S Ogura

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.

Predictive value of expression of p16INK4A, retinoblastoma and p53 proteins for the prognosis of non-small-cell lung cancers.

The predictive value of expression of p16INK4A, retinoblastoma (Rb) and p53 proteins for prognosis was evaluated in 76 patients with non-small-cell lung cancers (NSCLCs) that were potentially curatively resected between 1990 and 1995, using the results of immunostaining analyses of these proteins as reported in our previous study (Kinoshita et al, 1996). Of these NSCLCs, 22 (29%) lacked p16 protein expression and eight (11%) Rb protein, while 30 (39%) showed positive (altered) p53 protein expression. Survival of patients with p16-negative tumours was not significantly different from that of patients with p16-positive tumours (5-year survival rates 67% and 72% respectively, P = 0.8), nor was survival of patients with Rb-negative tumours significantly different from that of patients with Rb-positive tumours (5-year survival rates 42% and 69% respectively, P = 0.9). Moreover, survival of patients with p16/Rb-negative (either p16- or Rb-negative) tumours was not significantly different from that of patients with p16/Rb-positive (both p16- and Rb-positive) tumours (5-year survival rates 67% and 68% respectively, P = 0.7). In contrast, survival of patients with p53-positive (altered) tumours tended to be shorter than that of patients with p53-negative (unaltered) tumours (5-year survival rates 56% and 78% respectively, P = 0.06). In univariate analysis of potential prognostic factors, p16, Rb and p16/Rb proteins were not significant prognostic factors in the present cohort of potentially curatively resected NSCLCs. Altered p53 protein status tended to be a negative prognostic factor (P = 0.06 by the univariate analysis). These results indicate that loss of p16 protein alone, or in combination with loss of Rb protein, does not predict the clinical outcome of patients with resected NSCLCs.

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.

Retention index of thallium-201 single photon emission computerised tomography (SPECT) as an indicator of metastasis in adenocarcinoma of the lung

We examined the relationship between the retention of thallium-201 (201Tl) on a delayed scan and the metastatic potential of adenocarcinomas of the lung. We studied 43 patients with adenocarcinoma of the lung and divided them into two groups according to the presence or absence of lymph node metastasis. 201Tl single photon emission computerised tomography (SPECT) was conducted twice: 15 min (early scan) and 120 min (delayed scan) after intravenous injection of 3 mCi of 201Tl chloride. We calculated the retention index in order to evaluate the degree of 201Tl retention in the primary tumour. The retention indices were significantly higher in the group that was positive for lymph node metastasis than in the negative group. In adenocarcinomas with high metastatic potential, 201Tl SPECT demonstrated slow washout or increased retention on the delayed scan. The retention index of 201Tl SPECT is a useful indicator of metastatic potential, thereby facilitating the prediction of prognosis, and provides insight into the relationship between 201Tl uptake and malignancy. This is the first report demonstrating a significant relationship between the retention of 201Tl SPECT and lymph node metastasis.

Predicting chemotherapeutic response to small-cell lung cancer of platinum compounds by thallium-201 single-photon emission computerized tomography

Thallium-201 single-photon emission computerized tomography (SPECT) was used to clarify the relationship between 201Tl uptake and the response in chemotherapy to platinum compounds in 21 patients with small-cell lung cancer. 201Tl-SPECT scans were obtained twice: at 15 min (early scan) and 120 min (delayed scan) after an intravenous injection of 111 MBq (3 mCi) of thallium-201 chloride. We obtained the uptake ratio from each scan and calculated the retention index:uptake ratio = region of interest uptake/contralateral normal lung uptake; retention index = (delayed ratio - early ratio)/early ratio. After 201Tl scintigraphy, 12 patients received chemotherapy consisting of platinum compounds and nine were treated with chemoradiation. Among patients receiving only chemotherapy, the retention index correlated with the responses to chemotherapy. In an in vitro study, ouabain, an inhibitor of the Na,K-ATPase pump, reduced sensitivity to cisplatin and inhibited intracellular thallium uptake in the small-cell lung cancer cell line. These studies suggest that 201Tl-SPECT is a useful indicator of response to chemotherapy with platinum compounds in small-cell lung cancer, and that Na,K-ATPase is commonly involved in transporting both thallium and platinum compounds into cancer cells.

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.