Kunihiko Yoshimura

Pulmonary fibrosis in an individual occupationally exposed to inhaled indium-tin oxide

Despite the increasing industrial use of indium-tin oxide (ITO) to manufacture flat-panel displays, such as liquid-crystal displays or plasma display panels for televisions, little is known about the potential health hazard induced by occupational exposure to indium compounds. The current study describes a case of fibrotic lung disease that developed after a 4-yr exposure to ITO. The pathology of the lung demonstrated pulmonary fibrosis with the presence of cholesterol granulomas. In conclusion, more attention needs to be paid to the possible toxic effects of indium compounds, and maximum healthcare measures should be taken to protect industry workers from these toxicities.

Multicenter Phase I Study of Repeated Intratumoral Delivery of Adenoviral p53 in Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSE To determine the feasibility, safety, humoral immune response, and biologic activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled onto this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 x 10(9) to 1 x 10(11) plaque-forming units) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m2). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response. RESULTS Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing antiadenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting at least 9 months, and two patients had progressive disease. CONCLUSION Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

Efficacy of inhaled N-acetylcysteine monotherapy in patients with early stage idiopathic pulmonary fibrosis

Background and objective:  Idiopathic pulmonary fibrosis (IPF) is a fatal disorder for which there are currently no specific or effective medical treatments. A multicentre, prospective, randomized, controlled clinical trial was conducted to assess the efficacy of inhaled N‐acetylcysteine (NAC) monotherapy in Japanese patients with early stage IPF.

High-resolution computed tomography findings of lung cancer associated with idiopathic pulmonary fibrosis.

Objective: The purpose of this study was to evaluate high-resolution computed tomography (HRCT) findings of lung cancer associated with idiopathic pulmonary fibrosis (IPF). Methods: Thirty patients with lung cancer who had preceding IPF and were receiving regular follow-up between 1993 and 2002 were examined. Medical records, radiographs (including HRCT scans), and histologic slides were reviewed. Results: In 28 of the 30 patients, the most common HRCT pattern of lung cancer was a nodular lesion with soft tissue attenuation. Nodule margins were well defined in 23 lesions (82.1%), associated with lobulation in 24 (85.7%), or characterized by spiculation in 14 (50%). Air bronchogram was observed in 16 lesions (57.1%). All nodules were located in the peripheral area of fibrotic lesions. Squamous cell carcinoma and adenocarcinoma were the most frequent histologic types. Conclusions: The typical HRCT findings of lung cancer were well-defined nodular lesions with lobulation in peripheral areas of the lung.

Expression of progastrin-releasing peptide and gastrin-releasing peptide receptor mRNA transcripts in tumor cells of patients with small cell lung cancer.

Abstract Purpose. Small cell lung cancer (SCLC) is a rapidly growing neoplasm accounting for approximately 20% of patients with lung cancer. Progastrin-releasing peptide (proGRP) is produced in about two-thirds of SCLC tumors and is used as a specific marker for SCLC. Although GRP is known to have a variety of biological functions, only limited information is available concerning expression of proGRP mRNA and protein, and that of the receptor for GRP (GRPR) in SCLC tumors. Methods. In individuals with SCLC, the levels of serum proGRP(31–98) were measured by enzyme-linked immunosorbent assay. Expression of proGRP as well as GRPR mRNA in SCLC tumor tissues was investigated by reverse transcription-nested polymerase chain reaction (PCR) amplification. The proportions of alternatively spliced proGRP mRNA transcripts were analyzed in proGRP-producing tumors by nested and competitive PCR amplification. Finally, production of proGRP protein in SCLC tumor was evaluated by using immunohistochemical staining with a polyclonal human anti-proGRP antibody. Results. ProGRP mRNA transcripts could be detected only in tumor tissues recovered from individuals with high serum proGRP levels. The proportions of mRNA subtypes in each case were nearly the same, revealing type I of 55.4±7.6%, type II with 21-b deletion of 1.8±3.6%, and type III with 19-b deletion of 42.8±4.3%, respectively. ProGRP protein production was demonstrated in tumor tissues exclusively from individuals exhibiting high serum proGRP levels. In contrast, GRPR mRNA transcripts were detectable in cancer cells from two of five proGRP-expressing tumor tissues. Conclusions. ProGRP mRNA expression is closely related with the synthesis of proGRP protein which is eventually released into the blood. It is suggested GRP may function as an autocrine growth factor for cancer cells in a subgroup of SCLC patients through, at least in part, upregulation of GRPR expression.

