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Surgical approach to pleural diffuse mesothelioma in Japan
Lung Cancer 31 (2001) 57 – 65 www.elsevier.nl/locate/lungcan
Surgical approach to pleural diffuse mesothelioma in Japan Keigo Takagi a,*, Ryosuke Tsuchiya b, Yoh Watanabe c a
Department of Thoracic and Cardio6ascular Surgery, Toho Un6ersity School of Medicine, Tokyo 143 -8541, Japan b Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo 104, Japan c Department of Surgery, Kanazawa Uni6ersity, School of Medicine, Kanazawa 920, Japan Received 3 November 1998; received in revised form 23 March 2000; accepted 31 March 2000
Abstract The current status of the surgical treatment of patients with pleural diffuse mesothelioma in Japan was surveyed from the results of a questionnaire sent to members of The Japanese Association for Chest Surgery. Physicians at 57 institutions returned the questionnaire, and a total of 189 surgical cases of diffuse mesothelioma between 1987 and 1996 were analyzed. The age of the patients ranged between 18 and 80 years. They consisted of 154 males and 33 females (the gender of two patients was not indicated). By histological type, 104 cases had the epithelial type, 29 cases had the sarcomatous type, and 46 cases had the mixed type of diffuse mesothelioma (the histology of 10 patients was not indicated). As to the type of surgery, pleuropneumonectomy was performed in 116 cases (61%), and limited resection [including decortication (5 cases) and tumorectomy (68 cases)] was performed in 73 cases (39%). The goal of pleuropneumonectomy is radical resection of the tumor, which often requires combined resection of adjacent structures. The tumor was completely removed macroscopically in 84 (72%) of the 116 cases who underwent pleuropneumonectomy; however, among those with an epithelial-type tumor that was completely removed by pleuropneumonectomy, the tumor recurred postoperatively in 43% of these patients. Perioperative adjuvant therapy was performed in 83 of the 116 patients who underwent pleuropneumonectomy. The 2-year and 5-year survival rates of those who had undergone pleuropneumonectomy were 29.7 and 9.1%, respectively, and the perioperative mortality rate of this procedure was 6%. Limited resection, on the other hand, did not involve radical resection of the tumor. The 2-year and 5-year survival rates of the patients who had undergone limited resection were 26.1 and 9.5%, respectively, and the perioperative mortality rate was 6%. The survival rates and perioperative mortality rate of the patients who had undergone pleuropneumonectomy or limited resection did not significantly differ. The prognostic factors for survival included gender (P=0.0019) and adjuvant therapy (P= 0.0034) by Cox’s Regression Analysis. The goals of surgical treatment of pleural diffuse mesothelioma are relief of symptoms and prolongation of survival time. Selecting the appropriate surgical procedure and more effective adjuvant therapy for each particular case is necessary under a new, accurate staging system for diffuse mesothelioma. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Diffuse mesothelioma; Surgical treatment; Prognosis
* Corresponding author. Tel.: + 81-3-37624151; fax: + 81-3-37667810. E-mail address: [email protected] (K. Takagi). 0169-5002/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0169-5002(00)00152-5
K. Takagi et al. / Lung Cancer 31 (2001) 57–65
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1. Introduction Pleural diffuse mesothelioma is a rare disease, but its incidence has recently been increasing [1]. However, only a few patients with pleural diffuse mesothelioma are treated at any single institution, and the treatment options including supportive care for these patients vary widely at different institutions. Therefore, the outcome of a particular treatment is very difficult to analyze. This report shows the results of a retrospective analysis of patients who received surgical treatment for pleural diffuse mesothelioma in Japan. Data on the patients and the surgical treatments they received, were obtained by a questionnaire distributed to physician members of the Japanese Association for Chest Surgery. The role of surgery in the treatment of this disease is discussed.
2. Materials and methods
2.1. Methods Data on patients with pleural diffuse mesothelioma were obtained from a questionnaire that was distributed to physician members of the Japanese Association for Chest Surgery in November, 1996. In the questionnaire, the physician was asked to provide details on patients with pleural diffuse mesothelioma who were surgically treated at their institution between 1987 and 1996. Of the physicians at 141 institutions, 57 physicians at 57 institutions returned the questionnaire, and a total of 189 surgical cases that were treated Table 1 Characteristics of the patients with diffuse mesothelioma Number Age (years) Median (mean 9 SD) Sexa Histologya Operative procedure
189 patients 55 911 years (range, 18–80 years) 154 males, 33 females 104 epithelial, 29 sarcomatous, 46 mixed 116 pleuropneumonectomy, five decortication, 68 tumorectomy
a The sex of two patients and the histology of ten patients were not provided on the questionnaires.
for diffuse mesothelioma between 1987 and 1996 were retrospectively analyzed.
2.2. Statistical analysis The survival rate according to various prognostic factors was examined by the Log Rank test. Differences were considered to be significant at PB 0.05. The prognostic factors for survival were evaluated by Cox’s Regression Analysis.
3. Results
3.1. Characteristics of the patients The characteristics of the 189 patients are summarized in Table 1. The age of the patients at the time of surgery ranged between 18 and 80 years (mean9S.D., 55911 years). Eighty-two percent (154/189) of the patients were male. One hundred and four patients had solely the epithelial type of diffuse mesothelioma. The surgical treatment of the 189 patients included pleuropneumonectomy (116 patients), decortication (five patients), and tumorectomy (68 patients). The aim of pleuropneumonectomy is radical resection, while the aim of decortication and tumorectomy is partial resection of the mass that has no radicality. The 189 patients were divided according to age at the time of surgery, and the number of cases with each histological type in each age group was examined. Among the patients of ages 40–49, 50–59, and 60–69 years, the epithelial type and mixed type comprised the majority of cases in those age groups. There were no significant relationships between a histological type and a particular age group. The epithelial and mixed types also comprised the majority of cases in the 30–39, and 70–79-year-olds (Fig. 1). The patients were classified into two groups based on the type of operative procedure he/she underwent: (1) the Pleuropneumonectomy group (116 cases, 61% of all patients), and (2) the Limited resection group, which includes those who underwent decortication or tumorectomy (73 cases) (Fig. 2). The percentage of patients with each histological type in the Pleuropneumonec-
K. Takagi et al. / Lung Cancer 31 (2001) 57–65
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Fig. 1. Number of patients with each histological type of diffuse mesothelioma in each age group.
