Noriaki Sukoh

A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations

Retrospective analysis has shown that activating mutations in exons 18–21 of the epidermal growth factor receptor (EGFR) gene are a predictor of response to gefitinib. We conducted a phase II trial to evaluate the efficacy and safety of gefitinib as first-line therapy for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Patients with stage IIIB or IV chemotherapy-naïve NSCLC with EGFR mutation were treated with 250 mg gefitinib daily. For mutational analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations (deletions in or near E746-A750, n=16; L858R, n=4). Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75% (95% CI, 48–93%). After a median follow-up of 12.7 months (range, 3.1–16.8 months), 10 patients demonstrated disease progression, with median progression-free survival of 8.9 months (95% CI, 6.7–11.1 months). The median overall survival time has not yet been reached. Most of the toxicities were mild. This study showed that gefitinib is very active and well tolerated as first-line therapy for advanced NSCLC with EGFR mutations.

Endobronchial ultrasonography with guide-sheath for peripheral pulmonary lesions

The usefulness of endobronchial ultrasonography (EBUS) with guide-sheath (GS) as a guide for transbronchial biopsy (TBB) for diagnosing peripheral pulmonary lesions (PPL)s and for improving diagnostic accuracy was evaluated in this study. EBUS-GS-guided TBB was performed in 24 patients with 24 PPLs of ≤30 mm in diameter (average diameter=18.4 mm). A 20-MHz radial-type ultrasound probe, covered with GS was inserted via a working bronchoscope channel and advanced to the PPL in order to produce an EBUS image. The probe with the GS was confirmed to reach the lesion by EBUS imaging and X-ray fluoroscopy. When the lesion was not identified on the EBUS image, the probe was removed and a curette was used to lead the GS to the lesion. After localising the lesion, the probe was removed, and TBB and bronchial brushing were performed via the GS. Nineteen peripheral lesions (79.2%) were visualised by EBUS. All patients whose PPLs were visible on EBUS images subsequently underwent an EBUS-GS-guided diagnostic procedure. A total of 14 lesions (58.3%) were diagnosed. Even when restricted to PPLs <20 mm in diameter, the diagnostic sensitivity was 53%. In conclusion, endobronchial ultrasonography with guide sheath-guided transbronchial biopsy was feasible and effective for diagnosing peripheral pulmonary lesions.

Clinical benefit of readministration of gefitinib for initial gefitinib-responders with non-small cell lung cancer

BackgroundGefitinib, an oral agent of epidermal growth factor receptor tyrosine kinase inhibitor, has a certain efficacy against non-small cell lung cancer (NSCLC). Several predictive factors of gefitinib sensitivity have been well described. However, few studies have investigated the clinical features of gefitinib-responders. In the present study, we analyzed the response and disease progression of primary and metastatic lesions to gefitinib in responders and the results of gefitinib readministration following temporary cessation of gefitinib upon progression of initial gefitinib treatment and other treatments.MethodWe retrospectively evaluated the clinical courses of 27 NSCLC patients who received gefitinib and achieved either a complete or partial response.ResultsThe best-response rate and disease-control rate against the initial chemotherapy for the gefitinib-responders were 27.3% and 77.3%, respectively. Favorable efficacy was observed in the primary lesion and metastases to the lung, liver and brain, while there was no obvious effect on bone metastasis. The primary lesion and intrapulmonary metastasis were the sites of major recurrence. Median progression-free survival was 13.8 months, median duration of gefitinib treatment was 17.0 months and median overall survival was 29.2 months. Some of the patients who experienced disease progression after responding to gefitinib were again sensitive to readministration of gefitinib following temporary cessation of gefitinib and other treatments.ConclusionPatients may still be expected to have prolonged survival if they once responded to gefitinib and then underwent various subsequent treatments followed by readministration of gefitinib. These findings might provide valuable information for the management of gefitinib-responders.

Immunohistochemical distributions of cathepsin B and basement membrane antigens in human lung adenocarcinoma: association with invasion and metastasis.

The distributions of cathepsin B (CB) a lysosomal cysteine proteinase, type IV collagen (CIV) and laminin (LM), which are main components of basement membranes (BMs) were studied in a series of 64 human lung adenocarcinomas using an immunohistochemical technique. Over-expression of CB (>80% positive cells) was significantly associated with the grade of tumour differentiation (p<0.01), with lymph node metastasis (p<0.01) and with BM degradation (p<0.01) detected by the staining pattern of CIV and LM. It was significantly associated with a prognostic disadvantage (p<0.01). The immunohistochemical staining pattern of CB has a close relationship with degradation of BM, and may be used as a marker for tumour metastasis and prognosis in lung adenocarcinoma.

