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Morihito Okada
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MA 19 - Mesothelioma: Bench to Bedside (ID 680)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:Dean A Fennell, Hedy Lee Kindler
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 315
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MA 19.01 - A Phase II Study of Nivolumab: A Multicenter, Open-Label, Single Arm Study in Malignant Pleural Mesothelioma (MERIT) (ID 9111)
11:00 - 12:30 | Author(s): Morihito Okada
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a rare and highly aggressive malignancy with poor prognosis and limited treatment options beyond progression after platinum-based combination with pemetrexed chemotherapy. Nivolumab (anti-PD-1, ONO-4538, BMS-936558), a humanized monoclonal antibody, PD-1 immune-checkpoint inhibitor, has demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Here, we report the preliminary results of a phase II study to evaluate the efficacy and safety of Nivolumab in previously treated Japanese MPM patients (pts): ONO-4538-41/JapicCTI-No.163247.
Method:
This open-label study enrolled advanced or metastatic MPM pts previously treated with up to two regimens of chemotherapy including platinum-based combination therapy with pemetrexed. Enrollment criteria also included histologically-confirmed, unresectable MPM without prior surgery, measurable disease and ECOG performance status 0-1. There was no restriction of PD-L1 status. Pts received Nivolumab 240 mg flat dose Q2W until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) (modified RECIST by independent review committee, expected response rate was 19.2%); secondary endpoints included disease control rate (DCR), duration of response, progression-free survival (PFS), and overall survival (OS).
Result:
From July to October 2016, 34 pts were enrolled in 15 centers. Males: 85.2%, median age: 68.0 years (range 43-78), PS 1: 61.8%, epithelial/sarcomatoid/biphasic: 79.4%/8.8%/11.8%, 1 prior regimen: 70.6%. Median follow-up was 6.7 months. Independent review committee-assessed 6-month ORR was 29.4% (n=10, 95%CI: 16.8-46.2) and objective responses were observed across tissue types, epithelioid 7/27 (25.9%), sarcomatoid 2/3 (66.7%), biphasic 1/4 (25.0%). 13 pts (38.2%) had stable disease, resulting in a 6-month DCR of 67.6%. Median PFS was 6.1 months (95%IC: 2.9-NR). Median OS has not been reached. 6-month PFS and OS rates are 50.9% (95%CI: 32.7-66.5) and 85.3% (95%IC: 68.2-93.6). 23 (67.6%) pts experienced drug-related adverse event (DRAE), and 7 (20.6%) experienced grade 3/4 DRAEs. 2 pts required dose discontinuation because of pneumonitis (Grade2 and 3).
Conclusion:
Single-agent Nivolumab has significant activity in 2[nd]/3[rd] line MPM pts and met the primary endpoint, suggesting that Nivolumab has a potential to be a new therapeutic option for MPM.
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-002 - Diagnostic Utility of MUC4 Expression to Differentiate Epithelioid Mesothelioma from Lung Adenocarcinoma and Squamous Cell Carcinoma (ID 8372)
09:30 - 16:00 | Author(s): Morihito Okada
- Abstract
Background:
Malignant mesothelioma is a highly aggressive asbestos related cancer with poor prognosis and its diagnosis and differentiatiation from various cancers is challenging. In addition to histological features, many positive and negative immunohisotchemical markers are needed to differentiate epitheioid mesothelioma from lung adenocarcinoma and/or squamous cell carcinoma. The positive mesothelial markers calretinin, WT-1, D2-40, CK5/6; positive lung adenocarcinoma markers, TTF-1, Napsin-A, Claudin-4, CEA; and positive squamous cell markers, P40, P63, CK5/6, MOC31 are routinely used. However, these markers are not sufficient and novel markers have to be identified.
Method:
Patients and Histologic Samples Pathological specimens (formalin-fixed paraffin-embedded tissue blocks) of 65 epithelioid mesothelioma and 60 lung adenocarcinoma and 57 squamous cell carcinoma were obtained from the archives of the Department of Pathology, Hiroshima University. All histological sections were reviewed and reclassified according to recent 2015 WHO classification and was confirmed by histologic findings and an immunohistochemical marker panel recommended by 2012 IMIG update to practical guidelines Immunohistochemical Procedures and Evaluation of Expression of MUC4 Immunohistochemical staining was performed using the Ventana Benchmark GX automated immunohistochemical station (Roche Diagnostics, Tokyo, Japan). Cells showing nuclear staining for calretinin, WT1, p40, p63, and TTF-1, cytoplasmic staining for MUC4 and napsin A, membranous staining for D2-40, MOC-31, and claudin-4 or membranous and/or cytoplasmic staining for CK5/6 and CEA were regarded as ‘positive’. Positive Immunoreactivity was semiquantified scored from 0 to 3+.
