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CONTEXT: Palliative care research in Africa is in its relative infancy, with dedicated financial support extremely limited. Therefore, setting research priorities to optimize use of limited resources is imperative. OBJECTIVES: To develop a prioritized research agenda for palliative care in Africa. METHODS: We used a two-stage process involving palliative care professionals and researchers: 1) generation of an initial topic list at a consultative workshop of experts and 2) prioritization of that list using a consensus development process, the nominal group technique. RESULTS: Phase 1: 41 topics were generated across five groups, with several topics nominated in more than one group. Phase 2: 16 topics and three broad thematic areas were identified. The two most prioritized topics within each of the three themes were the following: Theme 1: patient, family, and volunteers-1) care outcomes and the impact of palliative care as perceived by patients and caregivers and 2) palliative care needs of children; Theme 2: health providers-1) impact of palliative care training on care and practice and 2) integration of palliative care and antiretroviral therapy services; and Theme 3: health systems-1) palliative care needs assessments at the micro-, meso-, and macro-levels and 2) integration of palliative care into health systems and educational curricula. CONCLUSION: Consensus-based palliative care topics determined by the study can assist researchers in optimizing limited research capacities by focusing on these prioritized areas. Subsequent to the identification and publication of the research agenda, concrete steps will be undertaken by the African Palliative Care Research Network and other partners to help implement it.

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The objective of this study was to establish a pharmacokinetic model for the estimation of unchanged cis-dichlorodiammine-platinum (II) (CDDP) concentration in peritoneal fluid after intraperitoneal administration of cisplatin-loaded microspheres (CDDP-MS) and to elucidate the accuracy of this model by comparisons between actual and simulated values after intraperitoneal administration of CDDP-MS. We developed a method enabling the precise and quick assessment of the drug concentration in the peritoneal cavity. The pharmacokinetic parameters obtained after intravenous bolus injection at a dose of 2 mg kg(-1) were total body clearance (1026 mL h(-1) kg(-1)), elimination rate constant (3.24 h(-1)) and distribution volume of systemic circulation (316.7 mL kg(-1)). After an intraperitoneal bolus injection at a dose of 5 mg kg(-1), the absorption rate constant from the peritoneal cavity (3.64 h(-1)) and the distribution volume of the peritoneal cavity (13.5 mL kg(-1)) were determined. The protein-binding rate constant in ascites was 0.58 h(-1). Using these pharmacokinetic parameters, we established a pharmacokinetic model consisting of two compartments. Administration of CDDP-MS at a dose of 10 mg kg(-1), which released CDDP over 7 days in-vitro, yielded sustained concentrations of unchanged CDDP (1-2 mg mL(-1)) in the peritoneal cavity that persisted for 7 days, and that were predictable by applying the in-vitro dissolution profile to the pharmacokinetic model. The findings obtained from this study are useful for understanding the basic pharmacokinetic characteristics of unchanged CDDP in the peritoneal cavity and may also be important in the development of optimized CDDP-MS formulations.

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A 64-year-old woman presented with hepatic and pulmonary tumors of mucosa-associated lymphoid tissue lymphoma occurring 8 years apart. The present case carries the possibility of pulmonary metastasis of hepatic lymphoma or double primary lymphoma. Mucosa-associated lymphoid tissue lymphomas tend to develop in the extranodal primary organ, rarely developing systemically among extranodal organs as in our case. Our experience is useful in understanding the progress and outcome of mucosa-associated lymphoid tissue lymphoma.

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A healthy 34-year-old man had a mediastinal cyst on the imaging study. Surgical treatment was performed. The cyst was diagnosed as a thoracic duct cyst from its anatomic location and contents. Pathologic examination found it to be consistent with thoracic duct cyst. Endothelial cells on its luminal surface were identified by an immunohistologic stain with the factor VIII-related antigen. Twenty-six cases of thoracic duct cysts have been reported. We report an additional case and review the previously reported cases. We found that the ligation of the inferior pedicle of the cyst is essential to prevent postoperative chylothorax.

