Comparison of thin-section CT and pathological findings in small solid-density type pulmonary adenocarcinoma: prognostic factors from CT findings.

OBJECTIVE: We divided pulmonary adenocarcinoma of ≤ 20 mm into air-containing and solid-density types based on a percentage reduction of the maximum tumor diameter in the mediastinal window image compared to the area in the lung window image on thin-section (TS) CT of ≥ 50% (air-containing type) and <50% (solid-density type). No relapse occurred in patients with air-containing type. The prognosis of solid-density type may be poor even when the tumor size is 20mm or smaller. We investigated whether CT findings for these tumors could serve as prognostic factors. METHODS: The subjects were 105 patients with solid-density type pulmonary adenocarcinoma that was identified on TSCT and found to have a diameter of 20mm or smaller after surgical resection during the period from April 1997 to November 2004. Notches, air bronchogram, pleural retraction, spiculation, venous involvement, and ground glass opacity were examined on TSCT, and their associations with pathological findings (i.e., pleural invasion, lymphatic permeation, vascular invasion, lymph node metastasis, and Noguchi's classification) and relapse were investigated using chi-square test and Cox proportional hazards model. RESULTS: The incidence of relapse was significantly higher in cases with notches. The incidence of notches increased with tumor growth and notches were frequent in Noguchi type D tumors, reflecting poorly differentiated adenocarcinoma. Lymphatic permeation and type D cases were independent factors associated with a poor prognosis using Cox proportional hazards model. CONCLUSIONS: TSCT findings may be useful for prediction of the prognosis of solid-density type pulmonary adenocarcinoma.

Paragonimiasis in a person whose symptoms were shown 22 years after emigrating to Japan from Laos.

We report a patient, a 52-year-old man from Laos, who had come to Japan at 30 years of age, but had maintained a habit of eating raw freshwater crabs. The patient visited a physician for left chest pain in January 2007. Infiltration and mass-like shadows were noted in the left superior and inferior lobes on chest X-ray. Diagnosis could not be made by bronchial brushing, but eggs were present in sputum cytology 3 days after bronchoscopy. Therefore, paragonimiasis was diagnosed. The peripheral eosinophil count had increased to 2550/µl and the serum IgE level was elevated, at 71000 IU/ml. Multiple-dot enzyme-linked immunosorbent assay (ELISA) for specific IgG antibodies in serum was positive for Paragonimus westermani and P. miyazakii. Paragonimiasis may have been caused by the style of Laotian cooking without heating. Because the habit of eating raw freshwater crabs is common in Laos, Laos is one of the countries where paragonimiasis is prevalent. For patients from Laos with lung diseases, differentiation including paragonimiasis is required.

Disseminated cryptococcal infection with eosinophilia in a healthy person.

A 23-year-old man with no recent medical history was hospitalized complaining of high fever and cough. In addition to very marked eosinophilia, chest X-ray revealed extensive bronchovascular bundle thickening. Transbronchial lung biopsy (TBLB) showed moderate eosinophil infiltration. Cryptococcus neoformans infection was diagnosed, based on blood culture, cerebrospinal fluid culture, urine culture, and lung biopsy specimens. The eosinophilia was successfully alleviated by treatment for cryptococcal meningitis. Furthermore, cryptococcal sepsis resolved with amphotericin B and 5-flucytosine treatment. Eosinophilia commonly occurs following chronic Aspergillus infection, but the present case suggests the involvement of Cryptococcus in another mechanism for eosinophilia.

Prognosis of small adenocarcinoma of the lung based on thin-section computed tomography and pathological preparations.

OBJECTIVE: We investigated the relationship between findings from tumor opacity in the mediastinal window image and solid lesions in pathological preparations and related the results to tumor recurrence. METHODS: The subjects were 115 patients with a lung adenocarcinoma of 20 mm or smaller who underwent surgical resection. The proportion of the reduction in the tumor opacity in the mediastinal window image maximum diameter to the maximum diameter of the tumor opacity was calculated as the reduction percentage, and the proportion of the maximum solid lesions in pathological preparation diameter to the maximum tumor diameter was calculated as the pathological ratio. RESULTS: The incidence of relapse was significantly higher in patients with a reduction percentage of less than 50% and in patients with a pathological ratio of less than 50%. CONCLUSIONS: Measurement of the reduction percentage and the pathological ratio may allow prediction of prognosis of small adenocarcinoma of the lung.