Clinical efficacy of micafungin for chronic pulmonary aspergillosis

The rising incidence of pulmonary aspergillosis is a major clinical concern. However, only a limited number of antifungal drugs are available in Japan that are effective for pulmonary Aspergillus infections. Micafungin (MCFG), a newly developed echinocandin family antifungal drug, has potent antifungal activity in vitro, but few reports detailing its clinical effectiveness have been published to date. A retrospective study was performed using data from nine patients (seven males and two females) with chronic invasive forms of pulmonary aspergillosis, who were treated with either MCFG alone or together with other antifungal drugs between April 2003 and March 2004. The overall efficacy of the treatments was evaluated in the terms of clinical, mycological, serological and radiological responses. The average age of the patients was 61.9 (20-83) years old. Four patients received only MCFG and the remaining five patients were treated with MCFG in combination with amphotericin B (AMB) only (1 patient), itraconazole (ITC) only (2 patients) or AMB backed up by ITC during AMB discontinuation periods (2 patients). The mean duration of MCFG administration was 59.2 (28-96) days. Overall, the treatment was judged to have been effective for seven of nine patients. No patients condition deteriorated in response to treatment. Administration of MCFG alone was judged to have been effective in three of four patients. No notable adverse effects were documented during MCFG administration. These data suggest that MCFG may be an effective and safe antifungal drug for the treatment of chronic invasive forms of pulmonary aspergillosis.

Efficacious pleurodesis with OK‐432 and doxorubicin against malignant pleural effusions

Malignant pleural effusion develops frequently in patients with advanced lung cancer. Chemical pleurodesis is the most effective palliative treatment for these patients. The efficacy of pleurodesis using both OK‐432, a preparation of Streptococcus pyogenes, and doxorubicin for 20 patients with cytology-proven malignant pleural effusion associated with lung cancer was evaluated. After complete removal of pleural effusion, OK‐432 and 30 mg of doxorubicin were injected via an inserted chest tube. Treatment was terminated when the volume of daily drainage reached <200 mL. If the daily volume remained >200 mL, an additional OK‐432 was administered every 3 days. In total, 16 patients (80%) revealed a complete response, two patients (10%) revealed a partial response, and no response was seen in two patients. Eighteen patients with complete or partial responses did not show subsequent reaccumulation of pleural effusion after pleurodesis. The chest tube remained in place for an average of 6.4 days, draining a mean of 2,854 mL. The main side-effects were fever and pain that were easily treated with nonsteroidal anti-inflammatory drugs. Pleurodesis using both OK‐432 and doxorubicin showed high efficacy for controlling malignant pleural effusions caused by lung cancer.

CFTR gene mutations in Japanese individuals with congenital bilateral absence of the vas deferens

Congenital bilateral absence of the vas deferens (CBAVD) is a monosymptomatic disease confined to the male reproductive system with similarity to the phenotype of cystic fibrosis (CF), and mutations in the CFTR gene are highly prevalent in Caucasian CBAVD patients. While CF is very rare in Japan, CBAVD is not. Our previous study demonstrated high prevalence of the 5T allele in the CFTR gene in Japanese CBAVD patients. We analyzed whole exons of the CFTR gene in 19 CBAVD patients and 53 normal individuals using polymerase chain reaction amplification-single strand conformation polymorphism analysis and direct sequencing. Three missense mutations (W216X, G1349S, Q1352H) were found in seven CFTR alleles, and the 5T allele was positive in 11 of 38 CFTR patient alleles. Consequently, 47% of CFTR chromosomes in the patients were affected, and 11 individuals (58%) had at least one mutated CFTR allele. In contrast, three of 53 normal individuals (5.7%) had a missense mutation in one of the CFTR genes, but no 5T allele was detected (both P<0.0001). Mutations of the CFTR gene are closely associated with Japanese patients with CBAVD.

Comparative Clinicopathology of Obliterative Bronchiolitis and Diffuse Panbronchiolitis

