Kyung-Ok Park

Predictors of the Response to Gefitinib in Refractory Non–Small Cell Lung Cancer

Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has a response rate of 10% to 20% in refractory non–small cell lung carcinoma. Although female gender, adenocarcinoma, and never having smoked are possible markers of a favorable response, mutations of the EGFR gene have also been reported to be highly significant predictors of response. Seventy patients with relapsed non–small cell lung carcinoma were enrolled in the Expanded Access Program. After the drug became available commercially, 28 more patients were treated with gefitinib. Response evaluations were feasible in 80 patients. Twenty-seven tumor specimens (8 responders and 19 nonresponders) were available for the sequence analysis of the EGFR gene. The response rate was 25% (20/80) and the disease control rate (remission + stable disease) was 47.5% (38/80). The response rate was significantly higher for adenocarcinoma (41.0%) versus non-adenocarcinoma (9.8%, P = 0.001), in those who never smoked (58.8%) versus smokers (15.9%, P < 0.001), and in females (42.1%) versus males (19.7%, P = 0.049). A deletion or mutation of the EGFR gene was found in six of eight responders. Remission was noted in all patients with a mutation, whereas the response rate was 9.5% (2/21) in patients without a mutation (P < 0.001). The predictors of response showed significant correlations with survival and time to progression. In a multivariate logistic analysis, the independent predictors of response were smoking history and adenocarcinoma. Given that 9.5% of smokers and 6.7% of those with non-adenocarcinoma showed a mutation of the EGFR gene, the genetic profile may replace those variables as an independent predictor of a response.

The interactive effect of Ras, HER2, P53 and Bcl-2 expression in predicting the survival of non-small cell lung cancer patients

In patients with non-small cell lung cancer (NSCLC), tumor expression of P21-Ras, HER2, P53, and Bcl-2 has been reported as independent predictors of prognosis. However, the prognostic information carried by these proteins has usually been determined separately, and their potential interaction has not been taken into account. We conducted immunostaining for P21-Ras, HER2, P53 and Bcl-2 on 238 cases of NSCLC in a Korean population with 203 squamous cell carcinomas, and 35 adenocarcinomas. P21-Ras, HER2, P53 or Bcl-2 was expressed at high levels in 54.6, 42.0, 18.1 and 71.8% of the NSCLC studied, respectively. A total of 59 tumors (24.8%) expressed only one protein, while 70 (29.4%) expressed two, 59 (24.8) expressed three, and 17 tumors (7.1%) expressed all four proteins. Univariate analysis testing the association of marker expression with survival found Bcl-2 expression to be significantly associated with a poor prognosis, as well as the co-expression of Bcl-2 + HER2, Bcl-2 + HER2 + P53, and Bcl-2 + HER2 + P53 + P21-ras with an increasing hazard ratio. By multivariate analysis controlling for age, tumor stage and tumor type, only the combination of Bcl-2 + HER2 expression was an independent marker of poor prognosis (hazard ratio = 1.91, P = 0.003). Thus, a prospective analysis of the co-expression of Bcl-2 + HER2 in NSCLC patients may identify patients with a poor prognosis who may benefit from more aggressive therapy.

Apoptosis and BCL-2 expression as predictors of survival in radiation-treated non–small-cell lung cancer

OBJECTIVES We assessed the role of apoptosis and the expression of bcl-2, p53, and c-myc oncoproteins in pretreatment histologic specimens as a predictor of response to radiation therapy and survival in non-small-cell lung cancer (NSCLC) patients. METHODS Pretreatment biopsy specimens of 68 patients with NSCLC (62 squamous cell carcinoma, 6 adenocarcinoma) were stained with hematoxylin and eosin. From 5 high-powered fields, the apoptotic index (AI) was calculated as the ratio of apoptotic tumor cells to the total number of tumor cells. Bcl-2, p53, and c-myc oncoprotein expression was detected by immunohistochemical staining. RESULTS Twenty-nine cases showed partial or complete remission, whereas 39 showed no response. AI ranged from 0.2 to 12.0% (mean +/- SD; 4.3 +/- 2.6%, median 4.0%). There was no difference in AI between responders (4.0 +/- 2.3) and nonresponders (4.5 +/- 2.8, p > 0.05). However, in the responders, AI was correlated with the degree of change in tumor volume (r = 0.41, p < 0.05). In an analysis of 53 subjects who survived more than 1 month after the completion of radiation therapy, the patients with a higher AI (n = 27, MST = 22.8 m) survived longer than those with a lower AI (n = 26, MST = 9.2, log-rank, p = 0.03). Patients expressing bcl-2 had poorer survival (n = 22, MST = 6.0 m) than patients without bcl-2 (n = 31, 22.8 m, p < 0.003). According to multivariate analysis, three variables, bcl-2 expression, AI, and response to radiation, were independent prognostic factors for survival. CONCLUSION A low level of spontaneous apoptosis and expression of apoptosis blocking bcl-2 protein in pretreatment histology predict a poor prognosis for radiation-treated NSCLC patients.

