A Randomized Controlled Trial of Betamethasone on Fatigue in Patients With Advanced Cancer.

CONTEXT: Fatigue is one of the most uncomfortable physical symptoms seen in patients with advanced cancer. Previous studies have reported on the efficacy of corticosteroids from Western countries. OBJECTIVES: To assess the effectiveness of 4mg betamethasone improving fatigue among Japanese patients with advanced cancer. METHODS: A randomized, double-blind, placebo-controlled trial enrolled eligible patients with advanced cancer expected to survive 1-2 months, with an Eastern Cooperative Oncology Group Performance Status of 2-3, and experiencing fatigue according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-15-palliative criteria. Participants received twice-daily oral administration of 2 mg betamethasone (4 mg/d) or placebo for seven days, with fatigue assessed using EORTC QLQ-C15-PAL subscale and numerical rating scale (NRS) score (at baseline and day seven). The trial was registered under the University Hospital Medical Information Network (UMIN)000011913. RESULTS: Among the 267 screened patients, 81 were eligible, of which 70 were evaluable (betamethasone, 33; placebo, 37). The mean difference in the EORTC-QLQ-C15-PAL fatigue subscale was -8.2 (95% CIs: -22.3, 0.0; P = 0.178) and in a NRS for fatigue was -1.2 (95% CIs: -2.5, -0.01; P = 0.048), respectively. Emotional function, appetite loss, and global-health were slightly better in the betamethasone group than in the placebo group. CONCLUSION: The impact of betamethasone 4 mg/d on alleviating fatigue in patients with advanced cancer in the last weeks of life did not reach statistical significance in the EORTC-QLQ-C15-PAL as the primary endpoint, however, it was significant in the NRS, the secondary endpoint.

Solitary fibrous tumor of the mediastinum.

An 18-year-old man was referred to our hospital for further evaluation of a right anterior mediastinal tumor that measured 6 cm in diameter. Computed tomography-guided transcutaneous aspiration biopsy was performed, but no definitive diagnosis could be obtained. Because the tumor did not appear to be a high-grade malignant tumor, we undertook resection of the tumor to obtain a definitive diagnosis and provide appropriate treatment. Total thymectomy with tumor resection was performed through a median sternotomy. The tumor was solid, measuring 5.2 x 4.2 x 3.5 cm. The histological diagnosis was solitary fibrous tumor (SFT) arising from the mediastinum. Most extrathoracic SFTs appear to pursue a benign course, although careful long-term follow-up of these patients is necessary because the tumors have been reported to recur or metastasize in some cases.

[Current status of adjuvant chemotherapy for resected lung cancer at our institute--focus on clinical trial enrollment].

Adjuvant chemotherapy after complete resection in Stage I B-III A non-small cell lung cancer is recommended. Several clinical trials of adjuvant chemotherapy are now underway in Japan. Our institute also participates in adjuvant clinical trials, but slow patient recruitment is a problem. In this paper, we reported the current status of adjuvant chemotherapy and recruitment for clinical trials at our institute. Between August 2001 and December 2008, candidates for adjuvant chemotherapy were 315 patients. Among them 186 who received adjuvant chemotherapy were younger and had less co-morbidity than those who did not receive adjuvant chemotherapy. Twenty-five of the 186 patients participated in the clinical trials. The major reason of refusal of a clinical trial was that patients preferred to choose their own treatment and disliked randomized trials.

Pulmonary angioplastic procedure for lung cancer surgery.

PURPOSE: Although bronchoplasty for the treatment of lung cancer is widely accepted as a reliable, safe procedure for the preservation of lung function, there have been only a few reports on pulmonary artery (PA) resection and reconstruction. METHODS: Retrospectively, we reviewed our medical records of pulmonary angioplastic procedures and assessed the results. RESULTS: A total of 25 patients (5 women, 20 men) with a mean age of 68 years (range 44-85 years) underwent a pulmonary angioplastic procedure for lung cancer surgery. Altogether, 13 patients had adenocarcinoma, and 11 had squamous cell carcinoma. The cancers were located in the left lung in 15 cases and in the right lung in 10 cases. The PA reconstructions comprised 4 circumferential resections and anastomoses, 18 wedge resections and end-to-end anastomoses, 2 tangential resections with direct suturing, and 1 wide wedge resection and autologous pericardial patch repair. Six patients underwent concomitant bronchoplasty with pulmonary artery reconstruction. Prior to surgical treatment, seven patients had received neoadjuvant therapy. Although early postoperative complications occurred in eight patients (32%), no operative or in-hospital deaths occurred. All the patients in this series were discharged from hospital and went home. The overall 5-year survival rate was 45%, with a mean 27 months of follow-up. CONCLUSION: Most operative complications after PA reconstruction were controllable despite the high morbidity rate. Pulmonary angioplastic procedures for the surgical treatment of lung cancer are both useful and feasible with good intermediate-term results.

