Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer.

BACKGROUND: This dose-finding study evaluated lenvatinib, an oral multitargeted receptor tyrosine kinase inhibitor, in combination with carboplatin/paclitaxel in chemotherapy-naïve non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Patients received lenvatinib twice daily (BID) with carboplatin (area under the curve 6 mg ml(-1) min(-1), day 1)/paclitaxel (200 mg m(-2), day 1) every 3 weeks. The initial dose of lenvatinib was 6 mg BID. The primary end point was maximum tolerated dose (MTD) of lenvatinib. At the MTD, the cohort was expanded by 16 patients. Safety, pharmacokinetics, pharmacodynamics, and antitumor effects were evaluated. RESULTS: Twenty-eight patients were treated. At 6 mg BID, dose-limiting toxicities (DLTs) included febrile neutropenia/gingival infection (n=2). No DLTs occurred with 4 mg BID, the recommended MTD for the expansion. Common grade 3/4 toxicities included neutropenia, leukopenia, hypertension, and thrombocytopenia. The combination had no significant impact on individual drug pharmacokinetics. Response rate and median progression-free survival were 68% and 9.0 months, respectively, with 4 mg BID. In the plasma biomarker analysis, stromal cell-derived factor 1α, stem cell factor, and granulocyte colony-stimulating factor correlated with antitumor activity. CONCLUSION: The MTD for lenvatinib with carboplatin/paclitaxel is 4 mg BID in advanced NSCLC patients. This regimen demonstrated manageable tolerability and encouraging antitumor activity.

Phase I study of irinotecan and gefitinib in patients with gefitinib treatment failure for non-small cell lung cancer.

BACKGROUND: Currently, no effective treatments exist for non-small cell lung cancer (NSCLC) after failure of gefitinib therapy. Pre-clinical studies have demonstrated that gefitinib-resistant NSCLC cells are more sensitive to irinotecan than parental cells, and that combined administration of irinotecan and gefitinib has a synergistic additive effect. We conducted a phase I study to evaluate the combination of irinotecan and gefitinib as a therapeutic option for NSCLC patients with progressive disease (PD) after initial gefitinib treatment. METHODS: Eligibility criteria included histologically confirmed NSCLC, age range of 20-74 years, refractory to or relapsed after gefitinib treatment, one or more previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and informed consent. Patients were treated with irinotecan on days 1 and 15, and treated daily with gefitinib from day 2 every 4 weeks. The treatment was continued until disease progression. The gefitinib dose was fixed at 250 mg. Irinotecan dosing started at 50 mg m(-2) and was escalated in patients by 25 mg m(-2) increments up to a maximum dose of 150 mg m(-2). RESULTS: Twenty-seven patients were enrolled: male/female=14/13; median age=60 (45-75); histology, adenocarcinoma/non-adenocarcinoma=25/2; performance status 0-1/2=19/8; previous response to gefitinib, partial response/stable disease/PD=21/2/4. Dose-limiting toxicities were observed in 2 patients at level 3. Maximum tolerated dose was not determined, and the full dose of irinotecan could be combined with the full dose of gefitinib. The disease control rate (DCR) and response rate (RR) were 69.2 and 26.9%, respectively. For 12 patients at level 5 (the recommended phase II dose), the DCR and RR were 75.0% and 41.7%, respectively. The median treatment cycles were 4; median time to treatment failure, 57 days (95% confidence interval (CI), 32-82 days); median overall survival, 244 days (95% CI, 185-303 days); and 1-year survival rate, 32.6%. CONCLUSION: The combination of irinotecan and gefitinib was well tolerated and potentially beneficial for NSCLC patients failing initial gefitinib monotherapy.

Phase II trial of S-1 and cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer.

