Kiyonobu Ueno

Increased serum levels of basic fibroblast growth factor in lung cancer patients: relevance to response of therapy and prognosis

Angiogenesis is controlled by inhibitors and angiogenic factors. Among these, basic fibroblast growth factor (bFGF) is closely involved in cancer proliferation and has been related to progression and prognosis of various cancers, including lung cancer. To evaluate the role of bFGF, we measured serum levels of bFGF from healthy controls (Ctrl) and 106 patients with lung cancer, including 31 adenocarcinomas (AD), 29 squamous cell carcinomas (SQ), and 46 small cell carcinomas (SCLC), by enzyme-linked immunosorbent assays. Moreover, we evaluated the relationship between serum levels of bFGF and clinical outcome. Serum levels of bFGF in AD, SQ, SCLC, and Ctrl were 7.6 (0.5-32.5) (median (range)), 7.4 (0.5-36.7), 7.1 (0.5-34.8) and 3.0 (1.5-6.0) pg/ml, respectively (P<0.05). Serum bFGF levels did not differ between clinical stages in non-small cell lung cancer (NSCLC; AD+SQ). In SCLC, we found a significant difference in serum levels of bFGF between chemotherapy (and/or radiotherapy) responders (complete response+partial response) and non-responders (no change+progressive disease) (9.2 (0.6-34.8), 4.4 (0.5-17.4) pg/ml, respectively (P=0.018)), whereas there was no difference in NSCLC. Moreover, serum bFGF levels in SCLC patients had significant impact in prognosis by uni and multivariate analysis (P=0.014, 0.018, respectively). We concluded that bFGF has an important role in the prognosis of patients with SCLC.

Phase II study of weekly irinotecan and carboplatin for refractory or relapsed small-cell lung cancer

We designed a phase II study of weekly irinotecan (CPT-11) and carboplatin for refractory or relapsed small cell lung cancer (SCLC) and assessed the response rate, survival, and toxicity. Twenty-nine patients with refractory or relapsed SCLC were entered onto the trial. The median time off chemotherapy was 3.5 months (range: 0.8-12.9). Patients were treated at 4-week intervals using CPT-11 (50 mg/m(2) intravenously on days 1, 8 and 15) plus carboplatin (AUC = 2 mg/ml min, intravenously on days 1, 8, 15). All patients were assessable for toxicity and survival; 28 patients were assessable for response. There were nine partial responses (PRs). Overall response rate was 31.0% (95% CI: 15.3-50.8%). The median time to progression was 3.5 months. Median survival time was 6.1 months. Major toxicity was myelosuppression. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 52 and 21% of patients, respectively. Grade 3-4 diarrhea was observed in 7%. There was one treatment-related death due to febrile neutropenia and sepsis. This combination of CPT-11 and carboplatin seems to be active second-line regimen with acceptable toxicity against small cell lung cancer.

Detailed deletion mapping of the short arm of chromosome 3 in small cell and non-small cell carcinoma of the lung

We constructed a detailed deletion map of the short arm of chromosome 3 (3p) for 55 lung cancer cases by using 17 restriction fragment length polymorphism (RFLP) probes. Initially, we examined 40 small cell lung cancer (SCLC) cases and found three regions of deletion at 3p25-26, 3p21.3 and 3p14-cen, suggesting the possibility of at least three different tumor-suppressor genes on 3p. In order to obtain more detailed deletion area, and to compare the pattern of 3p deletion, we also examined 15 non-small cell lung cancer (NSCLC) cases. Compared to NSCLC cases, most of SCLC cases have widespread deletion on 3p, suggesting multiple tumor-suppressor genes on 3p may be inactivated in this type of cancer. In 3p21.3 area, minimum overlapping area of deletion lays between two probes which are close to each other. These data will be useful to isolate the putative tumor-suppressor genes located on the chromosome 3p.