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The effect of protein binding on the pharmacokinetics of cisplatin (cis-diamminedichloroplatinum (II); CDDP) has been studied in analbuminemic rats, which genetically lack albumins, in comparison with normal rats. CDDP was reported to highly bind to serum components, and the major binder was thought to be an albumin. However, there were no significant differences in the serum disappearance profiles of platinum after intravenous (iv) bolus injection of CDDP to analbuminemic rats as compared with normal rats. The total body clearance, Cl(tot), of platinum in normal rats was 48.7+/-22.0 mL h(-1) (5 mg kg(-1)), 55.9+/-4.04 mL h(-1) (10 mg kg(-1)) and 49.0+/-3.57 mL h(-1) (20 mg kg(-1)), whereas Cl(tot) in analbuminemic rats was 52.0+/-8.48 mL h(-1) (5 mg kg(-1)), 62.9+/-10. 8 mL h(-1) (10 mg kg(-1)) and 62.8+/-6.81 mL h(-1) (20 mg kg(-1)). The serum blood urea nitrogen (BUN) and creatinine levels at 6 h after iv injection were higher in both groups of rats who received CDDP than those of pre-dose level. However, there were no significant differences in the renal function tests between analbuminemic rats and normal rats. The binding of CDDP to the serum samples obtained from analbuminemic rats and normal rats was measured by a centrifuging filtration method. The binding percentages were 68.0+/-5.9% (2.0 microg mL(-1)), 56.8+/-4.1% (5.0 microg mL(-1)) and 64.6+/-4.4% (10.0 microg mL(-1)) in analbuminemic rats and 52.9+/-3.5% (2.0 microg mL(-1)), 52.2+/-3.4% (5.0 microg mL(-1)), 56.9+/-1.9% (10.0 microg mL(-1)) in normal rats. Higher binding percentages were obtained in analbuminemic rats than in normal rats. In vitro binding studies under the two incubation conditions (5 min and 2 h) showed that the binding percentages of CDDP to serum proteins were 59.2+/-3.2% (5 min) and 72.3+/-6.5% (2 h) for albumin, 42.3+/-1.9% (5 min) and 39.5+/-2.5% (2 h) for alpha(1)-acid glycoprotein (AAG) and 51.7+/-5.3% (5 min) and 49. 2+/-1.9% (2 h) for gamma-globulin. From these studies, it was elucidated that albumin is not the major ligand in the rat serum and that other proteins also have important roles in the pharmacokinetics of CDDP.

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Three cases are reported who received brachytherapy with external irradiation for inoperable lung cancer and have shown long-term remission. The diseases were adenoid cystic carcinoma, recurrent adenocarcinoma and squamous cell carcinoma. The associated symptoms were severe cough and dyspnea in all 3 cases. They received 60 Gy of external irradiation. After an interval of 2 weeks, 6 Gy at a radius of 1 cm from the center of the source was delivered by iridium-192. They received 2-4 fractions at 1-week intervals. On termination of brachytherapy, complete response was observed in all cases. In 1 case, bronchial stenosis due to radiation-induced fibrosis was observed, but was successfully treated by bronchial stent. Cough and dyspnea disappeared, and all patients have been rendered asymptomatic for the last 2 years. Local disease was well controlled in 2 cases; however, minimal local recurrence was observed after a 2-year follow-up in 1 case.

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We previously proposed a new assay using the cytokinesis-block micronucleus (MN) technique to estimate the fraction of cells undergoing mitosis in vitro [dividing fraction (DF)], potential doubling time (Tpot), and radiosensitivity (in terms of MN frequency) of human tumors. In the present study, we applied this technique to primary lung cancers to evaluate their biological characteristics, and the assay results for the proliferative activity were compared with the treatment outcome. Tumor tissues were disaggregated to single cells, which were cultured in the presence of cytochalasin B after (or without) radiation. At intervals, the proportion of multinucleate cells (its maximum value is the DF), the average number of nuclei/cell, and MNs in binucleate cells were scored. The Tpot was the extrapolated time for the nuclei:cell ratio to reach 2.0. Of the 71 tumor samples obtained, the DF and Tpot were evaluable in 61 (86%), and the MN frequency was evaluable in 52 (73%). The median DF and Tpot values were 23% and 7.7 days, respectively, for adenocarcinoma (n = 41), 26% and 8.9 days for squamous cell carcinoma (n = 13), 27% and 6.5 days for large cell carcinoma (n = 3), and 30% and 7.0 days for small cell carcinoma (n = 4). There was no significant difference in the mean DF or Tpot values according to the histological type or disease stage. The mean MN frequency after 2 Gy of radiation (minus the 0 Gy frequency) was 0.15 for adenocarcinoma, 0.17 for squamous cell carcinoma, 0.16 for large cell carcinoma, and 0.20 for small cell carcinoma. The MN frequency after radiation was positively correlated with both the DF and the baseline (at 0 Gy) MN frequency. In non-small cell lung cancer, a DF above the median was associated with an increased recurrence rate after operation, and the Tpot was correlated with the time until relapse in patients who developed recurrence. Although the clinical significance of the MN frequency needs to be clarified in future studies, the DF and Tpot determined by this assay appear to be good parameters of tumor proliferative activity.