[Case of pulmonary MALT lymphoma with follow-up imaging for 10 years].

Although abnormal shadow in the left upper lung of an 84-year-old male patient was confirmed in an examination in November 1996, follow-up observation was discontinued. In July 2006, he first visited our department with a chief complaint of shortness of breath, and was hospitalized because of an abnormal shadow in the left upper lung field and left pleural effusion. Since atypical lymphocytes were found in the pleural effusion, and positive cellular surface markers CD19 and 20, and chromosomal aberration of t (11 ; 18) (q22 ; q21) were confirmed, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) was diagnosed. Transbronchial lung biopsy of the left upper lobe confirmed small lymphocyte-like cellular infiltration, as seen in the pleural effusion, and CD20 immunostaining was positive, leading to the diagnosis of MALT lymphoma. In addition, serum immunoelectrophoresis demonstrated the development of macroglobulinemia as a complication. This case is valuable as changes diagnostic image over 10 years can be compared.

Rapidly progressive invasive pulmonary aspergillosis in a diabetic man.

A 45-year-old man was admitted to our hospital with high fever and a large amount of gray sputum. His initial chest X-ray showed broncho-bronchiolitis and thickening of the large bronchus, and he was subsequently diagnosed with pulmonary aspergillosis based on his sputum culture, polymerase chain reaction for Aspergillus fumigatus, and mannan antigen for Aspergillus. His immune responses, including neutrophil phagocytosis function and neutrophil sterilizing function, were normal as far as we could determine. He was treated with itraconazole, amphotericin B, and meropenem trihydrate, but died of respiratory failure on the twenty-fifth hospital day. Chest X-ray showed rapidly progressive invasive shadows in both lung fields, resulting in multiple cavity formation. This was a rare case of invasive pulmonary aspergillosis in a diabetic man with normal neutrophil phagocytosis function and neutrophil sterilizing function.

Genomewide cDNA microarray screening of genes related to benefits and toxicities of platinum-based chemotherapy in patients with advanced lung cancer.

The authors conducted a study using cDNA microarray analysis to determine whether expression levels of genes in tumors were correlated with the outcome of chemotherapy. Forty-seven patients were studied, and all except 3 received platinum-based chemotherapy. The expression levels of 1176 genes in transbronchial biopsy specimens of tumors that were obtained before chemotherapy were analyzed using the Atlas Human Cancer 1.2 Array. Multivariate regression analysis revealed that 3 genes were each independent factors related to tumor resistance to chemotherapy and patient survival (P < 0.01). Among various chemotherapy-related toxicities, 1, 3, 3, 1, and 1 genes were also revealed to be independent factors that were correlated with neutropenia, anemia, diarrhea, infection, and increased serum creatinine respectively (P < 0.01). It is concluded that not only the benefits but also the toxicities of chemotherapy can be predicted by cDNA microarray using tumor specimens obtained before chemotherapy.

[A case of sub-acute onset pulmonary sarcoidosis with pulmonary dysfunction].

A 60-year-old man was admitted to our hospital because of shortness of breath and dry cough. Slight pleural thickening was observed on the chest X-ray film and chest CT on presenting. Three months later, bilateral hilar lymphadenopathy and multiple small nodular shadows were shown in both lung fields by chest CT. Serum ACE level and lysozyme levels were higher than normal upper limit. Elevation of CRP and left shift of leukocytes were not detected. Restrictive ventilatory impairment was shown in the respiratory function test. This case was diagnosed as sarcoidosis most probably with histological evidence of epithelioid cell granulomas in the lung tissue obtained by transbronchial lung biopsy. After prednisolone medication (40 mg per day) was started, symptoms, pulmonary function and chest CT findings improved. Our case was considered to be a rare case of pulmonary sarcoidosis with subacute onset of symptoms and restrictive pulmonary function abnormality which improved smoothly as a result of steroid therapy.

Genomic-wide cDNA microarray screening to correlate gene expression profile with chemoresistance in patients with advanced lung cancer.