Clinical Experience with Autofluorescence Imaging System in Patients with Lung Cancers and Precancerous Lesions

Background: It is important to detect preinvasive bronchial lesions before they become invasive cancer, because detection of early cancer is expected to lead to a cure. Autofluorescence bronchoscopy is a useful device in the detection of preinvasive and cancerous lesions. Recently, a new autofluorescence bronchoscopic system, autofluorescence imaging (AFI) system, has been developed. Objectives: We evaluated the efficacy of AFI in the diagnosis of precancerous and cancerous lesions. Methods: A total of 31 patients underwent both conventional white-light bronchoscopy (WLB) and AFI from January 2002 to September 2004. We evaluated autofluorescence findings using a four-point scale: AFI-I, II, III, and B. The findings in WLB were evaluated on a three-point scale: WLB-I, II, and III. Abnormal areas by WLB and AFI were biopsied for histopathological examinations. Results: A total of 64 lesions were evaluated. When the AFI-III finding was regarded as positive in AFI and WLB-III as positive in WLB, sensitivity for severe dysplasia or worse was 94.7% with AFI and 73.7% with WLB, respectively. Conclusions: AFI is an effective system for the detection of precancerous and cancerous lesions.

Cloning and tissue expression of cDNAs from chromosome 5q21-22 which is frequently deleted in advanced lung cancer

Abstract Previously, we have reported that the inactivation of putative tumor-suppressor gene(s) on chromosome 5q21–22 may play an important role in the progression of lung cancer. Here, we describe the establishment of a yeast artificial chromosome (YAC) contig that spans 8–10 Mb at the 5q21–22 region. Six cosmid contigs have also been established in this YAC contig. About 35 exon-like fragments have been detected by exon-amplification, direct screening, cross-species hybridization, and searches of a database. Thus far, 14 cDNAs have been isolated, and two of them coincide with known genes, viz., cysteine dioxygenase I and geranylgeranyltransferase I. The other 12 cDNAs are considered to be novel genes. Two of these novel cDNA show partial homology to known genes, viz., semaphorin CD100 and the 28S rRNA gene. In addition, four known genes, including APC (adenomatous polyposis coli), MCC (mutated in colorectal cancer), proto-oncogene tyrosine kinase FER, and genomic imprinted gene U2AF1-RS1, have also been mapped in this contig. This large contig and expression map should prove crucial in the identification of susceptibility gene(s) related to the progression of lung cancer.

High-Dose-Rate Brachytherapy for Small-Sized Peripherally Located Lung Cancer

Background:The demand for minimally invasive therapies is increasing in the treatment of small peripheral non-small cell lung cancer (NSCLC).Patients and Methods:Twelve patients with T1-2 N0 M0 peripheral NSCLC were treated by high-dose-rate brachytherapy with 192Ir radioactive source.Results:A 192Ir source was introduced into the tumors percutaneously in five patients (percutaneous brachytherapy) or transbronchially in seven patients (transbronchial brachytherapy). Whereas irradiation was performed with a single fraction of 20 Gy in percutaneous brachytherapy, it was hypofractionated from 5 × 5 Gy to 2 × 12.5 Gy in transbronchial brachytherapy. Complications were generally mild in all patients, although focal radiation pneumonitis was observed in most patients. Primary recurrence occurred in three patients, including one with a T2 tumor and one treated by brachytherapy as a salvage treatment for recurrence after conformal radiotherapy. When brachytherapy is evaluated as a primary treatment for T1 N0 M0 NSCLC, local control rate is 88.9% and estimated 5-year survival rate is between 60% and 70%.Conclusion:Brachytherapy has a potential to be a method to treat peripheral T1 N0 M0 NSCLC.Hintergrund:Das Erfordernis minimalinvasiver Eingriffe in der Behandlung kleiner, peripherer, nichtkleinzelliger Bronchialkarzinome (NSCLC) nimmt zu.Patienten und Methodik:Zwölf Patienten mit peripherem NSCLC der Stadien T1-2 N0 M0 erhielten eine High-Dose-Rate-Brachytherapie mit radioaktiver 192Ir-Quelle.Ergebnisse:Die 192Ir-Quelle wurde bei fünf Patienten über einen perkutanen Zugang (perkutane Brachytherapie) und bei sieben Patienten über einen bronchialen Zugang (transbronchiale Brachytherapie) eingeführt. Bei der perkutanen Brachytherapie wurde die Bestrahlung mit einer Einzeitdosis von 20 Gy durchgeführt, bei der transbronchialen Brachytherapie hypofraktioniert mit 5 × 5 Gy bis 2 × 12,5 Gy. Komplikationen waren im Allgemeinen geringgradig ausgeprägt, allerdings wurde bei den meisten Patienten eine fokale Strahlenpneumopathie beobachtet. Bei drei Patienten trat ein Lokalrezidiv auf (zwei Patienten mit T2-Tumor und ein Patient mit Brachytherapie als Salvage-Behandlung wegen eines Rezidivs nach konventioneller Strahlentherapie). Für die Brachytherapie in der Primarbehandlung von NSCLC des Stadiums T1 N0 M0 beträgt die lokale Kontrollrate 88,9%, und die geschätzte 5-Jahre-Überlebensrate liegt bei 60–70%.Schlussfolgerung:Die Brachytherapie ist eine effektive Behandlungsmethode bei peripherem NSCLC des Stadiums T1 N0 M0.

