Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma.

BACKGROUND: We previously reported that expressions of the pro-angiogenic cytokines angiopoietin-2 (Ang-2), follistatin, granulocyte colony-stimulating factor, hepatocyte growth factor, leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor were associated with the response to sorafenib in patients with advanced hepatocellular carcinoma (HCC). The aim of the present study is to examine the same relationship in a larger cohort. METHODS: In the current retrospective cohort study, we measured serum levels of the eight cytokines in 120 consecutive HCC patients who were treated with sorafenib. We evaluated the effects of increased expression of serum cytokines on progression-free survival (PFS) and overall survival (OS). RESULTS: Elevated expression of Ang-2 correlated both with significantly shorter PFS (hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.21-2.81), and OS (HR, 1.95; 95% CI, 1.21-3.17). Patients with more than three cytokines expressed above the median similarly had significantly shorter PFS (HR, 1.98; 95% CI, 1.30-3.06) and OS (HR, 1.94; 95% CI, 1.19-3.22). Differences in OS were evident in cases with the evidence of macroscopic vascular invasion or extrahepatic metastasis. CONCLUSION: High expression of Ang-2 or more than cytokines in serum is associated with poor PFS and OS in HCC patients treated with sorafenib.

Phase II study of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patients with stage IIIb and IV non-small-cell lung cancer.

A phase II study of cisplatin, ifosfamide, and irinotecan with recombinant human granulocyte colony stimulating factor (rhG-CSF) support was conducted in previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). Between June 1998 and August 2001, 50 patients were registered in this phase II study. Cisplatin (20 mg m(-2)) and ifosfamide (1.5 g m(-2)) were administered on days 1-4 and irinotecan (60 mg m(-2)) was given on days 1, 8, and 15, respectively. This regimen was repeated every 4 weeks. rhG-CSF was administered subcutaneously at a dose of 50 microg m(-2) on days 5-18 except on the days of irinotecan treatment. In total, 49 patients were assessable for toxicity and response and 50 for survival. In all, 33, patients (67.3%; 95% confidence interval 57.4-77.2%) achieved an objective response. The median response duration was 192 days and the median time to progression for 49 patients was 170 days. The median survival time was 540 days with 1- and 2-year survival rates of 63.5 and 30.7%, respectively. Grade 3 or 4 neutropenia and thrombocytopenia developed in 63.3 and 38.8% of the patients, respectively. In conclusion, the combination of cisplatin, ifosfamide, and irinotecan with rhG-CSF support was highly effective for the treatment of stage IIIB or IV NSCLC with acceptable toxicities.

Tracking of a bronchoscope using epipolar geometry analysis and intensity-based image registration of real and virtual endoscopic images.

This paper describes a method for tracking the camera motion of a flexible endoscope, in particular a bronchoscope, using epipolar geometry analysis and intensity-based image registration. The method proposed here does not use a positional sensor attached to the endoscope. Instead, it tracks camera motion using real endoscopic (RE) video images obtained at the time of the procedure and X-ray CT images acquired before the endoscopic examination. A virtual endoscope system (VES) is used for generating virtual endoscopic (VE) images. The basic idea of this tracking method is to find the viewpoint and view direction of the VES that maximizes a similarity measure between the VE and RE images. To assist the parameter search process, camera motion is also computed directly from epipolar geometry analysis of the RE video images. The complete method consists of two steps: (a) rough estimation using epipolar geometry analysis and (b) precise estimation using intensity-based image registration. In the rough registration process, the method computes camera motion from optical flow patterns between two consecutive RE video image frames using epipolar geometry analysis. In the image registration stage, we search for the VES viewing parameters that generate the VE image that is most similar to the current RE image. The correlation coefficient and the mean square intensity difference are used for measuring image similarity. The result obtained in the rough estimation process is used for restricting the parameter search area. We applied the method to bronchoscopic video image data from three patients who had chest CT images. The method successfully tracked camera motion for about 600 consecutive frames in the best case. Visual inspection suggests that the tracking is sufficiently accurate for clinical use. Tracking results obtained by performing the method without the epipolar geometry analysis step were substantially worse. Although the method required about 20 s to process one frame, the results demonstrate the potential of image-based tracking for use in an endoscope navigation system.

PHA (polyhydroxyalkanoate) production potential of activated sludge treating wastewater.