BACKGROUND: To assess the efficacy and safety of S-1 and cisplatin with concurrent thoracic radiation for unresectable stage III non-small-cell lung cancer (NSCLC). METHODS: Eligible patients were 20-74 years old and had histologically or cytologically confirmed NSCLC, a performance status of 0-1, and no prior chemotherapy. Patients were treated with cisplatin (60 mg m(-2) on day 1) and S-1 (orally at 40 mg m(-2) per dose, b.i.d., on days 1-14), with the treatment repeated every 4 weeks for four cycles. Beginning on day 2, a 60-Gy thoracic radiation dose was delivered in 30 fractions. RESULTS: Of 50 patients, 48 were eligible. Partial response was observed in 42 patients (87.5%; 95% CI: 79.1-96.9%). This regimen was well tolerated. Common toxicities included grade 3/4 neutropenia (32%), grade 3/4 leukopenia (32%), grade 3/4 thrombocytopenia (4%), grade 3 febrile neutropenia (6%), grade 3 oesophagitis (10%), and grade 3 pneumonitis (5%). Median progression-free survival was 12.0 months and median overall survival was 33.1 months. The 1- and 2-year survival rates were 89.5 and 56%, respectively. CONCLUSION: This chemotherapy regimen with concomitant radiotherapy is a promising treatment for locally advanced NSCLC because of its high response rates, good survival rates, and mild toxicities.

Gefitinib treatment affects androgen levels in non-small-cell lung cancer patients.

Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR, HER1/ErbB1) tyrosine kinase, has been shown to have clinical activity against non-small-cell lung cancers (NSCLCs), especially in women nonsmokers with adenocarcinomas. The aim of the present study was to clarify the relationship between androgen levels and gefitinib treatment in patients with advanced NSCLCs. Sera from 67 cases (36 men and 31 women) were obtained pretreatment and during treatment with gefitinib monotherapy (days 14-18) for examination of testosterone, dehydroepiandrosterone sulphate (DHEA), and dehydroepiandrosterone sulphate (DHEAS) levels. Testosterone and DHEA during treatment were significantly lower than the pretreatment values in both women and men, and the DHEAS levels during treatment were also significantly lowered in women. Gefitinib treatment significantly suppressed androgen levels, especially in women who had no smoking history. In addition, hormone levels in women responding to gefitinib were significantly lower during the treatment than in women who did not respond. Gefitinib-associated decrease in serum androgen levels may play a role in its clinical efficacy.

Improvement of neurological symptoms by enzyme replacement therapy for Gaucher disease type IIIb.

Enzyme replacement therapy might improve chronic liver dysfunction and contribute to the resolution of basal ganglia lesions in patients with type 3b Gaucher disease.

Early detection of lung cancer with laser-induced fluorescence endoscopy and spectrofluorometry.

STUDY OBJECTIVES: We performed a clinical trial of laser-induced fluorescence endoscopy (LIFE) for detection of precancerous lesions and cancer including carcinoma in situ (CIS), which are difficult to detect by white-light bronchoscopy. DESIGN: Results with LIFE were compared with the criterion standard, white-light bronchoscopy. The evaluation of these endoscopic results spectrofluorometrically was examined, and pixels of LIFE images composed of digital signals for the intensities of red and green were analyzed. SETTING: Tertiary-level hospital treating referrals and subjects with suspicious results in mass screening. PATIENTS: We examined 65 subjects with suspected lung cancer by both methods, and performed biopsy on 216 lesions. RESULTS: The accuracy of diagnosis by white-light bronchoscopy, with histopathologic results as the standard, was 48.6%. The accuracy by LIFE was 72.7%. The sensitivity of conventional bronchoscopy for detection of severe dysplasia (21 biopsy specimens) or cancer (28 biopsy specimens) was 61.2% and specificity was 85.0%. With results by LIFE added, these values were 89.8% and 78.4%, respectively. Of nine patients with CIS, only LIFE showed one lesion, and only LIFE showed the extent of seven of the lesions. The autofluorescence of eight lesions was measured spectrofluorometrically; normal bronchial tissue, severe dysplasia, and cancerous tissue had spectral differences. The red/green intensity of cancers on histograms of LIFE images generally was greater than the ratios for metaplasia or normal bronchial wall. CONCLUSIONS: Use of both methods should facilitate early detection. Evaluation by spectrofluorometry and analysis of digital signal intensity of results by LIFE make results more objective.

