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M. Tsuboi



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    P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.02-008 - Elevated microsatellite alterations at selected tetra-nucleotide (EMAST) in non-small cell lung cancers - a potential determinant of susceptibility to multiple malignancies (ID 1757)

      11:29 - 11:46  |  Author(s): M. Tsuboi

      • Abstract

      Background
      Microsatellite instability (MSI) can be analyzed by microsatellite markers consisting of mono-, di- and trinucleotide repeat sequences. In primary lung cancer, chromosomal instability including loss of heterozygosity (LOH) has been thought to play an important role in carcinogenesis. Although MSI was thought to be unrelated to lung carcinogenesis, recent findings suggest the role of tetranucleotide repeat sequence instability in prostate, skin, bladder and lung cancers. Unlike Bethesda panel markers (D17S250, D2S123, D5S346, BAT25 and BAT26) for Lynch syndrome, these tetranucleotide markers are not unified. Moreover, there are frequent elevated microsatellite alterations at selected tetranucleotides (EMAST) that are distinct from traditional MSI in several tumor types. EMAST in lung cancer has not been reported to date. We investigated EMAST in non-small cell lung cancers (NSCLCs) using selected tetranucleotide repeat markers (EMAST markers: D8S321, D20S82, UT5037, D8S348, D2S443, D21S1436, D9S747, D9S303, D9S304 and MYCL1) based on previous reports and analyzed their correlation to clinicopathological factors.

      Methods
      Sixty-five NSCLC tissue samples (19 squamous cell carcinomas, 39 adenocarcinomas, one adenosquamous cell carcinoma and six large cell carcinomas) without lymph node metastasis and preoperative chemotherapy or radiation therapy were obtained after resection from Yokohama City University Medical Center. Tumorous DNA was extracted by laser captured microdissection, and paired normal DNA was extracted from non-tumorous tissue or normal lymph nodes. Genotyping for EMAST determination was carried out using ten tetranucleotide repeat markers and five Bethesda panel markers.

      Results
      Using the ten tetranucleotide repeat markers, MSI was detected in 42 of 65 (64.9%) of the tissue samples. There was a higher rate of MSI at selected tetranucleotide markers than at Bethesda panel markers in the tissue samples (12.3%). The high EMAST group (MSI found at two or more markers) was significantly correlated to the presence of multiple malignant neoplasms (p=0.021) compared to the low EMAST group (MSI at none or one marker). We also examined a representative malignant neoplasm (renal pelvic carcinoma) complicated with NSCLC using EMAST markers. The tumor showed EMAST in the two markers (D2S443 and D21S1436).

      Conclusion
      Our results suggest that EMAST could participate in carcinogenesis of NSCLCs and lead to other malignant neoplasms.

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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): M. Tsuboi

      • 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