Phase II Study of Gefitinib Readministration in Patients with Advanced Non-Small Cell Lung Cancer and Previous Response to Gefitinib

Objective: Salvage treatment for acquired resistance to gefitinib has yet to be developed. We conducted the first prospective phase II study of gefitinib readministration in previous gefitinib responders. Methods: Gefitinib (250 mg/day) was readministered to patients with advanced/metastatic non-small cell lung cancer who had achieved objective response to initial gefitinib and subsequently received cytotoxic chemotherapy after disease progression with initial gefitinib. The primary endpoint was the objective response rate with gefitinib readministration. Secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), quality of life, and toxicity. Changes in lung cancer-related symptoms were evaluated using the seven-item lung cancer subscale of the questionnaire. Results: Sixteen patients were enrolled between February 2005 and January 2008. Most had received ≧3 regimens of chemotherapy. Response and disease-control rates for all patients were 0 and 44%. Median PFS and OS were 2.5 and 14.7 months, respectively. Four of 7 patients with stable disease experienced a long duration (≧6 months) of disease control without severe toxicity. Symptom improvement was observed in 2 of 12 patients (17%) for whom quality of life was evaluable. Conclusion: Gefitinib represents a useful therapeutic option for selected previous gefitinib responders.

Endobronchial Ultrasonography with a Guide Sheath for Pure or Mixed Ground-Glass Opacity Lesions

Background: Ground-glass opacity (GGO) lesions are difficult to diagnose by transbronchial biopsy (TBB). Objectives: We attempted to diagnose solitary peripheral GGO predominant-type lesions by TBB using endobronchial ultrasonography with a guide sheath (EBUS-GS) under X-ray fluoroscopic guidance, and to evaluate several factors associated with diagnostic yield. Methods: The medical records of 67 patients with GGO predominant-type lesions who underwent TBB using EBUS-GS under X-ray fluoroscopic guidance were retrospectively reviewed. Results: Of the 67 lesions, 38 (57%) were successfully diagnosed by EBUS-GS (5/11 pure GGO lesions and 33/56 mixed GGO lesions). The diagnosable lesions were significantly larger than the nondiagnosable lesions (24 vs. 17 mm, respectively; p < 0.01). Regarding the diagnostic yield by signs on computed tomography, the lesions with a bronchus leading directly to a lesion had a significantly higher diagnostic yield than the others (p < 0.05). When GGO lesions were confirmed under X-ray fluoroscopic guidance, the diagnostic yield was 79% (vs. 40% in lesions not visible on X-ray fluoroscopy; p < 0.05). Conclusions: EBUS-GS is a useful and valuable diagnostic modality, even for GGO predominant-type lesions located at the lung periphery.

Quantitative immunocytochemical assays of topoisomerase II in lung adenocarcinoma cell lines : Correlation to topoisomerase IIα content and topoisomerase II catalytic activity

The examination of topoisomerase II alpha content by Western blot analysis or topoisomerase II catalytic activity by decatenation of kDNA requires a large number of cells, but it is difficult to collect sufficient cells for these biochemical analyses from lung cancer patients by transbronchial brushing or aspiration. In this study, we explored the relationship between these biochemical analyses and topoisomerase II immunostaining in cytospin preparations of three lung adenocarcinoma cell lines. The levels of topoisomerase II alpha content were about 8.4 for A549, 2.9 for PC-3 and 1 for RERF-LC-MS, and the levels of topoisomerase II catalytic activity were about 4, 2, and 1, respectively. The percentages of strongly positive cells for topoisomerase II immunostaining were 60.9% for A549, 33.3% for PC-3, and 14.3% for RERF-LC-MS, and these were compatible with the levels of topoisomerase II alpha content or topoisomerase II catalytic activity. Our results indicate that topoisomerase II immunostaining can be utilized in place of biochemical analysis.

Clinical Evaluation of Serum Laminin P1 and 7S Collagen in Lung Cancer Patients.

健常者19例, 肺癌患者59例 (腺癌32例, 扁平上皮癌14例, 小細胞癌13例), 転移性肺腫瘍7例について, 血清ラミニンP1, 7Sコラーゲン濃度を測定した.小細胞癌患者のみで健常者より血清ラミニンP1, 7Sコラーゲン値ともに平均値が有意に増加し, 陽性率も高かった.腺癌, 扁平上皮癌患者では, 病期進行例で高値例を認めた.更に小細胞癌で治療によって測定値の変化を認め, 治療モニターとして有用となる可能性が考えられた.

Cytodiagnostic significance of AgNORs in body cavity fluids.

胸水・腹水などの体腔液細胞診で悪性細胞か否かの診断が困難な異型細胞に遭遇することがある.このような細胞の鑑別のため, 疑陽性と判定された異型細胞のSilver-bindingnucleolarorganizer regions (AgNORs) について検討した.同じく疑陽性と判定された異型細胞でも, 悪性体腔液中の異型細胞では核内AgNORs平均個数 (mean±SD) は3.4±0.7であり, 非悪性体腔液中にみられた異型細胞での2.0±0.6に比べて有意に高値であった (P<0.01).特に核内AgNORs平均個数が3以上のときは, その体腔液が悪性である可能性がきわめて高かった.また, 疑陽性と判定された悪性胸水では, 多くが胸水CEA・核内AgNORs平均個数とも高値であるが, 前者が正常, 後者が高値の例もあった.体腔液に疑陽性と判定された異型細胞がみられた場合, 核内AgNORsの計測は体腔液の良性・悪性の鑑別に有用であった.