Background: The progressive airway obliteration caused by obliterative bronchiolitis (OB) has been widely noted in the world. In contrast, the obstructive respiratory disorder caused by diffuse panbronchiolitis (DPB) has been reported mainly from Japan. Therefore, there might be a considerable overlap between OB and DPB in Japan. Objectives and Methods: To clarify the clinicopathological similarities as well as the differences between OB and DPB, 15 patients with OB and 6 patients with DPB were evaluated clinicopathologically. Results: The underlying disorders in OB were graft-versus-host disease (GVHD) in 7, rheumatoid arthritis in 3, Kartagener’s syndrome in 2, and polymyositis/dermatomyositis, non-tuberculous mycobacterial disease and mycoplasmal pneumonia in one each. The lung pathology demonstrated that the primary obstructive lesions were in the membranous bronchioli in OB. In contrast, they were confined to the respiratory bronchioli in DPB. In addition, OB was classified into two major morphologic types, namely, constrictive and cellular. Clinical manifestations included cough and/or dyspnea in 13 with OB and in 6 with DPB, chronic parasinusitis in 3 with cellular OB and in 6 with DPB. The pulmonary function tests revealed obstructive impairments in all patients with OB and DPB. The chest CT images showed small centrilobular nodules in 64% of those with OB and in all with DPB. The prognosis of constrictive OB was worse than that of cellular OB and DPB. Conclusions: This study demonstrated that histopathologically marked differences existed between OB and DPB, although striking similarities in clinical manifestations were also noted in both diseases.

A Japanese patient homozygous for the H1085R mutation in the CFTR gene presents with a severe form of cystic fibrosis

To the Editor: Cystic fibrosis (CF), the most common autosomal recessive disorder in Caucasians, has long been believed to be extremely rare in Orientals (1, 2). In Japan, there have been approximately 130 cases of CF reported in the literature during the last 5 decades, with the estimated incidence of one in 350000 live births (3). Besides, very limited information is available about the spectrum of CF transmembrane conductance regulator (CFTR) gene mutations among Japanese CF patients, although more than 800 mutations of the CFTR gene, including the most common DF508, have been accumulated worldwide through the CF Genetic Analysis Consortium [(4), personal communication]. Here we describe a 15-year-old female Japanese patient who exhibited typical manifestations of CF and proved to be a homozygote for a very rare missense mutation H1085R. She was born to consanguineous parents at full term. From 1 year old, she repeatedly suffered from respiratory symptoms associated with Pseudomonas aeruginosa infection and experienced occasional steatorrhea. At 8 years old, she developed fecal ileus and underwent surgical operation. At 9 years old, she was diagnosed as CF based on the elevated sweat chloride level at 201 mmol/l. She also had chronic sinusitis, and abdominal ultrasonography revealed fibrotic changes of the pancreas. The patient has recently developed shortness of breath on exertion, and room-air arterial blood gas analysis showed moderate hypoxemia. For evaluation of the CFTR gene mutations, her DNA sample was evaluated for 32 major CFTR gene mutations responsible for more than 90% of CF chromosomes in the Caucasian population of North America (5). However, none of these mutations were detected in her CFTR alleles. Next, all 27 exons of the CFTR gene, including both the 5%and 3%-intron–exon junctions, were polymerase chain reaction (PCR) amplified and studied by single strand DNA conformation polymorphism (SSCP) analysis (6, 7). When the PCR products were electrophoresed and silver-stained, the DNA bands with different mobility from those of the control were only detected in exon 17b. Direct sequencing of the band clearly demonstrated an alteration of the nucleotide residue at 3386 from A to G in a homozygous fashion, resulting in His to Arg change at the amino acid 1085, a missense mutation H1085R. The CFTR genotype analysis of her family by PCR amplification of exon 17b and subsequent RsaI restriction digestion revealed that both parents and her three siblings were heterozygous for the mutation (Fig. 1). Further evaluation for three polymorphic loci proved that the H1085R mutation allele was associated with a haplotype of (GATT)6 in intron 6a (8), (TG)12T7 in the TG repeat and polythymidine tract at the splice acceptor site in intron 8 (9, 10), and M470 (1540A) in exon 10 (11, 12), respectively. The mutation H1085R, first described by Mercier et al. (13, 14), was detected on one of the CFTR alleles of a French CF patient who was pancreatic insufficient and a compound heterozygote with DF508 on the other chromosome [(13), personal communication]. However, no other CF patients with H1085R have been reported since then, implying that it is an extremely rare mutation (14). Consistent with the previous report that other mutations located in exon 17b, such as R1066L and M1101R, were usually associated with pancreatic insufficiency, the case presented here and the French case had pancreatic insufficiency, suggesting that the H1085R is also a severe allele [(13), personal communication]. Since the amino acid residue 1085 is located between the fourth and the fifth transmembrane segments of the second membrane-spanning domain and resides at the gate of the channel in the cytoplasm, it is conceivable that a His to Arg alteration would profoundly affect Cl conductance by either reduced Cl flow through a single open channel or by shortened duration for the channel opening (1, 15). One important point is that the H1085R alleles of these 2 patients are most likely to be recurrent