Clinical value of pleural lavage cytological positivity in lung cancer patients without intraoperative malignant pleuritis. Recurrent pattern based on semiquantitative analysis of tumor cells in pleural lavage.

OBJECTIVES: We recently developed pleural lavage cytology for lung cancer patients without intraoperative signs of malignant pleuritis (Ann Surg Oncol, 4: 409, 1997). We analyzed recurrent patterns in pleural lavage cytology-positive lung cancer patients without intraoperative signs of malignant pleuritis based on semiquantitative evaluation of tumor cell clusters in pleural lavage solution. METHODS: Between December 1987 and December 1998, pleural lavage cytology-positive results after thoracotomy were obtained in 97 cases of lung cancer despite the lack of evidence of malignant pleuritis. Based on semiquantitative evaluation of the mean number of tumor cell clusters per slide in pleural lavage solution, patients were classified as Type I, in whom the mean number of clusters was < 1; Type II, in whom clusters numbered 1-10; and Type III, in whom clusters exceeded 10. RESULTS: Type I patients numbered 37, Type II 40, and Type III 20. By September 1999, pleural recurrence had occurred in 17 patients (18%)--2(5%) Type I, 4 (10%) Type II, and 11 (55%) Type III. The incidence of pleural recurrence was significantly higher for Type III patients, i.e., 5 of 11 Type III patients with pleural recurrence showed no sign of distant metastasis. In contrast, the main recurrent patterns in the other 2 groups were extrathoracic, nodal, and/or intrapulmonary. CONCLUSIONS: The semiquantitative evaluation of tumor cell clusters in pleural lavage cytology-positive patients provided useful information on postoperative recurrence. Since Type III patients are at high-risk for pleural recurrence, postoperative therapy targeting local control should be conducted in such patients.

Detection of bone marrow metastases of small cell lung cancer with magnetic resonance imaging: early diagnosis before destruction of osseous structure and implications for staging.

Small cell lung cancer (SCLC) frequently metastasizes to bone and bone marrow. Skeletal scintigraphy and bone marrow cytology or biopsy, are incorporated into the staging procedures to examine these organs. However, skeletal scintigraphy is not highly specific to metastases, and only one or two bone marrow sites can be examined by cytology or biopsy. We have already reported that magnetic resonance imaging (MRI) could improve the sensitivity in detecting bone marrow metastases. The result of the bone marrow MRI was an independent prognostic factor of SCLC patients [9]. In the present study, we analyzed the results of skeletal scintigraphy and bone marrow aspiration with special reference to the results of MRI examination. We also analyzed the relationship between bone marrow lesions and bone lesions. For this purpose, we visualized bone marrow metastases with MRI and determined their anatomical locations and sizes. Approximately half of bone marrow lesions stayed in bone marrow during follow-up period ranging from 57 to 154 days, whereas about half of them were accompanied by hot spots in follow-up skeletal scintigraphy, which indicates the destruction of osseous structure. Additionally, 87.5% of osteolytic changes that newly appeared in skeletal scintigraphy were preceded by adjacent bone marrow lesions. All new lesions that appeared in follow-up skeletal scintigraphy within 3 months after the initial presentation had the preceding bone marrow lesions. These results mean that almost all lesions in skeletal scintigraphy derived from bone marrow metastases. Furthermore, appreciable volume of cancer cells is present in bone marrow before osteolytic changes appear in skeletal scintigraphy.

Low-cost soft-copy display accuracy in the detection of pulmonary nodules by single-exposure dual-energy subtraction: comparison with hard-copy viewing.