tomy group and that in the Limited resection group, were nearly the same. Approximately 50% of those who underwent pleuropneumonectomy, and approximately 50% of those who underwent limited resection had the epithelial type of diffuse mesothelioma. Pleuropneumonectomy often requires the combined resection of adjacent structures. Of the 116 patients who underwent pleuropneumonectomy, the diaphragm was resected in 98 cases, the pericardium was resected in 78 cases, and the chest
wall was resected in 18 cases. Complete resection of the tumor was performed in 84 cases (72% of pleuropneumonectomy cases). On the other hand, part of the tumor remained in the diaphragm in 16 cases, in the esophagus in 10 cases, and in the pericardium in 5 cases. Perioperative adjuvant therapy including radiation, systemic chemotherapy, and/or intrapleural injection was performed in 82 (71%) of the 116 pleuropneumonectomy cases, and in 53 (73%) of the 73 limited resection cases. The percentage of
Fig. 2. Distribution of the histological types of diffuse mesothelioma among those who underwent pleuropneumonectomy and among those who underwent limited resection. Pleuropneumonectomy 116, limited resection 73.
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K. Takagi et al. / Lung Cancer 31 (2001) 57–65
Fig. 3. Survival curves of the patients who underwent pleuropneumonectomy and those who underwent limited resection (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time).
patients who received adjuvant therapy with pleuropneumonectomy, and the percentage who received adjuvant therapy with limited resection, did not significantly differ.
3.2. Sur6i6al cur6es following each operati6e procedure The survival time was measured from the date of surgery. The survival curves of the patients who underwent pleuropneumonectomy and those who underwent limited resection are shown in
Fig. 3. The 2-year and 5-year survival rates of those who underwent pleuropneumonectomy were 29.7 and 9.1%, respectively, and the 2-year and 5-year survival rates of those who underwent limited resection were 26.1 and 9.5%, respectively. The overall median length of survival among all of the patients was 12 months. The survival curves of those who underwent pleuropneumonectomy and those who underwent limited resection did not significantly differ. The patients who had undergone pleuropneumonectomy did not have a significantly better prognosis than those who had undergone limited resection. Considering only patients who had the epithelial type of mesothelioma, the survival curves of those who underwent pleuropneumonectomy and those who underwent limited resection did not significantly differ (Fig. 4). Among those who had the sarcomatous type and among those who had the mixed type, the survival curves of those who underwent pleuropneumonectomy and those who underwent limited resection also did not significantly differ. The 30-day mortality rate of both procedures was the same at 6%.
3.3. Relapse Postoperative relapse following pleuropneumonectomy is one of the biggest problems in diffuse mesothelioma. Of the 46 patients who had the epithelial type and underwent complete resection in pleuropneumonectomy, local recurrence occurred in 43% and distant metastasis occurred in 39%.
3.4. Sur6i6al cur6es according to 6arious parameters
Fig. 4. Survival curves of the patients who underwent pleuropneumonectomy and those who underwent limited resection among those with epithelial-type mesothelioma (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time).
The seven long-term survivors who survived over 5 years were examined to determine the prognostic factors for survival (Fig. 5). Of the seven long-term survivors, four had the epithelial type, two had the sarcomatous type, and one had the mixed type of diffuse mesothelioma. Five of the seven long-term survivors were under 50 years of age, and six of the seven long-term survivors were female. As to the type of procedure, four had undergone pleuropneumonectomy and three had undergone limited resection.
K. Takagi et al. / Lung Cancer 31 (2001) 57–65
Fig. 5. Characteristics of the seven long-term survivors who survived over 5 years following surgery (Ope, operative procedure; PP, pleuropneumonectomy; LR, limited resection) ( + :the two cases survived for five years after surgery, but were dead at the time of the questionnaire.).
The 189 patients were divided into those who were under 50 years of age, and those who were 50 years or older at the time of surgery. The survival curves showed that the prognosis of those who were under 50 years at the time of surgery, was significantly better than the prognosis of those who were 50 years or older (P =0.007) (Fig. 6). Comparison of the survival curve of males who underwent pleuropneumonectomy and that of females who underwent the same procedure showed that the female patients who underwent this pro-
Fig. 6. Survival curves of those who were younger than 50 years, and those who were 50 years or older at the time of surgery (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time).
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Fig. 7. Survival curve of males and survival curve of females who underwent pleuropneumonectomy (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time).
cedure had a better prognosis than the male patients significantly (P= 0.0160) (Fig. 7). Comparison of the survival curve of males who underwent limited resection and that of females who underwent limited resection showed that the female patients who underwent limited resection had a better prognosis than males by a marginally significant degree (P=0.0587) (Fig. 8). It can be said that the prognosis of female patients following surgical treatment for diffuse mesothelioma is superior to the prognosis of male patients.
Fig. 8. Survival curve of males and survival curve of females who underwent limited resection. (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time). The gender of 71 patients except one patient were known, among which male of three patients were not provided due to unknown survival time.
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K. Takagi et al. / Lung Cancer 31 (2001) 57–65
The survival curves of patients with each histological type of diffuse mesothelioma are shown in Fig. 10. The survival curves of the patients with the three histological types were similar. The prognosis of patients who had the epithelial type was not significantly better than the prognosis of patients who had the sarcomatous or mixed type.
3.5. Prognostic factors
Fig. 9. Survival curves of patients who did or did not receive adjuvant therapy (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time). With of without Adjuvant therapy was known in 178 patients except 11 patients, among which with therapy of five patients and without of five patients were not provided due to unknown survival time.
Next, the survival curves of patients who did or did not receive adjuvant therapy with the surgical procedure were compared. The patients who received adjuvant therapy had a significantly better prognosis than those who did not receive adjuvant therapy (P= 0.0023) (Fig. 9). Adjuvant therapy included many types of treatments, and we could not determine which treatments are effective. The background of the patients was also variable.