Effects of respiratory rate and tidal volume on gas exchange in total liquid ventilation.

Using a rabbit model of total liquid ventilation (TLV), and in a corresponding theoretical model, we compared nine tidal volume-respiratory rate combinations to identify a ventilator strategy to maximize gas exchange, while avoiding choked flow, during TLV. Nine different ventilation strategies were tested in each animal (n = 12): low [LR = 2.5 breath/min (bpm)], medium (MR = 5 bpm), or high (HR = 7.5 bpm) respiratory rates were combined with a low (LV = 10 ml/kg), medium (MV = 15 ml/kg), or high (HV = 20 ml/kg) tidal volumes. Blood gases and partial pressures, perfluorocarbon gas content, and airway pressures were measured for each combination. Choked flow occurred in all high respiratory rate-high volume animals, 71% of high respiratory rate-medium volume (HRMV) animals, and 50% of medium respiratory rate-high volume (MRHV) animals but in no other combinations. Medium respiratory rate-medium volume (MRMV) resulted in the highest gas exchange of the combinations that did not induce choke. The HRMV and MRHV animals that did not choke had similar or higher gas exchange than MRMV. The theory predicted this behavior, along with spatial and temporal variations in alveolar gas partial pressures. Of the combinations that did not induce choked flow, MRMV provided the highest gas exchange. Alveolar gas transport is diffusion dominated and rapid during gas ventilation but is convection dominated and slow during TLV. Consequently, the usual alveolar gas equation is not applicable for TLV.

Evaluation of video-assisted thoracoscopic surgery lobectomy requiring emergency conversion to thoracotomy.

OBJECTIVE: Video-assisted thoracoscopic surgery (VATS) lobectomy has been employed for the treatment of lung cancer. Many investigators have reported that the outcomes of VATS lobectomy for lung cancer are comparable to those of thoracotomy; however, several controversial issues remain. One of the critical concerns is the safety. VATS lobectomy often requires an emergency conversion to thoracotomy, for example, in the event of massive bleeding. In this study, cases in which VATS lobectomy for lung cancer was converted to thoracotomy intra-operatively (converted VATS lobectomy) were identified. The safety of the converted VATS lobectomy was evaluated. METHODS: Between 2003 and 2007, VATS lobectomy was converted to thoracotomy in 24 out of 492 cases. Information regarding the patients' characteristics, reasons for the conversion and perioperative complications as well as the recurrence and survival data were carefully reviewed. The reasons for the conversion were classified into two groups: (1) problems related to the VATS procedure (VATS-related problems) and (2) problems not related to the VATS procedure (non-VATS-related problems). RESULTS: Of the 24 converted cases, 19 (79%) had a history of smoking. Nine patients (38%) had a history of lung disease. Left upper lobectomy was the most frequently associated with conversion (11/24, 46%), followed by right lower lobectomy and right upper lobectomy. The most frequent reasons for the conversion were hilar lymphadenopathy and bleeding (seven patients each), followed by fused fissure. Eight of the conversions were considered to be attributable to VATS-related problems. Perioperative complications were observed in four patients, consisting of prolonged air leak in three patients and transient recurrent laryngeal nerve palsy in one patient. However, there were no life-threatening complications. The median follow-up period was 26 months. Recurrence occurred in two patients: pleural dissemination in one and bone metastasis in the other. Two deaths were observed during the follow-up period: one related to lung cancer and another related to other type of cancer. CONCLUSIONS: The safety of the conversion was acceptable. Our findings suggest that VATS lobectomy for lung cancer is feasible from the viewpoint of safety, even after taking into account the potential need for conversion to thoracotomy in some patients.

Variance analysis of a clinical pathway of video-assisted single lobectomy for lung cancer.