This study endeavored to clarify the usefulness of single-exposure dual-energy subtraction computed radiography (CR) of the chest and the ability of soft-copy images to detect low-contrast simulated pulmonary nodules. Conventional and bone-subtracted CR images of 25 chest phantom image sets with a low-contrast nylon nodule and 25 without a nodule were interpreted by 12 observers (6 radiologists, 6 chest physicians) who rated each on a continuous confidence scale and marked the position of the nodule if one was present. Hard-copy images were 7 x 7-inch laser-printed CR films, and soft-copy images were displayed on a 21-inch noninterlaced color CRT monitor with an optimized dynamic range. Soft-copy images were adjusted to the same size as hard-copy images and were viewed under darkened illumination in the reading room. No significant differences were found between hard- and soft-copy images. In conclusion, the soft-copy images were found to be useful in detecting low-contrast simulated pulmonary nodules.

Primary primitive neuroectodermal tumor of the lung: report of two cases.

Two cases of primitive neuroectodermal tumor of the lung are reported. The first case is a 41-year-old man with a tumor in the left upper lung, and the second case is a 30-year-old woman with a tumor in the right lower lung. In both cases, the tumors originated in the lung but not in the chest wall. No distant metastasis was detected. In case 1, transcutaneous fine-needle biopsy (TCNB) revealed small round cell proliferation, although bronchoscopic examination showed no abnormal findings. Both the expression of Mic2 protein and t(11;22)(q24;q12) translocation were proved in the tumor cells. The tumor cells were positive for periodic acid-Schiff (PAS), neuron-specific enolase (NSE), and vimentin, but negative for Leu7, chromogranin A, and pro-gastrin-releasing peptide (ProGRP). In case 2, bronchoscopic examination showed only compressive change in right lower lobe bronchi. TCNB revealed small round tumor cells expressing Mic2 protein. The tumor cells were negative for leukocyte common antigen, S100 protein, pankeratin, chromogranin A, and desmin, but weakly positive for NSE and moderately positive for Ki-67 (MIB1). Both patients were successfully treated by the combination of surgical resection and chemotherapy, and are alive with no sign of recurrence for approximately 22 months in case 1 and 16 months in case 2.

Successful removal of a primitive neuroectodermal tumor in the lung with gross extension into the left atrium.

We report here the successful multi-model treatment of a 31-year-old female demonstrating a primitive neuroectodermal tumor originating in the lower lobe of the right lung with gross extension into the left atrium via the inferior pulmonary vein. The tumor was markedly reduced by combination chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide, and ifosfamide. The residual tumor was completely removed through a combined left atrial resection and right middle and lower lobectomy, using a percutaneous cardiopulmonary support system.

Percutaneous brachytherapy for small-sized non-small cell lung cancer.

A patient with a small-sized pulmonary adenocarcinoma was successfully treated by percutaneous high dose rate interstitial brachytherapy alone. The patient, who had an adenocarcinoma with 12-mm diameter in the lingular lobe of left lung, was judged to be inoperable because of poor pulmonary function due to emphysema and extensive pleural adhesion. The tumor was punctured with a 21-gauge fine applicator needle followed by the introduction of an iridium 192 (192Ir) radioactive source through the applicator needle using a remote afterloader. The tumor was irradiated for 225.1 s in one fraction. The tumor was in the inside of the iso-dose line of 40 Gy. The delivered doses calculated at nine reference points, which were 12.5 mm distant from the center of the tumor, distributed between 19.225 and 32.169 Gy, with a mean of 24.8 Gy. No apparent side effect including pneumothorax and hemoptysis was observed. The tumor shrank and showed no increment of the size for about 2 years.

Usefulness of diagnostic criteria for aspiration cytology of hepatocellular carcinoma.