Five potential prognostic factors, i.e., age 50 years and above or below 50 years, gender, histology (epithelial, sarcomatous, mixed type), operative procedure (pleuropneumonectomy, limited resection), and adjuvant therapy, were evaluated by Cox’s Regression Analysis. Gender (i.e., being female) and adjuvant therapy were important prognostic factors for survival (P= 0.0019 and P =0.0034, respectively) (Table 2).
4. Discussion The exact role and benefits of surgical treatment for diffuse mesothelioma remain undefined and controversial. The options for surgical treatment include: (1) pleuropneumonectomy, and (2) limited resection, i.e., decortication and/or partial tumorectomy. The prognosis of patients who undergo a surgical treatment (either pleuropneumonectomy or limited resection) is superior to that of patients who receive only supportive care, whose median survival time is approximately 7 months [2,3]. The goal of pleuropneumonectomy Table 2 Prognostic factors for survival by Cox’s Regression Analysis
Fig. 10. Survival curves of patients with each histological type of diffuse mesothelioma. (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time). Histological types were known in 179 patients except 10 patients, among which epithelial type of eight patients and sarcomatous type of two patients and mixed type of one patient were not provided due to unknown survival time.
Variable
Risk ratio
95% C.I.
P value
Gendera Adj. Therapyb Histologyc Age 50d
0.427 0.523 1.252 1.409
0.249–0.731 0.339–0.807 1.011–1.551 0.928–2.139
0.0019 0.0034 0.0392 0.1078
a
Female. Patient received adjuvant therapy. c Epithelial type versus sarcomatous and mixed types. d Patient younger than 50 years. b
K. Takagi et al. / Lung Cancer 31 (2001) 57–65
is to achieve curative resection by en bloc resection. One hundred and sixteen (61%) of the 189 patients with diffuse mesothelioma underwent pleuropneumonectomy, and complete resection was performed in 84 cases (72% of the pleuropneumonectomy cases). However, the outcome of patients who had undergone pleuropneumonectomy was nearly the same as the outcome of those who had undergone limited resection. The local recurrence rate following pleuropneumonectomy was 43%. The 5-year survival rates of those who underwent pleuropneumonectomy and those who underwent limited resection, were nearly identical at 9.1% and 9.5%, respectively, and the median survival time among those who underwent pleuropneumonectomy and the median survival time among those who underwent limited resection, were the same at 12 months. These results indicate that we should focus on a surgical approach towards diffuse mesothelioma and perioperative adjuvant therapy. Pleuropneumonectomy requires a wider operative field than limited resection, especially in cases where the diaphragm will be resected, and the second skin incision should be made at the diaphragm level. The anterior part of a few ribs may need to be cut off to gain a direct view of the diaphragm [4]. On the other hand, pleurectomy is often performed because it is a less invasive surgery than pleuropneumonectomy, and has a similar rate of good results as pleuropneumonectomy. Three previous studies [5–7] showed that among patients who underwent pleurectomy, the 2-year survival rate was 9–27%, and the mean survival time was 9 – 16 months. Furthermore, in a prospective study of patients who received treatment with pleurectomy with postoperative adjuvant therapy (mitomycinC plus cisplatin), Rusch et al. [8], reported a 2-year survival rate of 40% and a mean survival time of 17 months. In the present study, we did not find any difference in the survival of patients who underwent pleuropneumonectomy and those who underwent limited resection. To be able to determine which surgery is appropriate for a particular patient, a prospective study should be performed based on an accurate staging system of diffuse mesothelioma. Patients with diffuse mesothelioma require a multidisciplinary ap-
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proach to treatment, and the prognosis of these patients is expected to improve with advances in each treatment. The underlying mechanism of the development of diffuse mesothelioma as well as its local recurrence has been discussed. VCAM-1 [9] or CD-44 [10], which conjugate with hyaluronic acid, is thought to be the adhesion molecule of tumor cells. Since tumor cells adhere very easily, local recurrence may occur by the adherence of tumor cells to the cut margin. Local control must be considered at the molecular biology level. Generally, the prognostic factors for survival in patients with diffuse mesothelioma are age, gender, histology, and lymph node metastasis. Age and gender were significant prognostic factors in the present study, as well as in a previous report [11]. It is believed that the epithelial cell type of diffuse mesothelioma grows slowly, and that patients with the epithelial cell type have a better prognosis than those with the sarcomatous type [12]. In the present study, histology was not a significant prognostic factor. This may indicate that the histological diagnosis does not always reflect the character of the whole tumor, or that the diagnostic criteria at different institutions differ. Data on routine lymph node sampling and dissection were not obtained in this study. Therefore, we could not analyze lymph node metastasis as a prognostic factor. Adjuvant therapy seems to be an important prognostic factor according to the findings of the present study. However, whether adjuvant therapy is actually effective or not is difficult to determine because prognosis depends on many factors, i.e., histology, gender, performance status, and therapeutic regimen. To be able to choose the most appropriate treatment for a patient among the various treatments, a more practical TNM staging system must be established. Research on establishing a new staging system for diffuse mesothelioma tumors has been conducted over the past several years. In 1996, Rusch [13] proposed a new TNM staging system according to the standards set by the International Mesothelioma Interest Group (IMIG), which is more practical than the previous TNM classification. However, physicians in Japan are not familiar with the TNM system for classification of diffuse
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mesothelioma, because the Buchart classification [14] has been widely used. We will now have to evaluate coming each case more precisely by the new TNM staging system in the future. One problem in Japan is that a panel or registration system like the IMIG [13] has not yet been established, and the diagnosis and treatment of diffuse mesothelioma are administered under the direction of each institution. If such a system were in place in Japan, it would be possible to standardize therapeutic options. Although these data are based on a retrospective study, they will provide many ideas for better surgical treatment of diffuse mesothelioma in the near future.
5. Conclusion Following are the conclusions from the analysis of 189 cases of diffuse mesothelioma: (1) The survival rate and the perioperative mortality rate among those who received pleuropneumonectomy and among those who received limited resection, did not significantly differ, even in those with the epithelial type. (2) The patients who underwent pleuropneumonectomy had a high local recurrence rate. (3) The patients who received perioperative adjuvant therapy had a significantly better prognosis than those who did not receive perioperative adjuvant therapy. (4) The prognostic factors for survival were gender and adjuvant therapy by Cox’s Regression Analysis. (5) An accurate and more practical staging system of diffuse mesothelioma is required.