PURPOSE: Clinical pathways have contributed to standardized postoperative management, but analyzing variance is also important to maintain quality control. To evaluate the validity of our own clinical pathway for managing video-assisted lobectomy for lung cancer, we analyzed the variances influencing postoperative recovery. METHODS: Between April 2003 and April 2004, 62 consecutive patients with lung cancer underwent video-assisted single anatomic lobectomy with lymph node dissection. We evaluated 61 of these patients after the exclusion of one, who deviated from the clinical pathway management immediately as a result of serious complications. RESULTS: There were 29 men and 32 women, with an average age of 65.7 years. Complications developed in 29 patients, but there was no operative mortality. The occurrence of variance ranged from 1.6% to 34.4% for each activity and included prolonged supplemental oxygen therapy, out-of routine examination, prolonged epidural anesthesia, and delayed bathing frequently. Complications and an abnormal body mass index were significant and independent clinical factors affecting the increase in variance. CONCLUSIONS: Our original clinical pathway management was tolerable for lung cancer patients undergoing a video-assisted lobectomy. Complications and an abnormal body mass index were significant predictive factors for an increase in variance of our clinical pathway.

Evaluation of lesions corresponding to ground-glass opacities that were resected after computed tomography follow-up examination.

BACKGROUND: Ground-glass opacity (GGO), which is closely related with bronchioloalveolar carcinoma (BAC), is being detected more frequently. BAC is considered to be a relatively less aggressive tumor, and immediate resection at the time of detection might not be necessary. Therefore, when GGO is detected, a CT follow-up examination is often performed. If growth is detected during the follow-up CT examination, resection is usually considered. However, the possible treatment delay caused by the scheduling of a CT follow-up examination is an issue that must be clarified. Since the cancer might progress during the follow-up period, such follow-up periods might have a negative influence on the patient's prognosis. This study attempted to clarify whether CT follow-up causes treatment delay. METHODS: A total of 113 lung cancer patients with pure or mixed GGO findings who underwent a resection after a CT follow-up examination between 1999 and 2005 were retrospectively examined. The CT findings at the initial detection, the changes in the CT findings during the CT follow-up period, the histology, the pathological stage and the outcomes after resection were reviewed and evaluated. RESULTS: The CT finding at the time of the initial detection showed pure GGO in 63 patients and mixed GGO in 50 patients. Histology revealed that adenocarcinoma was found in all 113 patients; squamous cell carcinoma was not found in any of the patients. One-hundred twelve patients were diagnosed as having Stage IA, and a singe patient with visceral pleura invasion was diagnosed as having Stage IB. Complete resections were performed in all the patients. The median postoperative follow-up period was 45.0 months. No recurrences or deaths were observed during the study period. CONCLUSIONS: No treatment delays or negative influences on patient outcome resulted from the CT follow-up period. A future prospective study should be conducted to establish the optimal CT follow-up program.

Immunohistochemical detection of neuroendocrine differentiation in non-small-cell lung cancer and its clinical implications.

PURPOSE: The purpose of this study was to prospectively assess the clinical implications of neuroendocrine (NE) differentiation in non-small-cell lung cancer (NSCLC) tumors. METHODS: This study accrued subjects suspected to have lung cancer who underwent diagnostic bronchoscopy. Bronchoscopically-biopsied specimens were subjected to routine pathologic examination, and immunohistochemical studies were then performed if lung cancer was diagnosed. Chromogranin-A, synaptophysin, neural cell adhesion molecule, and Leu7 were used to demonstrate NE differentiation. RESULTS: A total of 280 subjects were accrued to this study over a period of 2 years. Among them, 149 subjects were assessable for this study, and 130 were diagnosed as having NSCLC tumors (55 adenocarcinomas, 50 squamous cell carcinomas, 24 NSCLCs not otherwise specified, and 1 typical carcinoid). Large cell NE carcinoma was not observed in this study. Immunohistochemically, NE differentiation was detected in 16% of NSCLC tumors excluding typical carcinoid. By status of NE differentiation of NSCLC tumors, progression-free survivals were similar in 73 patients undergoing non-surgical treatment (positive, n = 10; negative, n = 63) and 43 patients undergoing surgical resection (positive, n = 8; negative, n = 35), respectively. Overall survival of patients with NE-positive tumors appeared to be favorable both for those undergoing non-surgical treatment and those undergoing surgical resection, though the differences in survival were not significant (P = 0.11 and 0.35, respectively). CONCLUSIONS: NE differentiation was detected in 16% of NSCLC tumors in our study. However, the prognostic implications of the presence of this feature could not be clearly determined in this study.

Very long-term outcomes of video-assisted thoracoscopic surgery for lung cancer.