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As compared to the conventional standard chemotherapy of solid cancer such as lung, biochemical modulation (BCM) therapy has been proven to have a good therapeutic efficiency. BCM therapy uses the low dose and low infusion rate of anti-cancer drug. To increase of the QOL of cancer patients, oral BCM therapy is needed. For this purpose, two kinds of new oral sustained-release cisplatin preparations were developed, micro-porous CDDP capsule made of ethylcellulose(EC) and CDDP-EC-stearic acid solid dispersion. After oral administrations of these preparations, serum CDDP levels were maintained over 0.2 microgram/ml for 24h. Experimental therapy using P815 tumor cells transplanted mice suggested the usefulness of CDDP solid dispersion preparation.

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STUDY OBJECTIVE: The objectives of the present study were to evaluate the importance of intrapulmonary lymph nodes (IPLNs) in the differential diagnosis of small pulmonary nodules and to review the CT findings of IPLNs. DESIGN: Retrospective analysis of patient records. SETTING: Chest Disease Research Institute Hospital, Kyoto University. PATIENTS: Between January 1991 and May 1996, we examined 26 patients with pulmonary nodular shadows smaller than 1 cm in diameter that could not be diagnosed before surgery. All patients (19 men, 7 women) underwent chest CT (28 to 72 years old; mean, 52.3 years). RESULTS: The pathologic diagnoses were IPLNs in 46.2% (12/26), pulmonary hamartoma in 23.1% (6/26), lung cancer in 11.5% (3/26), pulmonary tuberculoma in 11.5% (3/26), and metastatic lung tumor in 7.7% (2/26). IPLNs were located in the lower lobe in 72%. The characteristic CT findings of IPLNs were a clear border and location close to the pleura. Two of them resembled lung cancer. The CT features in these two IPLNs and in three small lung cancers overlapped. CONCLUSIONS: In the present study, we investigated small nodular shadows <1 cm in diameter and found that IPLNs located underneath the pleura are important to consider in the differential diagnosis of lung cancer. The CT scan findings of IPLNs were not necessarily specific and sometimes resembled those of lung cancer. Because of their location, video-assisted thoracic surgery is useful in making a definite diagnosis.

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Omentopexy has improved the treatment of chronic empyema and postpneumonectomy bronchopleural fistula, which otherwise are difficult to manage. However, omentopexy is not effective in some patients. Four of 17 patients who underwent omentopexy in our institution between January 1978 and March 1994 did not respond to the treatment and died. In two patients, a dead space remained after surgery and there was insufficient sterilization. In one patient, a dead space appeared after surgery and it was impossible to control infection. The fourth patient had dehiscence of the anastomosis triggered by postoperative acute gastritis. All four patients in whom omentopexy was not successful died. When omentopexy is used for empyema, the space should first be sterilized. If sterilization is insufficient, muscle filling and thoracoplasty must be performed and no dead space left.