Acknowledgements These data were obtained with the permission of the President of the Japanese Association for Chest Surgery (JACS, Prof. Yoh Watanabe) in 1997, and this paper was presented at the International Congress of Thoracic Surgery (ICTS) in Athens, Greece, 1997, which was supported by the IASLC. I would like to express my deep gratitude to the members of the JACS, ICTS, and IASLC. Following are the list of institutions and the
physician who collected the data at each institution. I would like to express my appreciation to them. Aichi Cancer Center: (Motokazu Sugiyama), Asahikawa Medical Collage, The First Dept. of Surgery: (Yoshihiko Kubo), Cancer Institute Hospital: (Ken Nakagawa), Chiba Cancer Center Hosp.: (Hideki Kimura), Chiba Rosai Hosp.: (Toshikazu Yusa), Chiba Univ. School of Medicine, Institute of Pulmonary Cancer Research, Dept of Surgery: (Yutaka Yamaguchi), Ehime National Hosp.: (N. Nakano), Fukui Red Cross Hosp.: (Akira Yamanaka), Fukuoka Univ. School of Medicine, Second Dept. of Surgery: (Takayuki Shirakusa), Hachioji Medical Center of Tokyo Medical College: (Osamu Taira), Hamamatsu Medical Center: (Suguru Hanazawa), Hiroshima City Hosp.: (Kazuhiro Kataoka), Hokkaido Univ. School of Medicine, Second Dept. of Surgery: (Tetsuzo Okubo), Hyogo Medical Center For Adults: (Noriaki Tsubota), Kagawa Medical Univ.: (Masazumi Maeda), Kagoshima Univ. School of Medicine, Second Dept. of Surgery (Shinji Shimokawa), Kobe Univ. School of Medicine, 2nd Dept. of Surgery: (Noboru Ishii), Kurashiki Central Hosp.: (Yasuo Miyake), Kyorin Univ. Second Dept. of Surgery: (Tomoyuki Goya), Kyoto Univ. Chest Disease Research Institute: (Hiromi Wada), Kyoto-Katsura Hosp. Respiratory Division: (Sadao Ikeda), Kyushu Univ. School of Medicine, Second Dept. of Surgery: (Keizo Sugimachi), Nagasaki Univ. School of Medicine, First Dept. of Surgery: (Hiroyoshi Ayabe), Nagoya City Univ. Medical School, The Second Dept. of Surgery: (Yoshitaka Fujii), Nara Medical Univ.: (Soichiro Kitamura), National Cancer Center Hosp. East: (Kanji Nagai), National Defense Medical College: (Yuichi Ozeki), National Okinawa Hosp.: (Keiichiro Genka), Nihon Univ. School of Medicine, The 2nd Dept of Surgery: (Kazumitsu Ohmori), Niigata Cancer Center Hosp.: (Teruaki Koike), Oita Medical Univ.: (Koichi Tanaka), Oita Prefectual Hosp.: (Yoshitaka Uchiyama), Okayama Univ. School of Medicine, Dept. of Surgery 2: (Nobuyoshi Shimizu), Osaka Medical Center for Cancer and Cardiovascular Diseases: (Osamu Doi), Osaka Prefectual Habikino Hosp.: (Tsutomu Yasumitsu), Saiseikai Central Hosp.: (Hi-
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roaki Nomori), Saitama Medical School, First Dept. of Surgery: (Koichi Kaneko), Saitama Ohara Cardiovascular Center: (Eishin Hoshi), Sasakikenkyujyo Fuzoku Kyoundo Byoin: (Naganobu Hayashi), Showa Univ. School of Medicine, the First Dept. of Surgery: (Matsutaka Kadokura), St. Marianna Univ. School of Medicine, 3rd Dept of Surgery: (Hiroaki Osada), Teikyo Univ. School of Medicine, First Dept. of Surgery: (Iwao Takanami), Tenri Hosp.: (Morihisa Kitano), Tokushima Univ., School of medicine, The 2nd Dept. of Surgery (Yasumasa Monden), Tochigi Cancer Center Hosp.: (Kohei Yokoi), Toho Univ. School of Medicine, Dept. of Thoracic & Cardiovascular Surgery: (Shiro Yamazaki) Tohoku Univ., Institute of Aging, Development and Cancer, Dept of Thoracic Surgery: (Shigefumi Fujimura), Tokai Univ. School of Medicine, First Dept. of Surgery: (Hiroshi Inoue), Tokyo Medical College Kasumigaura Hosp., Thoracic Surgery Division (Kazuo Yoneyama), Tokyo Medical College, Dept. of Surgery: (Harubumi Kato), Tokyo Metropolitan Fuchu Hosp.: (Hiroshi Yamamoto), Tokyo Teishin Hosp.: (Sadahiko Masuda), Toranomonn Hosp. Dept. of Resp. Surgery: (Jiro Banba), Toyama City Hosp.: (Yoshinori Kusajima), Toyama Medical and Pharmaceutical Univ.: (Toshiki Tatsumura), Univ. of Occupational and Environmental Health, Second Dept. of Surgery: (Kosei Yasumoto) Yamaguchi Univ. School of Medicine, First Dept. of Surgery: (Kensuke Esato)
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[2] Ruffie P, Feid R, Minkin S, et al. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol 1989;7:1157 – 68. [3] Harvey JC, Fleischman EH, Kagan AR, Streeter OE. Malignant pleural mesothelioma: a survival study. J Surg Oncol 1990;45:40 – 2. [4] Horio H, Nomori H. Thoracotomy technique for extrapleural pneumonectomy in treatment of diffuse mesothelioma. J Jpn Ass Chest Surg 1995;9:538 – 41. [5] Allen KB, Faber LP, Warrn WH. Malignant pleural mesothelioma-extrapleural pneumonectomy and pleurectomy. Chest Surg Clin North Am 1994;4:113 – 26. [6] Chahinian AP, Pajak TF, Holland JF, Norton L, Ambinder RM, Mandel EM. Diffuse malignant mesothelioma: prospective evaluation of 69 patients. Ann Int Med 1982;96:746 – 55. [7] Mychalsak BR, Nori D, Armstrong JG. Results of treatment of malignant pleural mesothelioma with surgery, brachytherapy and external beam irradiation. Endocurie Hypertherm Oncol 1989;5:245 – 9. [8] Rusch VW, Saltz L, Venkatraman E, et al. A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 1994;12:1156 – 63. [9] Ruco LP, DeLaat PA, Matteucci C, et al. Expression of ICAM-1 and VCAM-1 in human malignant mesothelioma. J Pathol 1996;179:266 – 71. [10] Attanoos RL, Webb R, Gibbs AR. CD44H expression in reactive mesothelium, pleural mesothelioma and pulmonary adenocarcinoma. Histopathology 1997;30:260 – 3. [11] Rusch VW. Mesothelioma and less common tumors. In: Pearson FG, Hiebert CA, Deslauriers J, McKneally MF, Ginsberg RJ, Urschel HC, Jr, editors. Thoracic Surgery. New York: Churchill Livingstone, 1995:1083 – 105. [12] Sugarbaker DJ, Jaklitsch MT, Liptay MJ. Mesothelioma and radical multimodality therapy: who benefits? Chest 1995;107:345s– 50s. [13] Rusch VW. Meeting report — a proposed new international TNM staging for malignant pleural mesothelioma from the International Mesothelioma Interest Group. Lung Cancer 1996;14:1 – 12. [14] Buchart EG, Ashcroft T, Barnsley WC, et al. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thorax 1976;31:15 – 24.