Endovascular Stenting as a First Choice for the Palliation of Superior Vena Cava Syndrome

To assess the effectiveness of endovascular stenting for the palliation of superior vena cava (SVC) syndrome, endovascular stent insertion was attempted in 10 patients with symptomatic occlusion of the SVC. All the patients had known malignant disease of the thorax. Eight patients had been treated previously with chemotherapy and radiotherapy (n=5), chemotherapy alone (n=2), or pneumonectomy and radiotherapy (n=1). After developing SVC syndrome, all the patients were stented before receiving any other treatment. After single or multiple endovascular stents were inserted, five of eight patients were treated with chemotherapy and radiotherapy (n=2) or chemotherapy alone (n=3). Resolution of symptoms was achieved in nine patients within 72 hr (90%). In one patient, the symptoms did not disappear until a second intervention. At follow up, symptoms had recurred in two of ten patients (20%) after intervals of 15 and 60 days. Five patients have died from their cancers, although they remained free of symptoms of SVC occlusion until death. In conclusion, endovascular stent insertion is an effective treatment for palliation of SVC syndrome. Endovascular stent insertion can be considered the first choice of treatment, due to the immediate relief of symptoms and excellent sustained symptomatic relief.

Dipyridamole modulated Tc-99m sestamibi lung SPECT in small cell lung cancer

PURPOSE In this study, the authors wanted to determine whether dipyridamole-modulated MIBI (dipyridamole-MIBI) could enhance the prediction of the response to chemotherapy in patients with small cell lung cancer. METHODS Twenty-seven patients with biopsy-proved small cell lung cancer (25 men, 2 women; mean age, 61 +/- 7 years) underwent dipyridamole-MIBI SPECT 3 to 7 days before starting chemotherapy (80 mg/m2 etoposide and 80 mg/m2 cisplatin every 3 or 4 weeks for at least two cycles). Tomographic images before and after dipyridamole (0.84 mg/kg) were acquired 1 hour after injection of 370 (10 mCi) and 1,110 (30 mCi) MBq MIBI, respectively. The response to chemotherapy was grouped as specified as complete response (CR), partial (PR), no change (NC), or progressive disease (PD), according to the change in tumor size on chest roentgenography and CT. Patients showing CR and PR were classified as responders, and those who showed NC and PD were considered nonresponders. RESULTS Among the 27 patients, 22 were responders (3 CR, 19 PR) and 5 were nonresponders (3 NC, 2 PD). The tumor-to-normal lung ratio (T:NL) of responders was significantly higher than that of nonresponders. The diagnostic accuracy of the T:NL ratio to differentiate responders and nonresponders was 33.3%, with a cutoff value of 2.5, which was significantly improved to 77.8% when an increased T:NL ratio after dipyridamole was assigned to a nonresponder. Furthermore, all patients with CR showed diminished T:NL ratios after dipyridamole, and all patients with NR showed an increased T:NL ratio after dipyridamole. CONCLUSION Dipyridamole-MIBI SPECT could enhance the prediction of response to chemotherapy in patients with small cell lung cancer.

Tc-99m MIBI Uptake in Simultaneous Thyroid and Lung Cancers

The authors present a patient with simultaneous follicular thyroid and small-cell lung cancers, both of which showed Tc-99m MIBI uptake. CT scans showed two masses: one involving the right lower neck including the right supraclavicular area and the right superior mediastinum, and the other involving the peripheral portion of the right upper lobe of the lung. I-131 imaging showed increased uptake in the right neck mass only. Tc-99m MIBI imaging, which was performed for evaluation of chest pain, showed intense uptake in the neck mass (tumor to heart ratios in planar and tomographic images were 0.92 and 0.96, respectively), and less uptake in the lung mass (tumor to heart ratios in planar and tomographic images were 0.53 and 0.40, respectively). Biopsy of the right supraclavicular mass revealed a follicular carcinoma, and a bronchoscopic biopsy of the right upper lobe mass revealed a small cell carcinoma.

Osteopontin, CD44, and NFkappaB expression in gastric adenocarcinoma.

PURPOSE Osteopontin (OPN) binds to CD44 and nuclear factor-kappaB (NFkappaB) and OPN mediates tumorigenesis, invasion and metastasis, but the interrelationships between OPN, CD44 and NFkappaB are not fully understood, and especially in gastric carcinogenesis. We examined the expressions of OPN, CD44, and NFkappaB in untreated gastric adenocarcinomas. MATERIALS AND METHODS The materials from 211 cases of gastric adenocarcinoma were immunostained for OPN, CD44 and NFkappaB by using a tissue microarray. The OPN mRNA expression was measured in 10 cases by performing real-time RT-PCR. RESULTS The expression of OPN, CD44 and NFkappaB was noted in 61.7%, 11.4% and 26.6% of the adenocarcinoma tissues, respectively. No significant correlation was detected among the expressions of these proteins. The OPN protein expression was negatively correlated with angioinvasion (p<0.05) and patient survival (p<0.05), whereas the CD44 and NFkappaB protein expressions were not correlated with any of the clinicopathological factors we examined. The depth of invasion, lymph node status and perineural invasions were prognostic factors based on the Cox analysis. The OPN mRNA expression showed no significant difference between the adenocarcinoma and the paired normal mucosa on real-time RT-PCR. CONCLUSION OPN may have a currently undetermined role in gastric carcinogenesis, and CD44 and NFkappaB may have minor roles in gastric adenocarcinoma.