We conducted a study using cDNA microarray analysis to determine whether expression levels of genes in tumors were correlated with tumor response to chemotherapy. Between September 2000 and December 2001, 47 patients were registered in the study. Eighteen patients had small cell lung cancer (SCLC), and others had non-small cell lung cancer (NSCLC). All patients except three received platinum-based chemotherapy. Sixteen of the 18 patients with SCLC (89%) and 13 of the 29 patients with NSCLC (45%) responded to chemotherapy, respectively. Transbroncheal biopsy specimens of tumors were obtained before chemotherapy. The expression levels of 1176 genes in tumor specimens were analyzed using the Atlas Human Cancer 1.2 Array. When we analyzed the data for correlations between gene expression levels and tumor response to chemotherapy, there was a significant increase in the expression of nine genes in non-responders compared with responders to chemotherapy (p< 0.01). Multivariate regression analysis revealed that allogenic inflammatory factor, HLA-DR antigen associated invariant subunit and MHC class II HLA-DR-beta precursor were independent chemo-resistant factors (p<0.0001). When we analyzed the differences in gene expression levels between patients with SCLC and NSCLC, expression levels of one or more resistant genes were increased in comparison with the mean expression of control house keeping genes in five of 18 SCLC patients and 19 of 29 NSCLC patients, respectively (p=0.012). In conclusion, some chemo-resistant genes were detected in the tumor tissue of lung cancer patients using cDNA microarray analysis. A prospective study is required to confirm whether expression levels of these genes reflect chemosensitivity.

Prognostic impact of survivin, cyclin D1, integrin beta1, and VEGF in patients with small adenocarcinoma of stage I lung cancer.

The purpose of this study was to investigate the impact of survivin, cyclin D1, integrin beta1, and vascular endothelial growth factor (VEGF) in tumor on survival of patients with small adenocarcinoma of the lung. Seventy-two patients with pathologic stage I resected tumors <2 cm in diameter were entered into the study. Each patient underwent curative surgical resection for lung cancer between July 1992 and November 1999. The resected tumors were subjected to immunostaining for each gene. Thirty-five, 26, 6, and 16 patients had tumors with >10% survivin-, >20% cyclin D1-, >10% integrin beta1-, and >10% VEGF-positive cells, respectively. When the survival of 72 patients was compared according to each gene expression, the overall survival of patients with positive expression of survivin, cyclin D1, and integrin [beta]1 was significantly worse than that of individuals whose tumors had negative expression of each gene. By multivariate analysis controlling for each gene expression, no gene expression was an independent marker of poor prognosis, however, the overall survival of the complex gene expression (2 or more gene-positive) group (n = 35) was significantly worse than that of 0 or 1 gene-positive group (n = 37; log-rank test, P = 0.0011; Wilcoxon test, P = 0.0011). When the association between survival and pathologic factors, including lymphatic invasion, venous invasion, type of bronchioalveolar carcinoma, and complex gene positive expression was analyzed, only complex gene-positive expression was found to be a significant independent factor (hazard ratio = 0.085, P = 0.0299). It can be concluded that multiple increased expression of oncogene is a poor prognostic factor in patients with small adenocarcinoma of the lung.

Phase II study of OK-432 intrapleural administration followed by systemic cisplatin and gemcitabine for non-small cell lung cancer with pleuritis carcinomatosa.

We conducted a phase II study of OK-432 intrapleural administration followed by systemic chemotherapy using cisplatin with gemcitabine to determine their combined effects on non-small cell lung cancer (NSCLC) with pleuritis carcinomatosa. Between December 1999 and October 2001, 15 patients were registered in the study. Fourteen patients had an Eastern Cooperative Oncology Group performance status (PS) of 1, and one patient had a PS of 2. Ten patients had adenocarcinoma, one had squamous cell carcinoma, and four had malignant mesothelioma. Patients underwent thoracocentesis and received an OK-432 intrapleural injection. They were then treated every three weeks with chemotherapy consisting of 80 mg/m2 cisplatin on day 1 and 1000 mg/m2 gemcitabine on days 1 and 8. Thirteen patients received two or more courses of chemotherapy. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in five, two and three patients, respectively. Non-hematological toxicities were mild, except for one patient who experienced a grade 3 elevation of transaminase and two patients who experienced grade 3 nausea. Of the 15 patients, one achieved partial response (PR), 13 a stable disease (SD) rating, and one a progressive disease (PD) rating, and the overall response rate was 6.7%. The median survival time was 13.5 months and the one-year survival rate was 60.0%. In conclusion, OK-432 intrapleural administration followed by cisplatin and gemcitabine systemic chemotherapy did not reduce patients' tumors but did prolong their survival time. A large-scale phase II study of the efficacy of this combination therapy is required.