Surgical approach to pleural diffuse mesothelioma in Japan Keigo Takagi a,*, Ryosuke Tsuchiya b, Yoh Watanabe c a
Department of Thoracic and Cardio6ascular Surgery, Toho Un6ersity School of Medicine, Tokyo 143 -8541, Japan b Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo 104, Japan c Department of Surgery, Kanazawa Uni6ersity, School of Medicine, Kanazawa 920, Japan Received 3 November 1998; received in revised form 23 March 2000; accepted 31 March 2000
Abstract The current status of the surgical treatment of patients with pleural diffuse mesothelioma in Japan was surveyed from the results of a questionnaire sent to members of The Japanese Association for Chest Surgery. Physicians at 57 institutions returned the questionnaire, and a total of 189 surgical cases of diffuse mesothelioma between 1987 and 1996 were analyzed. The age of the patients ranged between 18 and 80 years. They consisted of 154 males and 33 females (the gender of two patients was not indicated). By histological type, 104 cases had the epithelial type, 29 cases had the sarcomatous type, and 46 cases had the mixed type of diffuse mesothelioma (the histology of 10 patients was not indicated). As to the type of surgery, pleuropneumonectomy was performed in 116 cases (61%), and limited resection [including decortication (5 cases) and tumorectomy (68 cases)] was performed in 73 cases (39%). The goal of pleuropneumonectomy is radical resection of the tumor, which often requires combined resection of adjacent structures. The tumor was completely removed macroscopically in 84 (72%) of the 116 cases who underwent pleuropneumonectomy; however, among those with an epithelial-type tumor that was completely removed by pleuropneumonectomy, the tumor recurred postoperatively in 43% of these patients. Perioperative adjuvant therapy was performed in 83 of the 116 patients who underwent pleuropneumonectomy. The 2-year and 5-year survival rates of those who had undergone pleuropneumonectomy were 29.7 and 9.1%, respectively, and the perioperative mortality rate of this procedure was 6%. Limited resection, on the other hand, did not involve radical resection of the tumor. The 2-year and 5-year survival rates of the patients who had undergone limited resection were 26.1 and 9.5%, respectively, and the perioperative mortality rate was 6%. The survival rates and perioperative mortality rate of the patients who had undergone pleuropneumonectomy or limited resection did not significantly differ. The prognostic factors for survival included gender (P=0.0019) and adjuvant therapy (P= 0.0034) by Cox’s Regression Analysis. The goals of surgical treatment of pleural diffuse mesothelioma are relief of symptoms and prolongation of survival time. Selecting the appropriate surgical procedure and more effective adjuvant therapy for each particular case is necessary under a new, accurate staging system for diffuse mesothelioma. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Diffuse mesothelioma; Surgical treatment; Prognosis
* Corresponding author. Tel.: + 81-3-37624151; fax: + 81-3-37667810. E-mail address: [email protected] (K. Takagi). 0169-5002/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0169-5002(00)00152-5
K. Takagi et al. / Lung Cancer 31 (2001) 57–65
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1. Introduction Pleural diffuse mesothelioma is a rare disease, but its incidence has recently been increasing [1]. However, only a few patients with pleural diffuse mesothelioma are treated at any single institution, and the treatment options including supportive care for these patients vary widely at different institutions. Therefore, the outcome of a particular treatment is very difficult to analyze. This report shows the results of a retrospective analysis of patients who received surgical treatment for pleural diffuse mesothelioma in Japan. Data on the patients and the surgical treatments they received, were obtained by a questionnaire distributed to physician members of the Japanese Association for Chest Surgery. The role of surgery in the treatment of this disease is discussed.
2. Materials and methods
2.1. Methods Data on patients with pleural diffuse mesothelioma were obtained from a questionnaire that was distributed to physician members of the Japanese Association for Chest Surgery in November, 1996. In the questionnaire, the physician was asked to provide details on patients with pleural diffuse mesothelioma who were surgically treated at their institution between 1987 and 1996. Of the physicians at 141 institutions, 57 physicians at 57 institutions returned the questionnaire, and a total of 189 surgical cases that were treated Table 1 Characteristics of the patients with diffuse mesothelioma Number Age (years) Median (mean 9 SD) Sexa Histologya Operative procedure
189 patients 55 911 years (range, 18–80 years) 154 males, 33 females 104 epithelial, 29 sarcomatous, 46 mixed 116 pleuropneumonectomy, five decortication, 68 tumorectomy
a The sex of two patients and the histology of ten patients were not provided on the questionnaires.
for diffuse mesothelioma between 1987 and 1996 were retrospectively analyzed.
2.2. Statistical analysis The survival rate according to various prognostic factors was examined by the Log Rank test. Differences were considered to be significant at PB 0.05. The prognostic factors for survival were evaluated by Cox’s Regression Analysis.