OBJECTIVE: To establish new criteria for cytodiagnosis of hepatocellular carcinoma by comparing cytologic findings of hepatocellular carcinoma with those of liver cirrhosis. STUDY DESIGN: Review of cytologic findings of hepatocellular carcinoma on preoperative aspiration biopsy of 31 lesions from 27 patients who underwent surgical resection and comparison of these findings with those of liver cirrhosis in 17 patients. RESULTS: In the 11 lesions of moderately and poorly differentiated hepatocellular carcinoma, significant cytologic findings included monotonous and abundant cytoplasm, thick cytoplasm, increased nuclear/cytoplasmic ratio, irregular nuclear contours, increased chromatin density, intranuclear vacuoles and naked nuclei. In the 20 lesions demonstrating well-differentiated hepatocellular carcinoma, significant cytologic findings included monotonous and scant cytoplasm, well-defined cytoplasmic borders, thick cytoplasm, eccentric nuclei, increased nuclear/cytoplasmic ratio, thick nuclear membranes and increased chromatin density. We established the criteria for moderately and poorly differentiated hepatocellular carcinoma as including three cytologic parameters: increased nuclear/cytoplasmic ratio, irregular nuclear contours and increased chromatin density. We also established the criteria for well-differentiated hepatocellular carcinoma as including six cytologic parameters: monotonous cytoplasm, scant cytoplasm, well-defined cytoplasmic borders, thick cytoplasm, eccentric nuclei and increased nuclear/cytoplasmic ratio. For all 31 hepatocellular carcinoma lesions, including 27 lesions that were < or = 2 cm in diameter, both sensitivity and specificity were 100% by concurrently employing both criteria. CONCLUSION: The new criteria for cytodiagnosis we established were useful for differentiating hepatocellular carcinoma from liver cirrhosis. In particular, our criteria ensured appropriate diagnostic accuracy for well-differentiated hepatocellular carcinoma.

Involvement of small GTPases Rho and Rac in the invasion of rat ascites hepatoma cells.

Lysophosphatidic acid (LPA) triggers the invasion of a mesothelial cell monolayer by rat ascites hepatoma (MM1) cells. LPA also induces rapid morphological changes of MM1 cells, cell surface blebbing and pseudopodia formation. Pseudopodia formation is tightly correlated with cellular invasiveness. Clostridium Botulinum C3 exoenzyme and genistein abrogated the formation of blebs and pseudopodia together with the inhibition of invasion, indicating that GTPase Rho and certain tyrosine kinases are involved in both processes. MM1 cells expressing constitutively active Rho exhibited the invasion and the formation of blebs and pseudopodia in the absence of LPA. In contrast, MM1 cells expressing constitutively active Rac were not invasive in the absence of LPA, but were invasive in the presence of LPA. Their morphological response to LPA was almost the same as that of parental MM1 cells. Expression of dominant negative Rac suppressed the invasiveness to approximately 3% of that of parental MM1 cells, together with the inhibition of pseudopodia formation. Thus, Rho and Rac are cooperatively involved in both the invasion and the related morphological changes of MM1 cells. Rho activation is sufficient both for the induction of invasion and the morphological changes leading to the invasion, whereas Rac activation is necessary but not sufficient by itself. We propose that Rho activation is not mediated by Rac but the cooperation of both GTPases is essential to trigger the invasive behavior of MM1 cells.

Comparison of computed tomography and pathologic examination for evaluation of response of primary lung cancer to neoadjuvant therapy.

Twenty-four patients (nine with squamous cell carcinoma, 14 with adenocarcinoma, and one with large cell carcinoma) underwent neoadjuvant therapy followed by surgical resection. The authors studied changes in tumor size, shape, and contrast enhancement on computed tomography (CT), and compared them with results of pathologic examination of surgical specimens. The size of tumors on CT was evaluated according to the criteria of the World Health Organization. Surgical specimens were evaluated histologically on the basis of the area of viable cancer cells. Of 14 patients considered to have a partial response on the basis of World Health Organization criteria, five had pathologic changes of complete response. After therapy, the residual tumors in these five patients showed irregular shapes with concave tumor margins on CT images and no enhancement. The authors found that CT size criteria tended to underestimate the therapeutic effect demonstrated by pathologic examination. On the basis of these results, the authors propose three CT criteria for complete response: 1) more than 50% size reduction, 2) a change in tumor morphologic features from round or oval to irregular after neoadjuvant therapy, and 3) disappearance of contrast enhancement.

Expression of cathepsin B in small cell lung carcinoma cells in relation to in vitro invasiveness.