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A new oral sustained-release solid-dispersion preparation of cisplatin (cis-diamminedichloroplatinum(II): cisplatin) has been developed for administration to small experimental animals such as mice. This preparation was obtained by formulating cisplatin with the water-insoluble polymer ethylcellulose and with stearic acid in different ratios. In-vitro dissolution studies showed that cisplatin release characteristics were zero-order for the formulation cisplatin-ethylcellulose-stearic acid (1:10:5) and levels equilibrated 7 h after the start of the experiment. The availability of cisplatin from this preparation was evaluated both in rats and mice. The cisplatin preparation (20 mg kg-1) was administered orally to rats and the resulting curve of serum cisplatin levels against time was compared with that obtained after intravenous infusion (20 mg kg-1) to rats. By comparing the areas under serum concentration-time curves (AUCs), the bioavailability of cisplatin was estimated to be 31%. The mean residence time (MRT) of cisplatin solid dispersion was 6.13 +/- 0.43 h, whereas the MRT of cisplatin administered by intravenous infusion was 3.89 +/- 0.05 h. Serum cisplatin levels were maintained above 0.3 mg mL-1 (believed from our clinical studies to be the minimum effective concentration) for 24 h. The curve of serum cisplatin level against time suggested that cisplatin was released from the solid dispersion preparation in a sustained-release fashion. Similar levels were also maintained in mice for 24 h. The MRT of the cisplatin preparation was 10-16 h in mice, which is longer than that obtained after oral administration of the physical mixture. The serum free-cisplatin concentration was determined to be 0.10 mg mL-1 in mice serum in which the total cisplatin concentration was 0.30 mg mL-1. The free fraction of cisplatin in mice serum was the same as that in human patient serum. Pathological examination showed that this new sustained-release oral cisplatin preparation did not have any side effects on the gastrointestinal tract. These results suggest usefulness of this new solid-dispersion preparation for oral cisplatin therapy in lung cancer patients.

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A 57-year-old man was admitted because of dysphagia. Two year earlier, endoscopic ND-YAG laser treatment had been performed for squamous cell carcinoma of the tracheal carina. The esophagus was compressed and narrowed by invasion of lung cancer. After ballooning, under endoscopic and fluoroscopic control, a self-expanding nitinol stent (SENS, Ultraflex, Microvasive) was implanted in the esophagus. Immediately after esophageal prosthesis implantation, severe dyspnea and stridor developed because of tumor strictures in the left main bronchus. Under fluoroscopic and guide-wire control, SENS (Accuflex, Microvasive) was implanted in the tracheobronchial tree. Dyspnea, dysphagia and stridor were markedly improved after placement of two nitinol stents. Highly flexible, knitted, self-expanding nitinol stent is made of a nickel titanium alloy. Although the implantation of SENS in tracheobronchial stenosis has not previously been reported, it should be useful for prevention of airway obstruction.

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To investigate the chance of discovery of metastatic lung tumors and the five-year survival rates of patients undergoing surgical resection, we followed 99 patients who underwent initial surgical treatment at our hospital between 1979 and 1996. With regard to primary organs or sites, 32 patients had rectal cancer, 27 patients had breast cancer, 19 patients had colon cancer and 21 patients had osteosarcoma. For 22 of 99 patients (22%), discovery was due to subjective symptoms such as cough and sputum (n = 12), chest (or back) pain (n = 7) or hemosputum (n = 5). Ten of 19 patients (53%) with colon cancer experienced subjective symptoms which led to the discovery of metastases. In 76 of 99 patients (78%), metastatic lung lesions were not discovered through subjective symptoms. In 63 of those 76 patients, such lesions were initially found by plain chest roentgenography or CT. In 20 of 21 patients (95%) who had osteosarcoma, metastatic lung tumors were discovered by chest roentgenography or CT. In 14 of 76 patients, all of whom had metastatic lung carcinomas, the lesions were discovered through elevated levels of tumor markers. Therefore the importance of periodic chest roentgenography and tumor marker testing was demonstrated. Disease-free interval (DFI) was over six years in five of 32 patients (16%) with rectal cancer and 13 of 27 (48%) with breast cancer. DFI was less than five years for 15 of 19 patients (79%) with colon cancer, and less than two years for 16 of 21 (75%) with osteosarcoma. Thus, DFI differed according to the sites of the tumors. The five-year survival rates of 97 patients were examined. Patients were divided according to the sites of their primary tumors, and then subdivided according to the type of surgery they received. Patients were thus divided into five categories: I) those who underwent incomplete resection of metastatic lung lesions, II) those who underwent complete resection of both pulmonary lesions and involved mediastinal lymph nodes, III) those who had undergone previous treatment for tumors in organs other than the lung, IV) those who underwent complete resection of multiple lung lesions, and V) those who underwent complete resection of solitary lung lesions. For all primary sites, none of the patients in group I) survived for more than two years. Therefore complete resection seems very important for the treatment of metastatic lung tumors. With regard to the other groups, several facts were noted. For rectal cancer, the five-year survival rate of groups V) and III) was 55.6% in either case. Therefore complete resection of rectal cancer metastatic to the lung may improve the five-year survival rate even for patients who have previously been treated for cancers in organs other than the lung. For colon cancer, the five-year survival rate of group V) was 51.4%. Complete resection of only a solitary lung lesion may improve the five-year survival rate for colon cancer. For breast cancer, the five-year survival rate of group V) was 37.5% and that of group II) was 60.0%. This may indicate that for patients who have both pulmonary lesions and mediastinal lymph node involvement, complete resection of both is important. For osteosarcoma the five-year survival rate of group IV) was 26.0%. Thus, osteosarcoma patients have a chance of survival if they undergo complete resection of lung metastases.