3. Results
3.1. Characteristics of the patients The characteristics of the 189 patients are summarized in Table 1. The age of the patients at the time of surgery ranged between 18 and 80 years (mean9S.D., 55911 years). Eighty-two percent (154/189) of the patients were male. One hundred and four patients had solely the epithelial type of diffuse mesothelioma. The surgical treatment of the 189 patients included pleuropneumonectomy (116 patients), decortication (five patients), and tumorectomy (68 patients). The aim of pleuropneumonectomy is radical resection, while the aim of decortication and tumorectomy is partial resection of the mass that has no radicality. The 189 patients were divided according to age at the time of surgery, and the number of cases with each histological type in each age group was examined. Among the patients of ages 40–49, 50–59, and 60–69 years, the epithelial type and mixed type comprised the majority of cases in those age groups. There were no significant relationships between a histological type and a particular age group. The epithelial and mixed types also comprised the majority of cases in the 30–39, and 70–79-year-olds (Fig. 1). The patients were classified into two groups based on the type of operative procedure he/she underwent: (1) the Pleuropneumonectomy group (116 cases, 61% of all patients), and (2) the Limited resection group, which includes those who underwent decortication or tumorectomy (73 cases) (Fig. 2). The percentage of patients with each histological type in the Pleuropneumonec-
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Fig. 1. Number of patients with each histological type of diffuse mesothelioma in each age group.
tomy group and that in the Limited resection group, were nearly the same. Approximately 50% of those who underwent pleuropneumonectomy, and approximately 50% of those who underwent limited resection had the epithelial type of diffuse mesothelioma. Pleuropneumonectomy often requires the combined resection of adjacent structures. Of the 116 patients who underwent pleuropneumonectomy, the diaphragm was resected in 98 cases, the pericardium was resected in 78 cases, and the chest
wall was resected in 18 cases. Complete resection of the tumor was performed in 84 cases (72% of pleuropneumonectomy cases). On the other hand, part of the tumor remained in the diaphragm in 16 cases, in the esophagus in 10 cases, and in the pericardium in 5 cases. Perioperative adjuvant therapy including radiation, systemic chemotherapy, and/or intrapleural injection was performed in 82 (71%) of the 116 pleuropneumonectomy cases, and in 53 (73%) of the 73 limited resection cases. The percentage of
Fig. 2. Distribution of the histological types of diffuse mesothelioma among those who underwent pleuropneumonectomy and among those who underwent limited resection. Pleuropneumonectomy 116, limited resection 73.
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Fig. 3. Survival curves of the patients who underwent pleuropneumonectomy and those who underwent limited resection (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time).
patients who received adjuvant therapy with pleuropneumonectomy, and the percentage who received adjuvant therapy with limited resection, did not significantly differ.
3.2. Sur6i6al cur6es following each operati6e procedure The survival time was measured from the date of surgery. The survival curves of the patients who underwent pleuropneumonectomy and those who underwent limited resection are shown in
Fig. 3. The 2-year and 5-year survival rates of those who underwent pleuropneumonectomy were 29.7 and 9.1%, respectively, and the 2-year and 5-year survival rates of those who underwent limited resection were 26.1 and 9.5%, respectively. The overall median length of survival among all of the patients was 12 months. The survival curves of those who underwent pleuropneumonectomy and those who underwent limited resection did not significantly differ. The patients who had undergone pleuropneumonectomy did not have a significantly better prognosis than those who had undergone limited resection. Considering only patients who had the epithelial type of mesothelioma, the survival curves of those who underwent pleuropneumonectomy and those who underwent limited resection did not significantly differ (Fig. 4). Among those who had the sarcomatous type and among those who had the mixed type, the survival curves of those who underwent pleuropneumonectomy and those who underwent limited resection also did not significantly differ. The 30-day mortality rate of both procedures was the same at 6%.
3.3. Relapse Postoperative relapse following pleuropneumonectomy is one of the biggest problems in diffuse mesothelioma. Of the 46 patients who had the epithelial type and underwent complete resection in pleuropneumonectomy, local recurrence occurred in 43% and distant metastasis occurred in 39%.
3.4. Sur6i6al cur6es according to 6arious parameters
Fig. 4. Survival curves of the patients who underwent pleuropneumonectomy and those who underwent limited resection among those with epithelial-type mesothelioma (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time).
The seven long-term survivors who survived over 5 years were examined to determine the prognostic factors for survival (Fig. 5). Of the seven long-term survivors, four had the epithelial type, two had the sarcomatous type, and one had the mixed type of diffuse mesothelioma. Five of the seven long-term survivors were under 50 years of age, and six of the seven long-term survivors were female. As to the type of procedure, four had undergone pleuropneumonectomy and three had undergone limited resection.
K. Takagi et al. / Lung Cancer 31 (2001) 57–65
Fig. 5. Characteristics of the seven long-term survivors who survived over 5 years following surgery (Ope, operative procedure; PP, pleuropneumonectomy; LR, limited resection) ( + :the two cases survived for five years after surgery, but were dead at the time of the questionnaire.).
The 189 patients were divided into those who were under 50 years of age, and those who were 50 years or older at the time of surgery. The survival curves showed that the prognosis of those who were under 50 years at the time of surgery, was significantly better than the prognosis of those who were 50 years or older (P =0.007) (Fig. 6). Comparison of the survival curve of males who underwent pleuropneumonectomy and that of females who underwent the same procedure showed that the female patients who underwent this pro-
Fig. 6. Survival curves of those who were younger than 50 years, and those who were 50 years or older at the time of surgery (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time).
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Fig. 7. Survival curve of males and survival curve of females who underwent pleuropneumonectomy (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time).
cedure had a better prognosis than the male patients significantly (P= 0.0160) (Fig. 7). Comparison of the survival curve of males who underwent limited resection and that of females who underwent limited resection showed that the female patients who underwent limited resection had a better prognosis than males by a marginally significant degree (P=0.0587) (Fig. 8). It can be said that the prognosis of female patients following surgical treatment for diffuse mesothelioma is superior to the prognosis of male patients.
Fig. 8. Survival curve of males and survival curve of females who underwent limited resection. (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time). The gender of 71 patients except one patient were known, among which male of three patients were not provided due to unknown survival time.