BACKGROUND: The most critical parameter in the evaluation of the feasibility of video-assisted thoracoscopic surgery (VATS) lobectomy for lung cancer is long-term outcome. In this study, patients in whom more than 5 years had elapsed since they had undergone VATS lobectomy for lung cancer were identified, and the 5-year survival rate and frequency of recurrence were evaluated as the long-term outcomes; in addition, the frequency of perioperative complications were also evaluated as the short-term outcomes. METHODS: The stage, histology, perioperative complications, recurrence, and survival data were carefully reviewed in 198 patients who underwent VATS lobectomy for lung cancer between 1998 and 2002. RESULTS: Median postoperative follow-up period was 72.1 months. Of the 198 patients, 138 and 30 were diagnosed as having p-stage IA and IB disease, respectively, while the remaining 30 patients had more advanced disease. Perioperative complications were observed in 20 patients (10.1%), however, there were no perioperative mortalities. Recurrence was observed in 26 patients (13.1%): of these, 11 patients showed local recurrence, including malignant pleural effusion and mediastinal lymph node recurrence, and 16 patients showed distant metastasis, the lung being the commonest site of metastasis; six patients had both local recurrence and distant metastasis. During the study period, there were 26 deaths (13.1%), of which 17 were due to lung cancer and 9 were due to other causes. The 5-year overall survival rates of the patients with p-stage IA and IB disease were 93.5% and 81.6%, respectively. CONCLUSION: VATS lobectomy for the treatment of lung cancer is as feasible and safe as open lobectomy in terms of both very long- and short-term outcomes.

Expiratory flow limitation during gravitational drainage of perfluorocarbons from liquid-filled lungs.

Flow limitation during pressure-driven expiration in liquid-filled lungs was examined in intact, euthanized New Zealand white rabbits. The aim of this study was to further characterize expiratory flow limitation during gravitational drainage of perfluorocarbon liquids from the lungs, and to study the effect of perfluorocarbon type and negative mouth pressure on this phenomenon. Four different perfluorocarbons (PP4, perfluorodecalin, perfluoro-octyl-bromide, and FC-77) were used to examine the effects of density and kinematic viscosity on volume recovered and maximum expiratory flow. It was demonstrated that flow limitation occurs during gravitational drainage when the airway pressure is < or = -15 cm H(2)O, and that this critical value of pressure did not depend on mouth pressure or perfluorocarbon type. The perfluorocarbon properties affect the volume recovered, maximum expiratory flow, and the time to drain, with the most viscous perfluorocarbon (perfluorodecalin) taking the longest time to drain and resulting in lowest maximum expiratory flow. Perfluoro-octyl-bromide resulted in the highest recovered volume. The findings of this study are relevant to the selection of perfluorocarbons to reduce the occurrence of flow limitation and provide adequate minute ventilation during total liquid ventilation.

Advanced age is not correlated with either short-term or long-term postoperative results in lung cancer patients in good clinical condition.

OBJECTIVES: Several investigators have reported that operative mortality in the elderly is acceptable. However, their patients are potentially biased with regard to some factors such as performance status (PS) and comorbidity. In this study, we discuss surgical indications for the elderly and effects on perioperative mortality and prognosis. STUDY DESIGN: A retrospective study was carried out by reviewing the records of 1,114 patients who were referred for treatment of non-small cell lung cancer between January 1993 and December 2002. The patients were classified into younger (< or = 75 years of age) and elderly (> or = 76 years of age) groups. The histologic subtype, TNM stage, Eastern Cooperative Oncology Group PS, and treatment were reviewed for members of each group, and the proportion of patients who underwent surgery was compared between the two groups. The surgical procedures, perioperative mortality, and prognosis of the two groups were also compared. RESULTS: There was a significant difference in the histologic distribution with no difference in TNM staging between the two groups. Regarding treatment, 51.0% of those in the younger group and 36.1% of those in the elderly group underwent surgery. The proportion of elderly patients who underwent surgery was significantly lower than that of the younger patients, mainly due to worse PS and comorbidity in the elderly patients. The perioperative mortality rates for the younger and elderly groups were 0.9% and 4.1%, respectively, with no significant difference, and the overall survival was similar between the two groups. CONCLUSIONS: When compared to younger patients, fewer elderly patients underwent surgery because of worse PS and comorbidity. However, in elderly patients with good PS and no comorbidity, the rate of perioperative mortality and the prognosis were similar to those in the younger patients. Therefore, advanced age only is not a negative factor for surgery in elderly patients.

Flow limitation in liquid-filled lungs: effects of liquid properties.