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To assess the time trends and survivals after operations for primary lung cancer, the cases of 845 consecutive patients who underwent thoracotomy between 1976 and 1990 were retrospectively reviewed by groups corresponding to year of the operation (the early period was 1976 to 1980, n = 208; the middle period was 1981 to 1985, n = 291, and the late period was 1986 to 1990, n = 346). The 5-year survivals at the early, the middle, and the late periods were 31.5%, 39.0%, and 54.0%, respectively, with significant improvement particularly at the late period (p < 0.05 for the early period vs the middle period, p < 0.01 for the early or middle period vs the late period); the improvement was caused by increase in the ratio of patients with stage I disease (20.7% at the early period, 32.0% at the middle period, 44.2% at the late period), increase in the rates of complete tumor resection with lymph node dissection (57.2%, 68.0%, 74.3%, respectively), and decrease in the rates of operation-related death (3.8%, 3.4%, 0.9%, respectively). The postoperative prognosis of patients with stage II disease at the late period (5-year survival 74.8%) showed significant improvement compared with the other periods. Moreover, the prognosis of patients with stage IIIa, pN2 disease (5-year survival 41.5%) showed significant improvement, which was caused by the significant decrease in patients with pT3 N2 M0 disease and poor prognosis.

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An oral sustained-release cisplatin preparation was prepared by combining microporous water-insoluble pharmaceutical polymer, ethylcellulose, a membrane and a gel-forming polymer, poly(acrylic) acid (Carbopol). As cisplatin is an extremely hydrophilic and small compound, it was difficult to control the release rate solely by the micropores on the ethylcellulose capsule. To retain cisplatin within the capsule, gel-forming polymer was formulated inside the capsule. The release rate of cisplatin was dependent both on the number of micropores of the capsule and the formulated amount of Carbopol. The number of micropores ranged from 20 and 30 to 60, and the formulated amount of Carbopol varied from 15 to 100 mg. In-vitro release experiments suggested that the release rate decreased as the formulated amount of Carbopol increased when the pore number was 60 and 30. However, when pore number was decreased to 20, the effect of the amount of Carbopol was not clearly observed. In the in-vivo study using rabbits, the sustained-release cisplatin capsule was evaluated in comparison with solution after oral administration of 20 mg drug. With the pore number of 60, Cmax was 0.46 +/- 0.02 microgram mL-1 at 4 h and thereafter serum concentrations declined rapidly. When the pore number was 30, serum cisplatin level-time profiles showed long-acting patterns and AUC was reversely correlated with the formulated amount of Carbopol. Cmax and tmax were 0.41 +/- 0.02 microgram mL-1 and 3.33 +/- 0.88 h, respectively and 0.23 +/- 0.01 microgram mL-1 was obtained at 24 h after oral administration of capsule having 30 pores and 15 mg of Carbopol. We conclude that the possibility of developing an oral sustained-release cisplatin preparation is feasible.

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BACKGROUND: We analyzed the operative outcome of extensive surgery for invasive thymoma, especially in those with thymomas invading the superior vena cava, the left innominate vein, or both. METHODS: We treated 41 patients with invasive thymoma, including 34 stage III, 5 stage IVa, and 2 stage IVb thymomas. Thirty-eight patients received radiotherapy preoperatively or postoperatively. In 12 patients with invasion of the superior vena cava or innominate vein, we performed angioplasty, reconstruction, or both. RESULTS: The overall 5-year survival rate was 77% and the 10-year survival rate was 59%. In the stage III group, there was a significant difference between those with complete and those with incomplete resection. Ten of 12 patients who had angioplasty with or without reconstruction of the superior vena cava or innominate vein survived without recurrence of the tumors. CONCLUSION: Angioplasty and vascular reconstruction are recommended because successful treatment for invasive thymomas depends on complete resection of the tumors.