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The survival curves of patients with each histological type of diffuse mesothelioma are shown in Fig. 10. The survival curves of the patients with the three histological types were similar. The prognosis of patients who had the epithelial type was not significantly better than the prognosis of patients who had the sarcomatous or mixed type.
3.5. Prognostic factors
Fig. 9. Survival curves of patients who did or did not receive adjuvant therapy (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time). With of without Adjuvant therapy was known in 178 patients except 11 patients, among which with therapy of five patients and without of five patients were not provided due to unknown survival time.
Next, the survival curves of patients who did or did not receive adjuvant therapy with the surgical procedure were compared. The patients who received adjuvant therapy had a significantly better prognosis than those who did not receive adjuvant therapy (P= 0.0023) (Fig. 9). Adjuvant therapy included many types of treatments, and we could not determine which treatments are effective. The background of the patients was also variable.
Five potential prognostic factors, i.e., age 50 years and above or below 50 years, gender, histology (epithelial, sarcomatous, mixed type), operative procedure (pleuropneumonectomy, limited resection), and adjuvant therapy, were evaluated by Cox’s Regression Analysis. Gender (i.e., being female) and adjuvant therapy were important prognostic factors for survival (P= 0.0019 and P =0.0034, respectively) (Table 2).
4. Discussion The exact role and benefits of surgical treatment for diffuse mesothelioma remain undefined and controversial. The options for surgical treatment include: (1) pleuropneumonectomy, and (2) limited resection, i.e., decortication and/or partial tumorectomy. The prognosis of patients who undergo a surgical treatment (either pleuropneumonectomy or limited resection) is superior to that of patients who receive only supportive care, whose median survival time is approximately 7 months [2,3]. The goal of pleuropneumonectomy Table 2 Prognostic factors for survival by Cox’s Regression Analysis
Fig. 10. Survival curves of patients with each histological type of diffuse mesothelioma. (PP, pleuropneumonectomy; LR, limited resection; MST, median survival time). Histological types were known in 179 patients except 10 patients, among which epithelial type of eight patients and sarcomatous type of two patients and mixed type of one patient were not provided due to unknown survival time.
Variable
Risk ratio
95% C.I.
P value
Gendera Adj. Therapyb Histologyc Age 50d
0.427 0.523 1.252 1.409
0.249–0.731 0.339–0.807 1.011–1.551 0.928–2.139
0.0019 0.0034 0.0392 0.1078
a
Female. Patient received adjuvant therapy. c Epithelial type versus sarcomatous and mixed types. d Patient younger than 50 years. b
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is to achieve curative resection by en bloc resection. One hundred and sixteen (61%) of the 189 patients with diffuse mesothelioma underwent pleuropneumonectomy, and complete resection was performed in 84 cases (72% of the pleuropneumonectomy cases). However, the outcome of patients who had undergone pleuropneumonectomy was nearly the same as the outcome of those who had undergone limited resection. The local recurrence rate following pleuropneumonectomy was 43%. The 5-year survival rates of those who underwent pleuropneumonectomy and those who underwent limited resection, were nearly identical at 9.1% and 9.5%, respectively, and the median survival time among those who underwent pleuropneumonectomy and the median survival time among those who underwent limited resection, were the same at 12 months. These results indicate that we should focus on a surgical approach towards diffuse mesothelioma and perioperative adjuvant therapy. Pleuropneumonectomy requires a wider operative field than limited resection, especially in cases where the diaphragm will be resected, and the second skin incision should be made at the diaphragm level. The anterior part of a few ribs may need to be cut off to gain a direct view of the diaphragm [4]. On the other hand, pleurectomy is often performed because it is a less invasive surgery than pleuropneumonectomy, and has a similar rate of good results as pleuropneumonectomy. Three previous studies [5–7] showed that among patients who underwent pleurectomy, the 2-year survival rate was 9–27%, and the mean survival time was 9 – 16 months. Furthermore, in a prospective study of patients who received treatment with pleurectomy with postoperative adjuvant therapy (mitomycinC plus cisplatin), Rusch et al. [8], reported a 2-year survival rate of 40% and a mean survival time of 17 months. In the present study, we did not find any difference in the survival of patients who underwent pleuropneumonectomy and those who underwent limited resection. To be able to determine which surgery is appropriate for a particular patient, a prospective study should be performed based on an accurate staging system of diffuse mesothelioma. Patients with diffuse mesothelioma require a multidisciplinary ap-
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proach to treatment, and the prognosis of these patients is expected to improve with advances in each treatment. The underlying mechanism of the development of diffuse mesothelioma as well as its local recurrence has been discussed. VCAM-1 [9] or CD-44 [10], which conjugate with hyaluronic acid, is thought to be the adhesion molecule of tumor cells. Since tumor cells adhere very easily, local recurrence may occur by the adherence of tumor cells to the cut margin. Local control must be considered at the molecular biology level. Generally, the prognostic factors for survival in patients with diffuse mesothelioma are age, gender, histology, and lymph node metastasis. Age and gender were significant prognostic factors in the present study, as well as in a previous report [11]. It is believed that the epithelial cell type of diffuse mesothelioma grows slowly, and that patients with the epithelial cell type have a better prognosis than those with the sarcomatous type [12]. In the present study, histology was not a significant prognostic factor. This may indicate that the histological diagnosis does not always reflect the character of the whole tumor, or that the diagnostic criteria at different institutions differ. Data on routine lymph node sampling and dissection were not obtained in this study. Therefore, we could not analyze lymph node metastasis as a prognostic factor. Adjuvant therapy seems to be an important prognostic factor according to the findings of the present study. However, whether adjuvant therapy is actually effective or not is difficult to determine because prognosis depends on many factors, i.e., histology, gender, performance status, and therapeutic regimen. To be able to choose the most appropriate treatment for a patient among the various treatments, a more practical TNM staging system must be established. Research on establishing a new staging system for diffuse mesothelioma tumors has been conducted over the past several years. In 1996, Rusch [13] proposed a new TNM staging system according to the standards set by the International Mesothelioma Interest Group (IMIG), which is more practical than the previous TNM classification. However, physicians in Japan are not familiar with the TNM system for classification of diffuse
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mesothelioma, because the Buchart classification [14] has been widely used. We will now have to evaluate coming each case more precisely by the new TNM staging system in the future. One problem in Japan is that a panel or registration system like the IMIG [13] has not yet been established, and the diagnosis and treatment of diffuse mesothelioma are administered under the direction of each institution. If such a system were in place in Japan, it would be possible to standardize therapeutic options. Although these data are based on a retrospective study, they will provide many ideas for better surgical treatment of diffuse mesothelioma in the near future.