Dose escalation study of paclitaxel in combination with fixed-dose irinotecan in patients with advanced non-small cell lung cancer (JCOG 9807).

BACKGROUND: Both irinotecan (CPT) and paclitaxel (Pac) are effective against non-small cell lung cancer (NSCLC), and besides, preclinical studies have demonstrated an additive or synergistic interaction between camptothecin and taxane. METHODS: We conducted a phase I/II study of combination chemotherapy consisting of Pac and CPT to determine qualitative and quantitative toxicities and efficacy of the combination against advanced NSCLC. We fixed the dose of CPT at 60 mg/m(2) and escalated the Pac dose in 10 or 20 mg/m(2) increments from a starting dose of 80 mg/m(2), and repeated the cycle every 2 weeks. Prophylactic G-CSF was also administered. RESULTS: Between February 1999 and April 2001, 24 patients were registered in the study. None of the patients had a history of prior chemotherapy, but surgical resection had been performed in 3 of them. None of the patients experienced dose-limiting toxicity (DLT) up to and including level 6. At dose level 7 of Pac, 180 mg/m(2), 2 patients experienced DLT, that is grades 2 and 3 dyspnea due to pneumonitis. Another patient experienced grade 1 dyspnea due to pneumonitis. Neutropenia, diarrhea, and other toxicities were mild; however, we concluded that dose level 7 of Pac was the maximum-tolerated dose. An objective response was observed in 58.3%. The median survival time was 370 days, and the 1-year survival rate was 54.2%. CONCLUSION: Pneumonitis was the DLT in this study, and Pac 160 mg/m(2) and CPT 60 mg/m(2) every 2 weeks are recommended for the phase II study. This combination shows appreciable activity against NSCLC.

Genome-wide cDNA microarray screening to correlate gene expression profile with survival in patients with advanced lung cancer.

We conducted a study using cDNA microarray analysis to determine whether expression levels of genes in tumors were correlated with survival after chemotherapy. Between September 2000 and December 2001, 47 patients were registered in the study. Eighteen patients had small cell lung cancer (SCLC), and the others had non-small cell lung cancer (NSCLC). All patients except three received platinum-based chemotherapy. Transbroncheal biopsy specimens of tumors were obtained before chemotherapy. The expression levels of 1176 genes in tumor specimens were analyzed using the Atlas Human Cancer 1.2 Array. The expression levels of three genes, G1/S-specific cyclin, type II cGMP-dependent protein kinase and hepatocyte growth factor-like protein, were significantly correlated with survival (p<0.01). Ten of the 47 patients who showed an elevated expression level of one or more of the three genes had a significantly increased chance of survival (p=0.0056). In conclusion, some survival-related genes were detected in the tumor tissue of lung cancer patients using cDNA microarray analysis. A prospective study is required to confirm whether expression levels of these genes can be used for prognosis.

Phase II study of nedaplatin and irinotecan for elderly patients with advanced non-small cell lung cancer.

We conducted a phase II study of combination chemotherapy with nedaplatin (NP) with irinotecan (CPT) to determine the effects against unresectable non-small cell lung cancer (NSCLC) and to determine the qualitative and quantitative toxicities of this combination chemotherapy in 70 years or older patients. Thirty-eight patients received 100 mg/m2 NP on day 1 and 60 mg/m2 CPT on days 1 and 8 every four weeks. Twenty-five patients achieved PR, nine SD and three PD, and the overall response rate was 65.8%. Nineteen patients (50%) experienced grade 4 neutropenia. Neutropenic fever occurred in 11 patients (29%) and one of them died. Of other grade 3 non-hematologic toxicities, two patients experienced diarrhea; one interstitial pneumonitis; one liver injury; and one rash. The median survival time was 418 days and the one-year survival rate was 55.3%. In conclusion, NP combined with CPT is an active treatment for elderly patients with NSCLC.

