Mizuki Ikehara

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 Noguchis 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.

Prognostic impact of survivin, cyclin D1, integrin β1, 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 β1, 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 β1-, 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 β1 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.

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.

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/m2 and escalated the Pac dose in 10 or 20 mg/m2 increments from a starting dose of 80 mg/m2, 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/m2, 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/m2 and CPT 60 mg/m2 every 2 weeks are recommended for the phase II study. This combination shows appreciable activity against NSCLC.

Prophylactic administration of granulocyte colony-stimulating factor when monocytopenia appears lessens neutropenia caused by chemotherapy for lung cancer.

In a retrospective study, we showed that a monocyte count of <150/microl on days 6 to 8 might be a predictor of grade III or IV neutropenia during cancer chemotherapy given at 3- or 4-week intervals. In the present study, we investigated whether the administration of granulocyte colony-stimulating factor (G-CSF) when monocytopenia appears lessens neutropenia during chemotherapy for lung cancer. Between June 1997 and August 1998, 60 patients who received chemotherapy at 3- or 4-week intervals for unresectable lung cancer were randomized to receive G-CSF (2 microg/kg or 50 microg/m2) when monocytopenia (<150/microl) appeared on days 6 to 8 after chemotherapy (group A) or when neutropenia (<1,000/microl) or leukopenia (<2,000/ microl) appeared after chemotherapy (group B). The administration of G-CSF was stopped when the leukocyte or neutrophil counts reached > 10,000/microl or 5,000/microl, respectively. The blood cells counts were examined three times a week and the degree, duration, and frequency of chemotherapy-induced neutropenia of the two groups were compared. One patient in group A was excluded because whole brain irradiation during chemotherapy was required. Twenty-nine and 30 patients in groups A and B, respectively, received platinum-based chemotherapy and their chemotherapy-induced hematologic toxicities were analyzed. The mean neutrophil count nadir of group A (1,558 +/- 1,771/microl) was significantly higher than that of group B (810 +/- 639/microl, p = 0.032). The duration of grade III neutropenia in group A (1.4 +/- 1.7 days) was significantly shorter than that in group B (2.9 +/- 1.9 days, p = 0.004), and the frequency of grade III neutropenia in group A (48%) was significantly lower than that in group B (83%, p = 0.002). Infectious episodes occurred in five and eight patients in groups A and B, respectively. The durations of G-CSF therapy required by group A and B patients (4.8 +/- 3.1 vs. 4.7 +/- 2.7 days) were not significantly different. Prophylactic administration of G-CSF did not exacerbate anemia or thrombocytopenia induced by chemotherapy. We conclude that the prophylactic administration of G-CSF when monocytopenia appears can lessen neutropenia caused by chemotherapy for lung cancer without increasing the total G-CSF dose.

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.