Result:
MUC4 positivity was present in 50/60(83.3%) cases, case of adenocarcinoma and 50/56(89.3%) cases of squamous cell carcinoma but none of 65 epithelioid mesotheliomas (0%). Among lung adenocarcinoma cases, 21 cases showed score 3+, 9 cases 2+ and 20 cases score +1. In lung squamous cell carcinoma, 21 cases score 3+, 10 cases score 2+ and 19 cases score 1+. The sensitivity and specificity of MUC4 to differentiate epithelioid mesothelioma from lung adenocarcinoma were 100% and 83.3% respectively with accuracy rate of 92%. Similarly, sensitivity and specificity of MUC4 to differentiate epithelioid mesothelioma from lung squamous cell carcinoma 100% and 89.3% respectively with accuracy rate of 95%. MUC4 expression showed sensitivity of 100%, but lower specificity of 86.2% and accuracy rate of 91.2% than CEA or Claudin-4 expression. However, it showed better sensitivity, specificity and accuracy rate than that of MOC-31.
Conclusion:
MUC4 is an additional negative immunohistochemical marker to differentiate epithelioid mesothelioma from lung adenocarcinoma and/or squamous cell carcinoma.
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P1.02-052 - Identification of DAB2 and Intelectin-1 as Novel Positive Immunohistochemical Markers of Epithelioid Mesothelioma (ID 9299)
09:30 - 16:00 | Author(s): Morihito Okada
- Abstract
Background:
Malignant mesothelioma is a fatal malignant tumor. It is often difficult to diagnose and to differentiate from other carcinomas, especially pulmonary adenocarcinoma. As there are currently no absolute immunohistochemical positive markers for the definite diagnosis of epithelioid mesothelioma, the identification of additional “positive” markers that may facilitate this diagnosis becomes of clinical importance.
Method:
Gene Expression Analysis Formalin-fixed paraffin-embedded tissue sections from 6 epithelioid mesothelioma and 6 pulmonary adenocarcinoma cases were used for gene expression analysis. RNA extraction for gene expression analysis was performed from papillary or solid growth of tumor cells in each specimen. The Human Transcriptome 2.0 GeneChip Array containing gene transcript sets of 44,699 protein coding and 22,829 nonprotein coding clusters was used to analyze gene expression profiles. Validation by Real-time RT PCR & Western Blotting The increased mRNA expression of DAB2 and Intelectin-1 was validated by reverse transcriptase polymerase chain reaction of RNA from tumor tissue and protein expression was validated by Western blotting of 5 mesothelioma cell lines. Immunohistochemical Procedures and Evaluation of Expression of DAB2 and Intelectin-1 The utility of DAB2 and Intelectin-1 in the differential diagnosis of epithelioid mesothelioma and pulmonary adenocarcinoma was examined by an immunohistochemical study of 75 cases of epithelioid mesothelioma and 67 cases of pulmonary adenocarcinoma.
Result:
Differential Gene Expression Of the 44,699 protein coding and 22,829 nonprotein coding transcripts on the Human Transcriptome 2.0 GeneChip Array, 902 statistically significant mRNA transcripts were differentially expressed, with a greater than 1.3-fold difference, between epithelioid mesothelioma and pulmonary adenocarcinoma. Validation Realtime RT-PCR showed relative mRNA expression of DAB2 and Intelectin-1 was significantly higher in epithelioid mesothelioma than that in pulmonary adenocarcinoma. Western blot analysis showed DAB2 and Intelectin-1 protein expression in all 5 commercially available mesothelioma cells lines with anti-DAB2 and anti-Intelectin-1 antibody. Immunohistochemical Expression Profiles in Epithelioid Mesothelioma and Pulmonary Adenocarcinoma The expression of DAB2 and Intelectin-1 was localized in the cytoplasm of tumor cells in epithelioid mesothelioma cases. Positive DAB2 expression was observed in 60 of 75 epithelioid mesotheliomas (80.0%) and 2 of 67 pulmonary adenocarcinomas (3.0%). In half of epithelioid mesotheliomas, DAB2 immunoreactivity was generally strong and diffuse (score 3+). In contrast, pulmonary adenocarcinomas showing DAB2 expression was focal (score 1+).
Conclusion:
We identified 2 novel positive markers of epithelioid mesothelioma, DAB2 and Intelectin-1, by using gene expression microarray analysis and confirmed their utility to differentiate epithelioid mesothelioma from pulmonary adenocarcinoma by immunohistochemical study.