Cathepsin B expression and its relation to in vitro invasiveness were investigated in small cell lung carcinoma cells (OC-10 cells). A subclone derived from OC-10 cells (10N) was similar to the parental cells both in growth pattern and morphology. However, the in vitro invasive capacity of OC-10 cells was 4 times higher than that of 10N cells. Cathepsin B activities in the plasma membrane fraction and spent medium of OC-10 cells were 2-fold higher than those of 10N cells. The invasiveness of OC-10 cells was markedly blocked by the addition of cysteine proteinase inhibitors, E-64C or leupeptin, while treatment of 10N cells with 2% (v/v) DMSO resulted in a 2-fold increment both in invasive capacity and cathepsin B activity. Immunoblot analysis demonstrated that the intensity of the cathepsin B band from OC-10 or 10N cells was not remarkably different regardless of DMSO treatment. Although no significant correlation was observed between the biochemical activity and protein of cathepsin B, in vitro invasive capacity of OC-10 cells strongly correlated with cathepsin B activity. These results suggest that cathepsin B plays an important role in the invasiveness of human small cell lung carcinoma cells.

NG-nitro-L-arginine methyl ester inhibits bone metastasis after modified intracardiac injection of human breast cancer cells in a nude mouse model.

We investigated the effects of NG-nitro-L-arginine-methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on bone metastasis of human breast cancer, MDA-231 cells. Tumor cells (2 x 10(5) cells in 0.2 ml of phosphate-buffered saline; PBS) were injected through the diaphragm into the left ventricle of the heart of laparotomized nude mice (male 5-week-old ICR-nu/nu). L-NAME (2 mg/mouse/injection in 0.1 ml of PBS) was given intraperitoneally to mice 6 h and 3 h before and immediately, 3 h, 6 h, 18 h and 21 h after the intracardiac injection of tumor cells. As a control, 0.1 ml of PBS was injected instead of L-NAME. The effect of NG-nitro-D-arginine-methyl ester (D-NAME; 2 mg/mouse/injection), an inactive analogue of L-NAME, was also investigated to evaluate the specificity of L-NAME action. Radiographical examination 31 days after the tumor-cell injection showed that the incidence and number of osteolytic bone metastases and the number of bones with metastasis in L-NAME-treated mice were significantly reduced compared with those in PBS-treated mice (P < 0.05). The differences between PBS-treated and D-NAME-treated mice were not significant. Our findings suggest that specific and appropriate NOS inhibitors may represent a new pharmacological approach to therapy for cancer patients at risk of developing osteolytic bone metastases.

Pleural lavage cytology immediately after thoracotomy and before closure of the thoracic cavity for lung cancer without pleural effusion and dissemination: clinicopathologic and prognostic analysis.

BACKGROUND: The significance of intraoperative pleural lavage cytology (PLC) in lung cancer patients without malignant effusion remains undetermined in terms of staging, prognosis, and local management. METHODS: PLC was performed both after thoractomy and before closure of the thoracic cavity in 325 patients with lung cancer without malignant pleurisy. RESULTS: According to the PLC results (positive [+] or negative [-] after thoracotomy/before closure), the patients were classified as follows: group A (-/-), 262 patients; group B (+/-), 19; group C (-/+), 22; and group D (+/+), 22. In comparison with group A, group C showed more advanced stage with aggressive nodal involvement, and group D showed more advanced lung cancer related to pleural and nodal involvement, whereas group B showed characteristics similar to those of group A. The rate of pleural recurrence in group D was the highest (26%). In particular, pleural recurrence was seen in the patients with a relatively large number of adenocarcinoma cells in PLC after thoractomy. The patients in groups C and D, especially those with adenocarcinoma, showed poorer prognosis, but in a multivariate analysis, PLC status was not an independent prognostic factor. CONCLUSIONS: PLC status after thoractomy provides useful information in the detection of high-risk subgroup for pleural recurrence. Although PLC status is closely associated with survival, its prognostic value is not independent.