The main purposes of wastewater treatment systems are to remove organic pollutants, but it would be very attractive if there were a way to recover the organic pollutants as valuable organic materials. One of the possible ways to recover organic pollutants in wastewater is to convert them into polyhydroxyalkanoates (PHAs), which are biodegradable plastics. In this study, 18 activated sludge samples in 4 wastewater treatment plants (WWTPs) in Tokyo, Japan, were evaluated for their potential to produce PHAs by aerobic batch experiments with excess supply of acetate as the sole carbon source. The activated sludge samples tested had the capability to accumulate PHA up to 18.8% of dry cell weight on average, with the range of 6.0% to 29.5%. The results showed that the maximum PHA content was dependent on the influent more than on the operational conditions of the activated sludge, and that conventional activated sludge produced PHA as much as anaerobic-aerobic activated sludge did. The PHA content achieved in this study is still low, and further improvement is needed to put into practice the recovery process of organic pollutants as biodegradable plastics by activated sludge.

[Virtual bronchoscope system].

In this article, we describe the features of Virtual Bronchoscope System(VBS) and its practical use. VBS is constructed based on 3-D chest CT images. The bronchus region is automatically extracted from 3-D chest CT images by a three-dimensional region growing method. The surface rendering is employed for construction of virtualized tracheo-bronchial tree. It gives us an environment where we can observe inside the bronchi from an arbitrary viewpoint and a view direction. By mouse operation, the user can control the viewpoint and the view direction to fly through inside the airway in real time. VBS is applicable for a variety of purposes such as diagnosis, surgical planning, informed consent, education and training. One of extension of this system is a teaching tool for medical students. In the module for educational use, we have developed four functions for using the system as a teaching tool as follows: (a) automated display of bronchial anatomical names, (b) presenting questions about the currently observed branch in the endoscopic view, (c) display of the path which the user should follow, and (d) display of a question about the location of the artificially created tumor in the bronchus. These functions use the processed results of automated anatomical labeling. The method proposed here combines the knowledge based processing technique 'automated labeling of bronchial branch' and the novel visualization technique 'virtual bronchoscope'. This is one of new teaching tools of medical images. We conclude that this virtual bronchoscope system might have an important role in the medial students' education.

[A case of primary malignant hemangiopericytoma of the lung with marked response to combination chemotherapy with cisplatin, ifosfamide and gemcitabine].

A 51-year-old man was admitted because of complaints of cough and bloody sputa. A chest CT scan revealed a giant mass lesion in the right middle and lower lobes of the lung and mediastinal lymphadenopathy. Bronchoscopic findings showed a tumor which almost completely obstructed the intermediate bronchus. Histopathological examination of a biopsy specimen demonstrated malignant hemangiopericytoma. Two courses of chemotherapy that combined cisplatin, ifosfamide and gemcitabine were performed every 3 weeks. Both primary lesion and mediastinal lymph node metastases showed marked reduction and toxicity was manageable.

Combination chemotherapy in patients with malignant pleural effusions from non-small cell lung cancer : cisplatin, ifosfamide, and irinotecan with recombinant human granulocyte colony-stimulating factor support.

OBJECTIVES: Malignant pleural effusions develop frequently in patients with non-small cell lung cancer (NSCLC), and the prognosis for these patients is very poor. We evaluated the role of systemic chemotherapy for patients with malignant pleural effusions from NSCLC. METHODS: We analyzed 34 patients who were found to have malignant pleural effusions in the course of diagnosis of 118 patients enrolled in three consecutive clinical trials on advanced NSCLC assessing combination chemotherapy of cisplatin, ifosfamide, and irinotecan with recombinant human granulocyte colony-stimulating factor support. The objective response in the malignant pleural effusion was evaluated by CT scans every course with the response criteria of the Japan Lung Cancer Society. RESULTS: All patients had adenocarcinoma. The pleural effusion showed a complete response in 13 patients, a partial response in 7 patients, and no response in 14 patients. In the assessment of the efficacy of the treatment for the measurable primary or metastatic lesions, there was a partial response in 25 patients, no change in 8 patients, and progressive disease in 1 patient. The response rate in pleural effusions was 58.8%, and overall response in mensurable lesions was 73.5%. The median time to response and duration of response for pleural effusions were 54 days and 151 days, respectively. The median survival time and 1-year survival rates were 362 days and 48.5%, respectively. CONCLUSIONS: Both the response rate and survival data in this retrospective study suggest a high degree of activity of this combination chemotherapy in patients with malignant pleural effusions from NSCLC.

Combination chemotherapy of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patients with brain metastases from non-small cell lung cancer.