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P1.13 - Radiology/Staging/Screening (ID 699)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.13-011a - Stratification Based on PET/CT Findings for Malignant Grade of Radiologically Pure Solid Small-Sized (≪ 2cm) Lung Cancer (ID 9372)
09:30 - 16:00 | Author(s): Morihito Okada
- Abstract
Background:
Radiologically pure solid tumors are heterogeneity because of including various histological type, however, small-sized tumors are difficult to be preoperatively diagnosed histology. The aim of this study was to identify preoperative predictors for pathological malignant of pure solid lung cancer in clinical early stage.
Method:
The data from a multi-center database of 220 patients who underwent anatomical resection for radiologically pure solid, tumor size 2 cm or less, and clinical N0 lung cancer were retrospectively analysed. Factors affecting survival were assessed using Cox regression analysis. Predictors were found by drawing the receiver operating characteristic curves (ROC) and evaluated the possible cutoff value for independent prognostic factor.
Result:
Pure solid tumors included 164 (74%) adenocarcinoma, 33 (15%) squamous cell carcinoma, 16 (7%) neuroendocrine tumor, 5 (2%) pleomorphic carcinoma, and 3 (1%) adenosquamous cell carcinoma. In multivariate analyses, high malignant grade histology such as micropapillary and solid predominant adenocarcinoma, adenosquamous cell carcinoma, neuroendocrine tumor, or pleomorphic carcinoma and pathological lymph node metastasis were an independent prognostic factors for recurrence-free survival. The ROC showed that 3.55 in maximum standardized uptake value (SUV max) was cut-off value for detecting high malignant grade histology or lymph node metastasis (area under the curve, 0.71; 95% confidence interval, 0.63 – 0.78). Tumors with SUV max ≥ 3.55 had significantly more high-grade histology, the presence of lymphatic and vascular invasion, and lymph node metastasis and poorer recurrence-free survival rate than SUV max < 3.55 (Figure). Figure 1
Conclusion:
The prognosis of radiologically pure solid tumor with small size and clinical N0 lung cancer was stratified according to SUV max. SUV max could evaluate pathological malignant grade and help the decision of appropriate surgical procedure.
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P2.05 - Early Stage NSCLC (ID 706)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.05-011 - Segmentectomy versus Wedge Resection in Patients with Clinical Stage I Non-Small Cell Lung Cancer Who Were Unfit for Lobectomy (ID 8208)
09:30 - 16:00 | Author(s): Morihito Okada
- Abstract
Background:
The purpose of this study is to compare the surgical outcomes after segmentectomy versus wedge resection in patients with clinical stage I non-small cell lung cancer (NSCLC) who were unfit for lobectomy.
Method:
Between April 2007 and December 2015, 99 patients with clinical stage I NSCLC who were considered unfit for lobectomy and underwent sublobar resection were identified. Propensity scores were estimated including variables such as age, sex, smoking history, solid tumor size, SUVmax of the tumor, preoperative pulmonary functions, and Charlson comorbidity index. Surgical outcomes were compared between patients who underwent segmentectomy and those who underwent wedge resection.
Result:
Thirty-nine patients underwent segmentectomy and sixty patients underwent wedge resection. Operation time (median, 169 min vs. 72.5 min, P <0.001) and blood loss (median, 84 g vs. 10 g, P = 0.001) were significantly different between the procedures. Severe postoperative complications (> Grade IIIa) was more frequently in segmentectomy (15.4%) than in wedge resection (3.3%, P = 0.054). Propensity score-adjusted multivariable analysis showed that operative procedure was an independent predictive factor for severe postoperative complication (segmentectomy, odds ratio = 8.18; P = 0.021). Overall survival (OS) and recurrence-free survival (RFS) were not significantly different between segmentectomy (3 y-OS, 79.1%, 3 y-RFS, 77.7%) and wedge resection (3 y-OS, 86.3%, 3 y-RFS, 68.5%; P = 0.81, P = 0.91, respectively). Propensity score-adjusted multivariable Cox analysis revealed that operative procedure was not an independent factor for OS (segmentectomy, hazard ratio = 1.7, P = 0.24) or RFS (segmentectomy, hazard ratio = 1.1, P = 0.82). In propensity score matching method, similar results were observed.
Conclusion:
Segmentectomy is more toxic, but provides similar prognosis compared with wedge resection. Wedge resection may be an optimal procedure in patients with clinical stage I NSCLC who were considered unfit for lobectomy.
