tumor sizes were correlated to the CT tumor size by Pearson’s correlation analysis (correlation coefficient were 0.766, 0.700, and 0.682, respectively). DR% of Ⅱ and Ⅲ were significantly higher in Group A than Group S by Mann-Whitney U-test (Mean DR% of group A / S (p-values) of Ⅰ, Ⅱ, and Ⅲ were 17.0/13.8% (p=0.196), 25.8/19.3% (p=0.093), and 27.3/15.5% (p=0.032) , respectively).

      Conclusion
      There was a strong correlation between CT tumor size and each pathological tumor size, which shows that our preparation method of the specimen for the frozen section is appropriate to obtain sufficient information about the lung tumor. Furthermore, we found that the pathological tumor size is considerably underestimated by measuring tumor size on the frozen or permanent paraffin section, especially the tumor classified as “air-containing type” including adenocarcinoma with good prognosis. It is therefore important to inflate the lung specimen sufficiently and to transfer it to microscopical examination without tissue shrinking.

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-034 - Therapeutic outcomes in 24 cases of postoperative bronchopleural fistula in lung cancer surgery (ID 2737)

      09:30 - 09:30  |  Author(s): H. Nakayama

      • Abstract

      Background
      Bronchopleural fistula (BPF) after lung resection is a life-threatening complication. Thoracic surgeons should always consider the risk of postoperative BPF and the management to avoid worst scenario, but it is still controversial of which is the best way to manage BPF. We herein describe the results of BPF and explore optimal treatment.

      Methods
      Data on 2270 patients with lung resection for NSCLC over a period from 2000 to 2012 were retrospectively reviewed. Details regarding surgery and subsequent treatment were carefully reviewed. Followed information was recorded; age, sex, clinical diagnosis, associated condition, TNM stage, time from primary operation to rethoracotomy, and postoperative outcome.

      Results
      The overall BPF incidence was 1.1% (24/2270). There were 20(83.3%) male and 4(16.7%) female, mean age was 67.1 years. BPFs occurred after pneumonectomy in 2(8.3%), lobectomy in 20 (83.3%) and sleeve resections in 2 (8.3%). In side right was in 20 (83.3%) and left was in 4 (16.7%). The histological types were 9 adenocarcinomas, 9 squamous cell carcinomas, 6 others. The pathological stage were stage IA in 6 cases, IB in 4, IIA in 3, IIB in 4, IIIA in 6 cases. Mean postoperative day was 19.8. In initial treatment, fenestration was 12 cases, primary closure using various techniques was 8 cases, and completion pneumonectomy was a case. Massive hemoptysis causing death owing to bronchial pulmonary artery fistula (BPAF) was in 3 cases. Primary closure using various techniques succeeded in 3 cases, while the repair failed in the other 5 case and 2 cases subsequently developed further fatal complications. The mortality rate of primary closure was 25% (2/8) and success rate was 38% (3/8). The mortality rate of fenestration was 8.3% (1/12), and success rate was 91.6% (11/12). The overall mortality rate for postoperative BPF was 25% (6/24); 3 cases were BPAF, 3 cases were aspiration pneumonia.

      Conclusion
      BPF remains a major complication in the surgery of lung cancer because of its high mortality and morbidity rate. Especially, the mortality rate of primary closure using various techniques was high, and aspiration pneumonia with consequent ARDS is fatal complication. To avoid death related to BPF, the surgeons should consider the fenestration as soon as the BPF was diagnosed.

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    P3.19 - Poster Session 3 - Imaging (ID 181)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 2
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      P3.19-003 - The correlation between computed tomography findings and the clinicopathological factors in small-sized adenocarcinomas of the lung (10 mm or less in diameter) (ID 1220)

      09:30 - 09:30  |  Author(s): H. Nakayama

      • Abstract

      Background
      We previously reported the correlation among the thin-section computed tomography (TS-CT) findings, the pathological factors (Noguchi’s classification) and the prognosis of the patients. The purpose of this study was to examine the tumor shadow disappearance rate (TDR) on TS-CT findings, clinical course and pathological factors of small-sized adenocarcinomas of the lung according to the 2011 IASLC/ERS Classification.