BACKGROUND: Brain metastases develop frequently in patients with non-small cell lung cancer (NSCLC), and the prognosis for these patients is very poor. We evaluated the role of chemotherapy for patients with brain metastases from NSCLC. METHODS: We analyzed 30 patients who were discovered to have brain metastases during the diagnosis of 121 patients enrolled in three consecutive clinical trials on advanced NSCLC assessing combination chemotherapy of cisplatin, ifosfamide and irinotecan with rhG-CSF support. Response in the brain lesions was evaluated by contrast-enhanced MRI scans after at least two courses. RESULTS: Fourteen patients achieved a partial response (PR) but there was no change (NC) in 13 patients and progressive disease (PD) in 1. Among patients with extracranial lesions, 18 had a PR and 11 had NC. The response rate in brain metastases was 50.0%, and that in extracranial primary and metastatic lesions was 62.1%. The median duration of response for intra- and extracranial lesions was 140 and 147 days, respectively. After completing chemotherapy, Gamma Knife radiosurgery was performed on 2 patients in remission and 8 patients at disease progression. The median survival time and 1-year survival rate were 382 days and 56.1%, respectively. CONCLUSIONS: Both the response rate and survival data in this retrospective study suggest a high degree of activity of this combination chemotherapy in patients with brain metastases from NSCLC.

Combination of cisplatin, ifosfamide, and irinotecan with rhG-CSF support for the treatment of refractory or relapsed small-cell lung cancer.

OBJECTIVE: This study was conducted in refractory or relapsed small-cell lung cancer to determine activity and toxicity of the combination of cisplatin, ifosfamide, and irinotecan with rhG-CSF support. METHODS: Eighteen patients entered the trial. The median chemotherapy-free interval was 3.1 (range 1.0-14.5) months. Cisplatin (20 mg/m(2)) and ifosfamide (1.5 g/m(2)) were administered on days 1-4, and irinotecan (60 mg/m(2)) was administered on days 1, 8, and 15. In patients who experienced grade 4 hematological toxicity during the prior chemotherapy, the doses of cisplatin and irinotecan were reduced to 15 and 50 mg/m(2), respectively. After 10 patients were entered, cisplatin and irinotecan were administered at doses of 15 and 50 mg/m(2), respectively. This regimen was repeated every 4 weeks. rhG-CSF was administered subcutaneously at a dose of 50 microgram/m(2) from days 50 to 18, except on the day of irinotecan treatment. RESULTS: All patients could be assessed for response and toxicity. There were 1 complete and 16 partial responses, and an overall response rate of 94.4%. The median survival time of all patients was 339 days, and the 1-year survival rate was 47.5%. Hematological toxicities were significant. Grade 4 neutropenia and thrombocytopenia were observed in 61 and 33% of the patients, respectively. Diarrhea was mild and transient. There was no treatment-related death. CONCLUSION: The combination of cisplatin, ifosfamide, and irinotecan with rhG-CSF support was highly active for the treatment of refractory or relapsed small-cell lung cancer.

[Intrathoracic neurofibroma originating in the left vagus nerve].

A 20-year-old man was admitted because of an abnormal mass shadow on chest X-ray film. Computed tomography (CT) and magnetic resonance imaging (MRI) disclosed a mass lesion in the superior portion of the left mediastinum. CT scans showed a well-defined mass with low density. Axial MRI rendered the mass lesion with intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images. The preoperative diagnosis was bronchogenic cyst. Video-assisted thoracic surgery revealed that the tumor originated in the truncus of the left vagus nerve. The resected tumor was 90 x 24 x 18 mm in size. The postoperative course was uneventful and hoarseness did not develop. The pathologic diagnosis was benign mediastinal neurofibroma without von Recklinghausen's disease. Such cases are extremely rare in the Japanese literature.

Phase I study of carboplatin, docetaxel and irinotecan with recombinant human granulocyte colony stimulating factor support in patients with advanced non-small cell lung cancer.

A phase I study was conducted in patients with stage IIIB or IV non-small cell lung cancer to determine the maximum tolerated dose (MTD) of irinotecan combined with a fixed schedule of docetaxel and carboplatin with recombinant human granulocyte colony stimulating factor (rhG-CSF) (nartograstim) support. Docetaxel was given at 60 mg/m2 on day 1 with carboplatin. The dose of carboplatin was calculated using the Calvert formula to achieve an estimated AUC of 5.0 mg/ml x min. Irinotecan was administered at a starting dose of 40 mg/m2 on day 1 and increased in increments of 10 mg/m2. rhG-CSF was given at 1 microg/kg on days 5-15. Cycles were repeated every 3 weeks. Between February 1998 and March 1999, 22 patients were enrolled in this phase I study. Five patients were chemotherapy naive. The MTD of irinotecan was 60 mg/m2. Diarrhea was considered to be the dose-limiting toxicity. The irinotecan dose intensity of 16.7 mg/m2/week was low compared with other irinotecan-containing regimens. The overall response rate was 38.1% and median survival was 278 days. Irinotecan 50 mg/m2 in combination with 60 mg/m2 docetaxel and carboplatin on day 1 with rhG-CSF support is recommended for phase II study. The response rate and survival data in this phase I study are encouraging.