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We report herein the cases of two patients who underwent resection of a primary pulmonary hemangiopericytoma. The first patient was a 58-year-old man found to have a mass-like shadow of about 5 cm in diameter in the right hilum by a routine chest X-ray. Subsequent magnetic resonance imaging (MRI) showed a probable mediastinal tumor, and surgery was performed. Postoperative pathological examinations confirmed the diagnosis of pulmonary hemangiopericytoma. The second patient was a 21-year-old woman found to have a mass-like shadow of about 2 cm in diameter in the left middle lung field. As a preoperative diagnosis could not be made, exploratory surgery was performed and the left S6 segment was excised. A definitive diagnosis of pulmonary hemangiopericytoma was established postoperatively by pathological examination. Primary pulmonary hemangiopericytoma is an extremely rare type of tumor, with only 36 cases having been reported in the Japanese literature to date, including out 2 cases. A discussion following the case reports examines the sex, age, initial manifestations, sites, and methods of surgery employed in these 36 cases.

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Eighteen patients underwent combined preoperative irradiation and radical resection for a Pancoast tumor at the Department of Thoracic Surgery, Chest Disease Research Institute, Kyoto University between 1977 and 1993. Four patients were applied a full radiation dose of 50-70 Gy and fourteen patients were applied a reduced dose of 33-40 Gy preoperatively. Eleven of these fourteen were applied a supplemental dose postoperatively up to a total dose of at least 50 Gy. Fourteen lobectomies, three partial resections, and one pneumonectomy were performed with combined resection of chest wall or adjacent structures: rib in 14, vertebra in 4, brachiocephalic vein in 3, subclavian artery in 2, spinal nerve in 3, sympathetic truncus in 2, phrenic nerve in 2 cases. Chest walls were reconstructed with marlex mesh in 5 patients, and two subclavian arteries and one brachiocephalic vein were repaired with artificial grafts. In 13 patients complete resections were achieved, but in the other 5 only incomplete resections leaving residual tumor were achieved. Incomplete resections consisted of 4 positive stumps at the brachial plexus of the apex and one aortic involvement by a metastatic lymph node. There was one operative death. Median survival was 21.6 months and the 5-year-survival rate was 38.5% for all 18 patients. In the complete resection group 5-year-survival was 56.4%, but in the incomplete-resection group 0%, showing a significantly more favorable result for the complete resection group. It is considered that evidence of incomplete resection influences the prognosis and that particularly tumor invasion to the brachial plexus may serve as a limiting factor for surgery.

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To assess the effect of chemotherapy on postoperative survival of patients with small cell lung carcinoma (SCLC), 46 patients who underwent surgery at Kyoto University between 1976 and 1991 were retrospectively reviewed. Seventeen patients (37.0%) received chemotherapy prior to as well as after surgery (neoadjuvant therapy group), 23 (50.5%) received chemotherapy only after surgery (adjuvant therapy group), and the other six received no chemotherapy (non-chemotherapy group). The 5-year survival rate of patients with c-Stage I or II disease in the neoadjuvant therapy group was as high as 80.0%, which seemed to be higher, although with no statistical significance, than that in the adjuvant therapy group (37.7%, P = 0.10). The 5-year survival rate of patients with c-Stage III (IIIa or IIIb) disease in the neoadjuvant therapy group, although not satisfactory (10.0%), was significantly higher than that in the adjuvant therapy group (0.0%, P = 0.04). No patients in the non-chemotherapy group had survived 5 years. Moreover, multivariate analysis showed that failure to employ preoperative chemotherapy was the strongest prognostic factor causing a poor prognosis (P = 0.01). On the other hand, eight (30.8%) out of 26 patients with c-Stage I or II disease postoperatively proved to have mediastinal lymph node involvement (pN2-3), and two (7.7%) proved to have intrapulmonary metastasis (PM). Considering the advantage of preoperative chemotherapy and the discrepancy between c- and p-stage, sufficient chemotherapy prior to surgery should be employed, and may realize a good prognosis in patients with c-Stage I or II disease. In contrast, patients with c-Stage III disease are not appropriate as candidates for surgery even if preoperative chemotherapy is performed.

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