Improved Diagnostic Efficacy by Rapid Cytology Test in Fluoroscopy-Guided Bronchoscopy

Background: Fluoroscopy-guided bronchoscopy is a safe and routine method used to obtain a histologic or cytologic specimen of peripheral lung nodules, but it has low sensitivity in diagnosing malignant tumors. Although feedback from rapid cytology tests are expected to improve diagnostic rates, the value of the routine use of rapid cytology tests has not been established. Materials and Methods: We prospectively studied 657 patients with suspected peripheral malignant lung lesions on chest computed tomography who underwent fluoroscopy-guided bronchoscopy between January 2002 and December 2004. Rapid on-site cytopathologic examinations (ROSE) were performed during bronchoscopic examinations. The additional approach to the lesions was performed immediately after conventional bronchoscopic examinations when ROSE was not considered diagnostic. Results: There were 528 patients diagnosed as having malignant lesions. In 477 of these patients (90.3%), final malignant diagnosis was established by the initial bronchoscopy. Among these, 84 patients (15.9%) were diagnosed only with the additional feedback from ROSE. Of 240 peripheral lesions ≤2 cm, 174 were found to be malignant. Without ROSE, 110 (63.2%) of peripheral malignant lesions were diagnosed by bronchoscopy. The integration of ROSE enabled us to diagnose an additional 40 patients (23.0%) by bronchoscopy. ROSE improved diagnostic yield independent of the site and histology of the lesions and experience of the operators. Conclusion: ROSE increased the diagnostic yield of bronchoscopy from 74.4% to 90.3% and therefore is an effective reinforcement in bronchoscopic diagnosis of peripheral pulmonary malignancies. The use of ROSE in routine bronchoscopy should be encouraged.

Crazy-paving sign in high-resolution computed tomography in parainfluenza virus pneumonia

Abstract The crazy-paving sign is the appearance of a smooth linear pattern superimposed on an area of ground-glass opacity on thin-section computed tomography (CT). A 69-year-old woman was admitted to our hospital for treatment of pneumonia. Thoracic CT showed a crazy-paving sign in the right lung field on admission. She received ceftriaxone and clarithromycin, and the symptoms and infiltration shadow promptly disappeared. Serologic testing revealed a greater than 4-fold increase in the IgG titer for parainfluenza virus I. To our knowledge, there is no previous report of the crazy-paving sign in associated with viral pneumonia in a non-immunocompromised host or with parainfluenza pneumonia.

A frequent deletion of chromosome 5q21 in advanced small cell and non-small cell carcinoma of the lung

We have examined the deletion of the long arm of chromosome 5 (5q) in 59 cases of advanced lung cancer [39 cases of small cell lung cancer (SCLC), 20 cases of non-SCLC] using 12 restriction fragment length polymorphism markers on 5q. Of 59 lung cancer cases, 48 (81%) exhibited deletion at any portion of the 5q locus (loci). Such a high frequency of 5q deletion has not been reported in surgically resectable non-SCLC. One SCLC case showed a 5q deletion only in metastatic sites but not in the primary cancer. These data suggest that the inactivation of putative tumor-suppressor gene(s) on 5q may be a late event in the progression of lung cancer. There was no significant difference in frequency of 5q deletion between SCLC and non-SCLC. Compared to non-SCLC, however, SCLC usually showed widespread deletion on 5q. While the most frequent target region was estimated to be about 3-5 megabases at 5q21 around the adenomatous polyposis coli (APC) gene locus, some cases showed more telomeric deletion (5q33-35), suggesting that there are at least two different tumor-suppressor genes on 5q associated with the progression of lung cancer.