Phase I/II study of cisplatin, ifosfamide and irinotecan with rhG-CSF support in patients with stage IIIB and IV non-small-cell lung cancer.

PURPOSE: We conducted a phase I/II study in previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) to: (1) determine the maximum tolerated dose (MTD) of cisplatin combined with a fixed schedule of ifosfamide and irinotecan with rhG-CSF support; and (2) to determine the overall response rate and median survival of patients entered on this study. METHODS: Ifosfamide (1.5 g/m2) and irinotecan (60 mg/m2) were administered at fixed doses on days 1-4 and on days 1, 8 and 15, respectively. Cisplatin was given on day 1 at 60 mg/m2 and was increased in 10-mg/m2 increments. This regimen was repeated every 4 weeks. rhG-CSF (nartograstim) was administered subcutaneously at a dose of 1 microg/kg on days 5-18 except on the day of irinotecan treatment. RESULTS: Between June 1995 and April 1998, 46 patients were registered onto this phase I/II study. The MTD of cisplatin was defined according to toxicity and the dose during three courses was increased. Since at the 80 mg/m2 dose level more than one-third of the patients were treated with dose modification, the dose of 70 mg/m2 was recommended for phase II study. The dose-limiting toxicity was leukopenia. The overall response rate was 62.2% (95% CI 48.0-76.4%, the median response duration was 144 days, and the median survival time was 393 days. CONCLUSION: For phase II study, we recommend doses of cisplatin 70 mg/m2 on day 1 combined with ifosfamide and irinotecan with rhG-CSF support. Both the response rate and preliminary survival data in this study suggest a high degree of activity of this combination in previously untreated NSCLC.

Allergic bronchopulmonary aspergillosis due to Aspergillus niger without bronchial asthma.

A 65-year-old woman was admitted to our hospital with a dry cough and pulmonary infiltrates. Chest radiograph and CT revealed mucoid impaction and consolidations. Peripheral blood eosinophilia and elevated serum IgE were observed. Aspergillus niger was cultured repeatedly from her sputum, but A. fumigatus was not detected. Immediate skin test and specific IgE (RAST) to Aspergillus antigen were positive. Precipitating antibodies were confirmed against A. niger antigen, but not against A. fumigatus antigen. She had no asthmatic symptoms, and showed no bronchial hyperreactivity to methacholine. Thus, this case was diagnosed as allergic bronchopulmonary aspergillosis (ABPA) without bronchial asthma due to A. niger, an organism rarely found in ABPA. The administration of prednisone improved the symptoms and corrected the abnormal laboratory findings.

[Period of time patients with advanced non-small cell lung cancer could remain at home during CIC--therapy (cisplatin + ifosfamide + CPT-11)].

Two phase I studies (CIC-therapy) were conducted in advanced non-small cell lung cancer (NSCLC) to determine the maximum tolerable dose (MTD) of CPT-11 combined with cisplatin and ifosfamide, and MTD of cisplatin combined with CPT-11 and ifosfamide with G-CSF support, respectively. Both regimens were repeated every 4 weeks. G-CSF was administered on days 5 to 18. Eighty-eight patients were registered in both studies. The overall response rate was 59.1%, and the median survival time was 393 days. In all patients enrolled, we examined retrospectively the period of time they could remain at home during chemotherapy. We examined this period divided into day 1-18 and day 18-28 until the third course. Although myelotoxicity occurring during the third course was the most severe, the mean time was 7.1 days (day 1-18 2.2, day 18-28 4.9) for the first course, 10.1 days (day 1-18 4.0, day 18-28 6.0) for the second course, and 11.0 days (day 1-18 4.7, day 18-28 6.3) for the third course. Only two patients came to the hospital because of acute upper respiratory tract infection. Although CIC-therapy was an aggressive chemotherapy with G-CSF support, most of the patients were able to stay at home during chemotherapy.

Phase I study of cisplatin, ifosfamide and irinotecan with rhG-CSF support in advanced non-small cell lung cancer.

