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.

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.

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.

Changes in cardiac performance after dialysis in patients with chronic renal failure.

The effect of hemodialysis on left ventricular performance in 10 uremic patients was studied utilizing echocardiography. Left ventricular function curves constructed by a lower body negative pressure method were compared before and after dialysis. Although hemodialysis caused a decrease in the stroke volume index at rest from 55 +/- 17 to 50 +/- 20 ml/m2, the left ventricular function curve did not show any detectable shift. Thus, it is concluded that a decrease in stroke volume secondary to dialysis is attributable to the reduction in preload, rather than to changes in the contractile state of the left ventricle.

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.

Sequence variations in the envelope protein of the hepatitis C virus: comparison with partial cDNA sequence of a new variant virus obtained by the polymerase chain reaction.

It has been reported that the envelope region located at the 3' portion of the structural protein coding region is one of the most variable regions at both nucleotide and amino acid sequence levels in the hepatitis C virus (HCV) genome. We cloned HCV cDNA fragments of an envelope protein coding region (HCVNK), which were derived from serum of a Japanese patient with hepatocellular carcinoma and were amplified by polymerase chain reaction. After determining the nucleotide sequence, deduced amino acid sequence of the envelope protein region was compared with those of six HCV strains already published (HCJ1, HCVUS, HCJ4, HCVJH, HCVJ and HCVBK). Homology analysis among the strains revealed that the seven strains were classified into two subtypes; a US subtype (HCJ1 and HCVUS) and a Japanese subtype (HCJ4, HCVJH, HCVJ, HCVBK and HCVNK), since percentage homologies between two subtypes (70.3-77.3%) were significantly lower than those within each subtype (83.9-93.5%). Detailed analysis of the amino acid sequences also indicates that the region at aa246-aa258, tentatively named intersubtype variable region-1, may distinguish the US subtype from the Japanese subtype.

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.

[Infection rate of Chlamydia trachomatis in sexual partners from pregnant women with Chlamydia trachomatis infection].

We investigated the infection rate of Chlamydia trachomatis in sexual partners who had pregnant wives with C. trachomatis diagnosed by means of serum-antibody test (Ipazyme) or antigen test (Chlamydiazyme, IDEIA-chlamydia). Antibody-positive rate was 60.4% (90/149 cases), and antigen-positive rate was 7.4% 11/149 cases). All cases with Chlamydial antigen had anti-Chlamydial antibody. Eleven cases with Chlamydial antigen had no symptom of urethritis. Among these cases, eight cases had abnormal laboratory findings. However, the other three cases who had no abnormal finding were careers of C. trachomatis. In this study, sexual partners who had Chlamydial antigen were few, however, those who had anti-chlamydial antibody were many. Therefore, C. trachomatis will disseminate among many families as a latent infection.

[Clinical experience with ampicillin-cloxacillin (Viccillin S 'Meiji') by intravenous drip infusion in gynecological infections (author's transl)].

Ampicillin-cloxacillin (Viccillin S 'Meiji') by intravenous drip infusion was used in gynecological infections, with the following satisfactory results. 1) The drug was markedly effective in 2 out of 6 cases, effective in 4, being the efficacy rate 100%. 2) No abnormal laboratory findings and side effects were observed in our study.

[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 pilot study of combination chemotherapy with cyclophosphamide, adriamycin, chronic daily dosing of oral etoposide for patients with SCLC ineligible for intensive chemotherapy].

Twenty-two patients with small cell lung cancer (SCLC) ineligible for intensive chemotherapy were treated with a combination of cyclophosphamide 800 mg/m2 iv day 1, adriamycin iv 40 mg/m2 day 1, and oral etoposide 40 mg/m2 once daily day 1-21. The overall response rate was 72.7% with 2 complete and 14 partial responders. The median survival time was 272 days in LD and 231 days in ED. The side effects were acceptable but not as mild as expected.

[Pilot study of irinotecan in refractory small cell lung cancer].

Sixteen patients with refractory small cell lung cancer (SCLC) were treated with an irinotecan starting dose of 100 mg/m2 given as a 90-minute iv infusion every week with subsequent doses based on toxicity. Mean age was 64 years; 14 male and 2 female; 4 with limited disease and 12 with extensive disease; all patients pretreated with combination chemotherapy containing etoposide. The overall response rate was 50% (95% CI 25-75%) with no CR and 8 PR. The median duration of response was 46 days. Major toxicities were leukopenia, diarrhea and pulmonary toxicity. Irinotecan was thus an effective agent in refractory SCLC.

[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%.

[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.

[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.

[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.

[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.

[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.

[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.