Flow limitation in liquid-filled lungs is examined in intact rabbit experiments and a theoretical model. Flow limitation ("choked" flow) occurs when the expiratory flow reaches a maximum value and further increases in driving pressure do not increase the flow. In total liquid ventilation this is characterized by the sudden development of excessively negative airway pressures and airway collapse at the choke point. The occurrence of flow limitation limits the efficacy of total liquid ventilation by reducing the minute ventilation. In this paper we investigate the effects of liquid properties on flow limitation in liquid-filled lungs. It is found that the behavior of liquids with similar densities and viscosities can be quite different. The results of the theoretical model, which incorporates alveolar compliance and airway resistance, agrees qualitatively well with the experimental results. Lung compliance and airway resistance are shown to vary with the perfluorocarbon liquid used to fill the lungs. Surfactant is found to modify the interfacial tension between saline and perfluorocarbon, and surfactant activity at the interface of perfluorocarbon and the native aqueous lining of the lungs appears to induce hysteresis in pressure-volume curves for liquid-filled lungs. Ventilation with a liquid that results in low viscous resistance and high elastic recoil can reduce the amount of liquid remaining in the lungs when choke occurs, and, therefore, may be desirable for liquid ventilation.

A prototype of a liquid ventilator using a novel hollow-fiber oxygenator in a rabbit model.

OBJECTIVE: A functional total liquid ventilator should be simple in design to minimize operating errors and have a low priming volume to minimize the amount of perfluorocarbon needed. Closed system circuits using a membrane oxygenator have partially met these requirements but have high resistance to perfluorocarbon flow and high priming volume. To further this goal, a single piston prototype ventilator with a low priming volume and a new high-efficiency hollow-fiber oxygenator in a circuit with a check valve flow control system was developed. DESIGN: Prospective, controlled animal laboratory study. SETTING: Research facility at a university medical center. SUBJECTS: Seven anesthetized, paralyzed, normal New Zealand rabbits INTERVENTIONS: The prototype oxygenator, consisting of cross-wound silicone hollow fibers with a surface area of 1.5 m2 with a priming volume of 190 mL, was tested in a bench-top model followed by an in vivo rabbit model. Total liquid ventilation was performed for 3 hrs with 20 mL.kg(-1) initial fill volume, 17.5-20 mL.kg(-1) tidal volume, respiratory rate of 5 breaths/min, inspiratory/expiratory ratio 1:2, and countercurrent sweep gas of 100% oxygen. MEASUREMENTS AND MAIN RESULTS: Bench top experiments demonstrated 66-81% elimination of CO2 and 0.64-0.76 mL.min(-1) loss of perfluorocarbon across the fibers. No significant changes in PaCO2 and PaO2 were observed. Dynamic airway pressures were in a safe range in which ventilator lung injury or airway closure was unlikely (3.6 +/- 0.5 and -7.8 +/- 0.3 cm H2O, respectively, for mean peak inspiratory pressure and mean end expiratory pressure). No leakage of perfluorocarbon was noted in the new silicone fiber gas exchange device. Estimated in vivo perfluorocarbon loss from the device was 1.2 mL.min(-1). CONCLUSIONS: These data demonstrate the ability of this novel single-piston, nonporous hollow silicone fiber oxygenator to adequately support gas exchange, allowing successful performance of total liquid ventilation.

Partial liquid ventilation does not affect BALF TNF-, MIP-2, CINC-1 concentrations, or CD11b cell surface expression, but does increase macrophage proportion among BALF cells in the acute phase of rat LPS-induced lung injury.

To elucidate the mechanism of anti-inflammatory effect of partial liquid ventilation (PLV), cytokine concentration, surface CD11b, and macrophage expression were investigated in BALF. The 30-minutes group was treated with gas ventilation (GV) for 30 minutes after intratracheal LPS administration. The GV group was prepared in the same manner as the 30-minutes group, then the GV was continued for the following 2 hours. The PLV group was treated in the same manner as the 30-minutes group, and then received PLV with perflubron for the following 2 hours. Animals were euthanized to receive BAL. The PLV group showed a tendency to have a higher concentration than the GV group of TNF-alpha, MIP-2, and CINC-1 as measured by ELISA, although there were no significant differences. The ratio of expressions of CD11b and macrophages to total leukocytes were determined by flow-cytometry. There were no significant differences in the ratio of CD11b-positive expression to acquired cells (GV: 63.6 +/- 8.4%, PLV: 60.5+/-5.4%, P=0.73). However, the proportion of macrophages was significantly increased (GV: 5.6 +/-1.5, PLV: 14.0+/-1.3, P=0.006). These results suggest that the anti-inflammatory effect of PLV is not caused by the change in CD11b expression, and that PLV affects the proportion of macrophage among BALF cells.