A phase I study was conducted in advanced non-small cell lung cancer to determine the maximum tolerated dose (MTD) of irinotecan combined with a fixed schedule of cisplatin and ifosfamide with rhG-CSF support. In addition, efficacy including survival time was evaluated at 2 years after the completion of patient registration. Cisplatin (20 mg/m2) and ifosfamide (1.5 g/m2) were administered at fixed doses on days 1-4, and irinotecan was given on days 1, 8 and 15 starting at 40 mg/m2, which was increased in 10 mg/m2 increments. This regimen was repeated every 4 weeks. rhG-CSF was administered subcutaneously at a dose of 50 microg/m2 on days 5-18 except on the day of irinotecan treatment. Forty-five patients were registered and 35 had received no prior chemotherapy. MTD or irinotecan was defined according to toxicity and the dose during three courses was increased up to 70 mg/m2. The dose 60 mg/m2 was recommended for phase II study. The dose-limiting factor was thrombocytopenia. The overall response rate was 57.8% and the median survival time was 492 days. In chemotherapy-naive patients, the response rate was 65.7% (95% CI; 50-81.4%), median response duration 161 days, median survival time 513 days, 1-year survival rate 62.4%, and 2-year survival rate 27.3%.

[Efficacy of systemic chemotherapy in adenocarcinoma of the lung with pleuritis carcinomatosa].

The efficacy of systemic chemotherapy (CDDP + IFO + 5-FU or CDDP + IFO + CPT-11) was evaluated in 41 patients with malignant pleural effusion secondary to adenocarcinoma of the lung. The overall response rate for measurable disease was 56.1%. The response for pleural effusion was evaluated according to the criteria of the Japan Lung Cancer Society. The overall response for pleural effusion was 53.7% (34.1% CR and 19.5% PR). The median survival time was 361 days. These results suggested that systemic chemotherapy is an effective treatment for pleuritis carcinomatosa.

[Three cases of resected primary mediastinal yolk sac tumor following six courses of bleomycin, etoposide and cisplatin (BEP) combination chemotherapy].

We experienced three cases of primary mediastinal yolk sac tumor which were resected after 6 courses of BEP chemotherapy with G-CSF support. All cases had high levels of AFP. CT scan revealed an anterior mediastinal tumor infiltrating the surrounding tissue in all cases, and multiple pulmonary nodules in one case. The serum AFP level decreased markedly, but did not return to normal after the chemotherapy was completed. The markedly decreased mediastinal tumor masses were removed with en-bloc resection of the lung and pericardium. Viable tumor cells were not present in the resected tumors. These three cases remain free of disease at present, 3 years, 9 months and 5 months after operation.

[Phase I study of cisplatin, ifosfamide and CPT11 with granulocyte colony-stimulating factor support in advanced non-small cell lung cancer].

A phase I study was conducted to define the maximal tolerated dose of cisplatin, ifosfamide and CPT-11 with granulocyte colony stimulating factor support in advanced non-small cell lung cancer. CPT-11 was given on days 1, 8 and 15 in combination with a fixed dose of cisplatin (20 mg/m2 i.v. on days 1-4) and ifosfamide (1.5 g/m2 i.v. on days 1-4) every 4 weeks. G-CSF (50 micrograms/m2/day s.c.) was administered on days 5 to 18, except on the days of CPT-11 treatment. The starting dose of CPT-11 was 40 mg/m2, and the dose was escalated in increments of 10 mg/m2. Forty-five patients with stage III or IV, and 35 with no prior chemotherapy, were entered in the study. The dose limiting toxicity of the combination was thrombocytopenia. The maximal tolerated dose of CPT-11 was 70 mg/m2, and the recommended phase II dose is 60 mg/m2. There were 26 partial responses among 45 entered patients for an overall response rate of 57.8%. In 35 chemotherapy-naive patients, the objective response rate was 65.7%, the median response duration was 155 days, and 1 year survival was 62.3%.

[Evaluation of chemotherapy for stage IV non-small cell lung cancer employing a regression tree type method for quality-adjusted survival analysis to determine prognostic factors].

To evaluate the effect of chemotherapy on QOL, the survival period was categorized by 3 intervals: one in the hospital for chemotherapy (TOX), on an outpatient basis (TWiST Time without Symptom and Toxicity), and in the hospital for conservative therapy (REL). Coefficients showing the QOL level were expressed as ut, uw and ur. If uw was 1 and ut and ur were plotted at less than 1, ut TOX+uwTWiST+urREL could be a quality-adjusted value relative to TWiST (Q-TWiST). One hundred five patients with stage IV non-small cell lung cancer were included. Sixty-five were given chemotherapy, and the other 40 were not. The observation period was 2 years. Q-TWiST values for age, sex, PS, histology and chemotherapy were calculated. Their quantification was performed employing a regression tree type method. Chemotherapy contributed to Q-TWiST when ut approached 1 i.e., no side effect was supposed). When ut was less than 0.5, PS and sex had an appreciable role.