      Methods
      We retrospectively analyzed 111 peripheral non-mucinous adenocarcinomas of the lung ≤ 10 mm in diameter that were surgically resected at our institute between January 1997 and February 2013. CT scans were obtained by commercially available scanners (X-Vigor/Real or Aquilion M/16 CT scanner; Toshiba Medical Systems; Tokyo, Japan). TS images were obtained with a 1 mm section thickness, pitch of 1, section spacing of 1 mm, 512 × 512 pixel resolution and 1 second scanning time. TDR was defined as the ratio of the maximum diameter of the tumor opacity of the mediastinal window to that of the lung window on TS-CT. We also examined the relationship among the TDR, the patient backgrounds, pathological findings (i.e., lymph node metastasis, pleural invasion, vascular invasion and lymphatic invasion) and clinical course. The histologic subtypes were analyzed according to the 2011 IASLC/ATS/ERS International Multidisciplinary Classification of Lung Adenocarcinoma.

      Results
      The median age of the patients was 64 (range, 23-83) years, and 66 patients (59.5%) were female. Sixty-four patients (57.7%) were never-smokers. The average tumor size was 8.7 mm (range, 5-10 mm). Regarding the histological subtypes, 70 cases were adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA), 19 were acinar predominant (AP), 13 were papillary predominant (PP) and seven were solid predominant (SP). Two cases could not be determined. Seventy cases diagnosed AIS or MIA were all stage IA, and none of these patients relapsed. Six cases relapsed after surgery; three cases of AP, two of PP and one of a SP tumor. In a comparison of the clinical course, the pathological differentiation and the TS-CT findings, all six cases relapsed after surgery showed ≤ 40% in TDR. Four cases diagnosed with lymph node metastasis (i.e., cases diagnosed in stage IIA or higher) showed ≤ 22% in TDR. Twelve cases with pleural invasion or vascular invasion or lymphatic invasion in the pathological factors of the resected lesions showed ≤ 28% in TDR. The TDR of AIS and MIA cases were all ≥ 50%.

      Conclusion
      There are sometimes pathologically invasive lesions even in small-sized adenocarcinomas of the lung. We found that the TDR is related to the clinical course and pathological factors in small-sized adenocarcinomas of the lung (10 mm or less in diameter). The lesions with a TDR ≤ 40% in the TS-CT images may be a group of highly malignant with an increased risk of relapse. The TDR may contribute to the determination of the optimal therapeutic strategy. We need a more robust prospective study to validate the efficacy of TDR.

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      P3.19-010 - The Status of EGFR Mutations in Mixed Ground-Glass Opacity (part-solid GGO) on Thin-section CT (ID 1826)

      09:30 - 09:30  |  Author(s): H. Nakayama

      • Abstract

      Background
      Thin-section CT (TS-CT) provides us with a more precise image of small pulmonary carcinomas. Thin-slice sections with thicknesses of 0.5 mm-1mm reflect, with some accuracy, the histopathological findings; mixed ground-glass opacity (part-solid GGO) is one characteristic finding of pulmonary adenocarciomas. These findings are vary in appearance, for example; some contain mainly GGO components, and some contain mainly solid portions. CT findings of mixed GGO, pathological findings and prognoses have been reported. Presently, we do not fully understand the correlation between TS-CT findings of mixed GGO and the status of EGFR mutation.

      Methods
      We retrospectively reviewed the records and TS-CT scans of 115 patients with mixed GGO tumors. All patients had undergone surgical resection between 2002 and 2008. Tumor diameters measured 20mm or less in size. All TS-CT images were acquired by Aquillion CT scanner (Toshiba Medical System). TS-CT images of tumors were obtained at 135kVp at 250mAs with 0.5-1mm section thickness. All images were photographed using mediastinal (level, 40HU; width, 400HU) and lung (level, -600HU); width, 1600HU) window settings. All TS-CT images on lung window setting were classified as: (1) Predominant GGO type (pGGO; solid portion areas less than 50% of tumor), (2) Heterogeneous type (heterogenous increased density), (3) Predominat solid type (pSolid; Solid portion areas took up more than 50% of tumor). We analyzed EGFR and Kras mutations, and then studied the correlations between these TS-CT findings and the status of EGFR mutations.

      Results
      The tumors in all 115 cases were well-differentiated adenocarcinomas. GwS type; 24 cases, Heteogenous type; 30 cases, and SwG type 61 cases. The EGFR mutation ratio was 66.6% in pGGO type, 90% in Heterogenous type and 52.7% in pSolid type. The ratio of EGFR mutation was greater in Heterogenous types compared to pGGO and pSolid types. (pGGO/Hetero p=0.045, pSolid/Hetero p=0.00038).

      Conclusion
      There is a correlation between the thin-section findings of mixed GGO and the status of EGFR mutations.