Phase I/II study of escalating doses of nedaplatin in combination with irinotecan for advanced non-small-cell lung cancer.

We conducted a phase I/II study of combination chemotherapy with nedaplatin (NDP) and irinotecan to determine the effects against advanced non-small-cell lung cancer (NSCLC) and to determine the qualitative and quantitative toxicities of the combination chemotherapy. NDP was given on day 1 and irinotecan on days 1 and 8. The treatment cycle was designed to be repeated every 3 weeks. We fixed the dose of irinotecan as 60 mg/m(2) and escalated the NDP dose from a starting dose of 50 mg/m(2) by 10-mg/m(2) increments until the maximum tolerated dose (MTD) was reached. The MTD was defined as the dose level at which at least two of three or three of six patients experienced a dose-limiting toxicity (DLT). Between April 1997 and November 2000, 42 patients were registered in the study. Of the 42 patients, 37 had no prior treatment, 3 had received whole-brain irradiation, 1 had undergone surgical resection, and 1 had had one regimen of chemotherapy before enrolling in this study. In the phase I study, we observed DLTs such as grade 4 neutropenia lasting 7 days and grade 3 diarrhea lasting 1 day in one patient at level 2, grade 3 elevated of GPT in one patient at level 3, and acute myocardial infarction in one patient at level 6. We could not determine the MTD until dose level 6 was reached, so decided on a recommended dose of 100 mg/m(2) NDP, which is recommended for NDP-alone chemotherapy. Because of prolonged neutropenia in the phase I study, we repeated the treatment every 4 weeks in the phase II study. In the phase II study, a total of 16 patients, including 6 patients from the phase I study, were registered and a total of 42 cycles were administered. Grade 3 or 4 neutropenia, grade 3 anemia and grade 3 or 4 thrombocytopenia occurred in 50%, 12% and 7% of cycles, respectively. Febrile neutropenia occurred in eight cycles (19%) but there were no severe infections. Grade 3 elevation of GPT occurred in one patient. Of the 16 patients, 7 had an objective response. Of the 42 patients, 13 achieved a partial response (PR) and the overall response rate was 31.0%. The median duration of PRs was 226 days (range 59 to 646 days). The median survival time was 341 days and the 1-year survival rate was 45.2%. In conclusion, the combination of NDP and irinotecan was highly effective and well tolerated in NSCLC.

Detection of occult tumor cells in peripheral blood from patients with small cell lung cancer by promoter methylation and silencing of the retinoic acid receptor-beta.

In order to investigate the possibility of detecting occult tumor cells of small cell lung cancer (SCLC), we used the methylation-specific PCR assay to detect methylation of retinoic acid receptor-beta (RARbeta) in peripheral mononuclear cells (PMNC). The methylation-specific PCR assay can detect one tumor cell per 10(3) normal cells. Seventy-two patients participated in this study. They received an initial full-dose of combination chemotherapy for SCLC between October 1995 and June 2000. The patients were classified according to the clinical stage of their tumors as limited disease (LD) in 31 patients and extensive disease (ED) in 41. PMNC were obtained before each patient underwent chemotherapy. We detected RARbeta methylation in PMNC from 42 of the 72 SCLC patients (58.3%). Nineteen of 31 patients with LD-SCLC (61.3%) and 23 of 41 patients with ED-SCLC (56.1%) were positive for RARbeta methylation. The overall survival for patients who were positive and negative for RARbeta methylation was not significantly different in both the LD- and ED-SCLC groups (log-rank test, p=0.13 and p=0.38, respectively); however, 2-year survival was significantly greater in the RARbeta methylation-positive LD-SCLC patients (chi(2) test, p=0.044). In conclusion, occult tumor cells can be detected in the peripheral blood of patients with SCLC using methylation of RARbeta, and long-term survival appears to be better in LD-SCLC patients with occult tumor cells in their blood.

Expression of cyclin D1 but not of cyclin E is an indicator of poor prognosis in small adenocarcinomas of the lung.