Different cutoff values of Cyfra 21-1 for cavitary and noncavitary lung cancers

STUDY OBJECTIVES Cell lysis and tumor necrosis release cytokeratin, a tumor marker of lung cancer, into the serum. The serum cytokeratin level can also be elevated in benign cavitary lung diseases. The purpose of this study was to evaluate whether Cyfra 21-1 can differentiate malignant lung diseases from benign diseases with cavitary lesions. DESIGN This study is a retrospective review of the case records of patients with lung lesions seen during a 4-year period from January 1993 to May 1996. SETTING AND PATIENTS Serum Cyfra 21-1 levels were measured in 306 patients with lung cancer (n = 143) or benign lung disease (n = 163). The patients were grouped according to radiologic evidence of cavitary lung lesions. Lung cancer included both non-small cell (n = 123) and small cell (n = 20) lung cancers, and the benign diseases include tuberculosis (n = 87), abscess (n = 26), pneumonia (n = 4), and others (n = 46). MEASUREMENTS AND RESULTS Although Cyfra 21-1 clearly differentiated cavitary lung cancer (15.0, 9.1-29.8 ng/ml, median and interquartile range, n = 39) from benign cavitary disease (P < 0.001), and noncavitary lung cancer from benign noncavitary disease (1.7, 0.9-2.6 ng/ml, n = 108, P < 0.001), it could not differentiate noncavitary lung cancer (5.0, 2.1-12.4 ng/ml, n = 104) from benign cavitary diseases (3.3, 1.4-8.3 ng/ml, n = 55, P = 0.45). CONCLUSIONS Serum Cyfra 21-1 is a useful tumor marker for differentiating benign from malignant lung diseases. However, different cutoff values are needed, depending on the presence of cavitary lesions. We recommend cutoff values of 30 ng/ml for cavitary lung diseases and 6 ng/ml for noncavitary lung diseases. If there are no radiologic data, a cutoff value of 15 ng/ml is recommended.

A case of completely resolved pneumatocoeles in desquamative interstitial pneumonia

Abstract:  Desquamative interstitial pneumonia (DIP), also known as alveolar macrophage pneumonia (AMP), represents a subset of idiopathic interstitial pneumonia that responds better to steroids and has a more favourable prognosis than usual interstitial pneumonia. Recently, we encountered a case of DIP with the formation of multiple pulmonary cysts during corticosteroid maintenance treatment. After the introduction of cyclophosphamide, the cysts gradually disappeared. This complete resolution is believed to have resulted from the clearance of check‐valve‐like bronchiolar obstructions that may be another interesting terminal airway pathology in DIP.

Results of Curative Radiation Therapy with or without Chemotherapy for Stage III Unresectable Non-Small Cell Lung Cancer

PURPOSE We retrospectively analyzed the patients who received curative radiotherapy for unresectable stage III NSCLC to investigate the impact of chemotherapy. MATERIALS AND METHODS From 1998 to 2001, the records of 224 patients who completed curative radiotherapy for NSCLC were reviewed. There were 210 males and 14 females, and their median age was 64 years (range 38 approximately 83). 54 patients had stage IIIA disease and 170 patients had stage IIIB disease. Conventional radiotherapy was given and the radiation dose ranged from 50 approximately 70 Gy with a median of 60 Gy, and chemotherapy was combined for 116 patients (52%). RESULTS The median survival, the 2-year, and 5-year actuarial survival rates of all 224 patients were 15 months, 30%, and 7%, respectively. The median survival of the patients with stage IIIA and IIIB disease were 21 months and 13 months, respectively (p=0.14). The median survival of patients who received chemoradiation was 18 months compared to 14 months for the patients who received RT alone (p=0.02). Among the chemoradiation group of patients, the median survival time of the patients who received 1 to 3 cycles of chemotherapy was 16 months and that for the patients who received more than 3 cycles was 22 months (p=0.07). We evaluated the effects of the timing of chemoradiation in 57 patients who received more than 3 cycles of chemotherapy. The median survival of the patients with the concurrent sequence was 25 months and that for the patients with the sequential chemotherapy was 19 months (p=0.81). CONCLUSIONS For advanced stage III non-small cell lung cancer patients who completed the curative radiotherapy, the addition of chemotherapy improved the survival compared to the patients who received radiotherapy alone.