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P2.09 - Mesothelioma (ID 710)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.09-008 - Usefulness of Immunohistochemistry in the Differential Diagnosis of Epithelioid Mesothelioma and Lung Squamous Cell Carcinoma (ID 9268)
09:30 - 16:00 | Author(s): Morihito Okada
- Abstract
Background:
The differential diagnosis between epithelioid mesothelioma (EM) showing a solid histological pattern (solid EM) and poorly differentiated squamous cell carcinoma (SCC) can be challenging with conventional light microscopy (haematoxylin and eosin-stained specimen) alone. The role of immunohistochemistry in distinguishing pleural EM from lung adenocarcinoma (LAC) has received much attention. Currently, many immunohistochemical markers are available for distinguishing pleural EM from LAC. . However, there are only a few reports on the immunohistochemical differential diagnosis of EM and lung SCC. Ordonez et al. have reported the immunohistochemical analyses of 30 EMs showing a solid pattern and 30 pulmonary non-keratinizing SCCs, and have recommended the combination of two positive (Wilms' tumour gene product; WT1 and calretinin/mesothelin) and two negative (p63 and Epithelial-related antigen; MOC31) markers for differentiating EM from lung SCC. The aims of this study were to clarify the usefulness of immunohistochemistry in the differential diagnosis of solid EM and poorly differentiated SCC, and to confirm the validity of a specific type of antibody panel. Additio nally, we aimed to clarify the pitfalls of immunohistochemical analyses.
Method:
Formalin-fixed paraffin-embedded specimens from 36 cases of solid EM and 38 cases of poorly differentiated SCC were immunohistochemically examined for calretinin, podoplanin (D2-40), WT1, cytokeratin (CK) 5/6, p40, p63, carcinoembryonic antigen (CEA), MOC31, claudin-4, thyroid transcription factor-1 (TTF-1), and napsin A.
Result:
WT1 showed the highest diagnostic accuracy (85.1%) as a mesothelial marker, and CEA, p40 and claudin-4 showed higher diagnostic accurac ies (95.9%, 94.6%, and 93.2%, respectively) as carcinoma markers. Calretinin (diagnostic accuracy: 75.7%), D2-40 (diagnostic accuracy: 67.6%), CK5/6 (diagnostic accuracy: 63.5%), TTF-1 (diagnostic accuracy: 55.4%) and napsin A (diagnostic accuracy: 52.7%) could not differentiate between solid EM and poorly differentiated SCC. Among these markers, the combination of calretinin and WT1 showed the highest diagnostic accuracy (86.5%) as a positive marker, and the combination of p40 and CEA showed the highest diagnostic accuracy (97.3%) as a negative marker. The combin ation of CEA and claudin-4 also showed relatively high diagnostic accuracy (94.6%) as a negative marker.
Conclusion:
We recommend the combination of WT1 and calretinin as a positive maker, and the combination of CEA and claudin-4 as a negative marker, for diff erential diagnoses of solid EM and poorly differentiated SCC.
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P2.15 - SCLC/Neuroendocrine Tumors (ID 716)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.15-011 - Therapeutic Strategies and Genetic Comparisons in SCLC and LCNEC of the Lung Using Next-Generation Sequencing (ID 9119)
09:30 - 16:00 | Author(s): Morihito Okada
- Abstract
Background:
Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung are highly malignant tumors and classified as variants of endocrine carcinoma and subdivided into pure or combined type. Clinical benefit of this stratification and strategy for target therapy has not been established in these tumors.
Method:
This study aimed to compare genetic and clinicopathological features between SCLC and LCNEC or pure and combined types, evaluate the usefulness of classification methodology, and explore the possibility of target therapy using next-generation sequencing (NGS). NGS custom panel was designed to cover 36 genes with median coverage percentage of 99.57% (80.89-100). As clinicopathological features, patients’ characteristics and immunohistochemistry using 8 antibodies were evaluated.
Result:
In 13 SCLC and 22 LCNEC cases, 72 point mutations, 19 deletions, and 3 insertions were detected. As therapeutically targetable variants, mutations in EGFR (L858R), KRAS (G12D, G12A, G12V), and PIK3CA (E545K) were detected in 5 cases. One combined LCNEC cases harboring EGFR mutation (L858R) showed response to EGFR-tyrosine kinase inhibitor. However, these therapeutically targetable cases were not accompanied by specific features in immunohistochemistry or histology. And there was no significant genetic feature between SCLC and LCNEC or pure and combined types.
Conclusion:
Although even SCLC and LCNEC cases harbored therapeutically targetable mutations and potentially include the benefit for target therapy, they were not identifiable by clinicopathologic background. And there was not significant genetic difference between SCLC and LCNEC, including between pure and combined types. Classifying SCLC and LCNEC in same category is reasonable. However, distinguishing the pure type from combined type was not validated. Comprehensive genetic analysis should be performed to detect targetable variants in any type of SCLC and LCNEC.