We investigated the significance of cyclin D1 and cyclin E expression in resected tumors on the survival of patients with small adenocarcinomas of the lung. Seventy-two patients with resected tumors <2 cm in diameter and of pathological stage I were entered into the study. There were 29 males and 43 females, with a median age of 64 years (range 26-83 years). The patients underwent curative surgical resection for lung cancer between July 1992 and November 1999. The resected tumors were subjected to immunostaining for cyclin D1 and cyclin E expression. Twenty-six patients had tumors with >20% cyclin D1-positive cells, but only 1 patient had a tumor with >20% cyclin E-positive cells. When the survival of 72 patients was compared in relation to their oncogene expression, the overall survival of patients with positive expression of cyclin D1 was significantly worse than that of individuals whose tumors had negative expression of the gene (log-rank test p=0.0049). Increased expression of cyclin D1 but not of cyclin E is an indicator of poor prognosis in patients with small adenocarcinomas of the lung.

Increased expression of integrin beta1 is a poor prognostic factor in small-cell lung cancer.

The purpose of this study was to investigate the possible association between the expression of integrin beta1 and response to chemotherapy and survival in patients with small cell lung cancer (SCLC). One-hundred and four patients with SCLC, who had received an initial course of chemotherapy between February 1989 and July 1999, were entered into the study. There were 91 males and 13 females, with a median age of 65 years (range 40-85 years). The clinical stage of the tumors was recorded as limited disease in 43 patients and extensive disease in 61. Each patient received a full-dose of combination chemotherapy. Transbroncheal biopsy specimens of tumors obtained before chemotherapy were subjected to immunostaining for integrin beta1. Twenty-nine patients could not be evaluated for integrin beta1 immunostaining, because the tissue samples had been crushed during the biopsy procedure. Fifty-three patients had tumors with < or = 25% integrin beta1-positive cells and 22 patients had tumor with > 25% integrin beta1-positive cells. Among 75 patients whose biopsy specimens were evaluable for integrin beta1, the overall response rate to chemotherapy was 87%. When the relationship between integrin beta1 expression and tumor response to chemotherapy was considered, 17 out of 22 patients with high expression of integrin beta1 and 48 out of 53 patients with low expression of integrin beta1 showed tumor response, although the resistance rate in patients with high expression of integrin beta1 was over twice that of patients with low expression of integrin beta1 (23% vs. 9%, respectively). By comparison, the overall survival of patients with high expression of integrin beta1 (n = 22) was significantly worse than that of individuals whose tumors had low expression of integrin beta1 (n = 53; log-rank test, p=0.043; Wilcoxon test, p=0.049). The association between survival and prognostic factors was examined by multivariate regression analysis; clinical stage and integrin beta1 were found to be independent factors (p = 0.018 andp = 0.041, respectively). In conclusion, the high expression of integrin beta1 in tumor cells is a poorprognostic factor in patients with SCLC.

Expression of survivin correlated with vessel invasion is a marker of poor prognosis in small adenocarcinoma of the lung.

The purpose of this study was to investigate the possible association between expression of survivin, pathological findings in the tumor and survival in patients with small adenocarcinoma of the lung. Seventy-nine patients with resected tumors <2 cm in diameter were entered into the study. There were 33 males and 46 females, with a median age of 64 years (range 26-83 years). The pathological stage of the tumors was recorded as stage I, II, III and IV in 72, one, five and one case, respectively. Each patient underwent curative surgical resection for lung cancer between July 1992 and November 1999. The resected tumors were subjected to immunostaining for survivin. Thirty-eight patients had tumors with < or = 10% survivin-positive cells and 41 patients had tumors with >10% survivin-positive cells. When survivin expression and pathological findings in the resected tumors were analyzed, the frequency of venous invasion was significantly higher in the survivin-positive group (36.6% vs. 13.2%; p=0.0167). In contrast, the overall survival of survivin-positive patients (n=41) was significantly worse than that of individuals whose tumors were negative for survivin expression (n=38; log-rank test, p=0.014; Wilcoxon test, p=0.021). It can be concluded that the expression of survivin in tumor cells is a factor of poor prognosis in patients with small adenocarcinoma of the lung.

Expression of vascular endothelial growth factor and basic fibroblast growth factor in small adenocarcinomas.

The expression of two angiogenetic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), in small adenocarcinomas (