5. Conclusion Following are the conclusions from the analysis of 189 cases of diffuse mesothelioma: (1) The survival rate and the perioperative mortality rate among those who received pleuropneumonectomy and among those who received limited resection, did not significantly differ, even in those with the epithelial type. (2) The patients who underwent pleuropneumonectomy had a high local recurrence rate. (3) The patients who received perioperative adjuvant therapy had a significantly better prognosis than those who did not receive perioperative adjuvant therapy. (4) The prognostic factors for survival were gender and adjuvant therapy by Cox’s Regression Analysis. (5) An accurate and more practical staging system of diffuse mesothelioma is required.
Acknowledgements These data were obtained with the permission of the President of the Japanese Association for Chest Surgery (JACS, Prof. Yoh Watanabe) in 1997, and this paper was presented at the International Congress of Thoracic Surgery (ICTS) in Athens, Greece, 1997, which was supported by the IASLC. I would like to express my deep gratitude to the members of the JACS, ICTS, and IASLC. Following are the list of institutions and the
physician who collected the data at each institution. I would like to express my appreciation to them. Aichi Cancer Center: (Motokazu Sugiyama), Asahikawa Medical Collage, The First Dept. of Surgery: (Yoshihiko Kubo), Cancer Institute Hospital: (Ken Nakagawa), Chiba Cancer Center Hosp.: (Hideki Kimura), Chiba Rosai Hosp.: (Toshikazu Yusa), Chiba Univ. School of Medicine, Institute of Pulmonary Cancer Research, Dept of Surgery: (Yutaka Yamaguchi), Ehime National Hosp.: (N. Nakano), Fukui Red Cross Hosp.: (Akira Yamanaka), Fukuoka Univ. School of Medicine, Second Dept. of Surgery: (Takayuki Shirakusa), Hachioji Medical Center of Tokyo Medical College: (Osamu Taira), Hamamatsu Medical Center: (Suguru Hanazawa), Hiroshima City Hosp.: (Kazuhiro Kataoka), Hokkaido Univ. School of Medicine, Second Dept. of Surgery: (Tetsuzo Okubo), Hyogo Medical Center For Adults: (Noriaki Tsubota), Kagawa Medical Univ.: (Masazumi Maeda), Kagoshima Univ. School of Medicine, Second Dept. of Surgery (Shinji Shimokawa), Kobe Univ. School of Medicine, 2nd Dept. of Surgery: (Noboru Ishii), Kurashiki Central Hosp.: (Yasuo Miyake), Kyorin Univ. Second Dept. of Surgery: (Tomoyuki Goya), Kyoto Univ. Chest Disease Research Institute: (Hiromi Wada), Kyoto-Katsura Hosp. Respiratory Division: (Sadao Ikeda), Kyushu Univ. School of Medicine, Second Dept. of Surgery: (Keizo Sugimachi), Nagasaki Univ. School of Medicine, First Dept. of Surgery: (Hiroyoshi Ayabe), Nagoya City Univ. Medical School, The Second Dept. of Surgery: (Yoshitaka Fujii), Nara Medical Univ.: (Soichiro Kitamura), National Cancer Center Hosp. East: (Kanji Nagai), National Defense Medical College: (Yuichi Ozeki), National Okinawa Hosp.: (Keiichiro Genka), Nihon Univ. School of Medicine, The 2nd Dept of Surgery: (Kazumitsu Ohmori), Niigata Cancer Center Hosp.: (Teruaki Koike), Oita Medical Univ.: (Koichi Tanaka), Oita Prefectual Hosp.: (Yoshitaka Uchiyama), Okayama Univ. School of Medicine, Dept. of Surgery 2: (Nobuyoshi Shimizu), Osaka Medical Center for Cancer and Cardiovascular Diseases: (Osamu Doi), Osaka Prefectual Habikino Hosp.: (Tsutomu Yasumitsu), Saiseikai Central Hosp.: (Hi-
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roaki Nomori), Saitama Medical School, First Dept. of Surgery: (Koichi Kaneko), Saitama Ohara Cardiovascular Center: (Eishin Hoshi), Sasakikenkyujyo Fuzoku Kyoundo Byoin: (Naganobu Hayashi), Showa Univ. School of Medicine, the First Dept. of Surgery: (Matsutaka Kadokura), St. Marianna Univ. School of Medicine, 3rd Dept of Surgery: (Hiroaki Osada), Teikyo Univ. School of Medicine, First Dept. of Surgery: (Iwao Takanami), Tenri Hosp.: (Morihisa Kitano), Tokushima Univ., School of medicine, The 2nd Dept. of Surgery (Yasumasa Monden), Tochigi Cancer Center Hosp.: (Kohei Yokoi), Toho Univ. School of Medicine, Dept. of Thoracic & Cardiovascular Surgery: (Shiro Yamazaki) Tohoku Univ., Institute of Aging, Development and Cancer, Dept of Thoracic Surgery: (Shigefumi Fujimura), Tokai Univ. School of Medicine, First Dept. of Surgery: (Hiroshi Inoue), Tokyo Medical College Kasumigaura Hosp., Thoracic Surgery Division (Kazuo Yoneyama), Tokyo Medical College, Dept. of Surgery: (Harubumi Kato), Tokyo Metropolitan Fuchu Hosp.: (Hiroshi Yamamoto), Tokyo Teishin Hosp.: (Sadahiko Masuda), Toranomonn Hosp. Dept. of Resp. Surgery: (Jiro Banba), Toyama City Hosp.: (Yoshinori Kusajima), Toyama Medical and Pharmaceutical Univ.: (Toshiki Tatsumura), Univ. of Occupational and Environmental Health, Second Dept. of Surgery: (Kosei Yasumoto) Yamaguchi Univ. School of Medicine, First Dept. of Surgery: (Kensuke Esato)
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