Document Z4ZOmbBRvyJzXgpr7vr92yG9J

CLINICAL REVIEW Pleural Mesothelioma: Clinical Features and Therapeutic Implications SEWA S. LEGHA, M.O. FAC.P.; and FRANCO M. MUGGIA, M.D. FAC.P.; Bethesda, Maryland A detailed review of Via Dterature *as dona to define the epidemiology. pathology, dMeal features, and traatmanl a( pleural mesothelioma. It appears that pleural mesothelioma account* for approximately 400 daatha aach yaar in tha Unitad States. Aabastoa has baan dafWtaty Implicated In tha etiology at tMs disease. Tha common clinical faaturaa Include chest pain, pleural effusion, and radiologic findings of irregular plaural thickaning or plaural danaHtaa. Therapeutic modalities used In tha past have included surgery, radiation therapy, and. more recently, chemotherapy. A combined modality approach to treatment appears more promising. Forty-five years AGO. largely because of difficulties in diagnosis, there was little consensus supporting mesothe lioma as a distinct disease entity. Because of wide varia tions in the appearance of the growth both grossly and microscopically, pleural tumors cither wars believed to arise in the chest wall and were variously named endothe liomas, pieural sarcomas, or endothelial carcinomas, or they were presumed to be metastaaea from primary tu mors located elsewhere. In 1931, Klemperer and Rabin (1) advocated general use of the tans mesothelioma far primary-pleural tumors originating from tha surface lin ing cells or the mesothelium. The confirmation of the origin of mesothelioma came in 1942 from tha dasus cul ture studies by Stout and Murray (2), who showed that mesothelial cells could differentiate into epithelial as well ss mesenchymal elements. They also showed tha ability of fibroblastic calls in mesotheliomas to transform into epithelial elements and vice versa. In addition to their pleural origin, mesotheliomas of other serosal surfaces sueh as peritoneum pericardium and tunica vaginalis of the testis art wall known. The pleural site is most frequently involved and accounts for 60% to 70% ofall reported mesotheliomas, whereas peri 1toneal tumors occur in approximately one third of tha cases (3-5). Pleural mesotheliomas art classified into the v Fraei is* Omit TWiijp g-thudes frofw. DKWnSCiMeTiWM, KummI Cmr Isamu. Numl lauitwu *f Kssltk. VS Dsptitaaa f H--UX. Mwsn--. we Wdbr ankwSa Msrylsae. I arsi sari, i stt diffuse tumor type, which is present in about 75% of the eases, and solitary or localized tumors, which comprise the remaining 25% (Table 1). The highly malignant dif fuse disease has a rapidly fatal course but the solitary tumors are generally benign. Peritoneal and testicular mesotheliomas have been dis cussed recently (13,14) but despite many reports of indi vidual cases or institutional series of pleural mesothelio ma, no recent review of literature on this subject is avail able- This paper will discuss the natural history of the disease, define its diagnostic features, and evaluate vari ous treatment modalities that have been used. Because Shabanah and Sayegh (10) have recently reviewed the topic of solitary pleural mesothelioma, we will concen trate principally on diffUae pleural mesothelioma and mention the solitary type only as noteworthy differences arise. Epidemiology INCIDENCE Past estimates established by analyzing necropsy series have shown a low incidence of mesothelioma; for exam ple, Hochberg (15) reported a rate of 0.07% based on 43 cases found in 60 042 autopsies. However, recent tumor registries compiled by carefUl data collection in England, Canada, and the United Slates indicate that the disease is really not so uncommon (Table 2). Two hundred fortysix cases ware identified in England during 1967 and 1961 for an annual incidence of 2.29% cases per million popu lation (4). Tha currant U3. data from tha Third National Cancer Survey (1969-1971) of seven metropolitan areas with a population of 21 million showed 131 cases for a yearly incidence of 2.2 eases par million (16). Similarly, tha Connecticut Tumor Registry, which has recorded cancer incidence by site sioce 1935, showed 24 cases in 1970-1972 for an annual rata of 2.6 per million (personal communication from J.T. Flannery, Connecticut State Department of Health). The apparendy equal mesotheli oma rates in tha U.S. and England are twice as high as tha rate of 1.0 per million in Canada (5). The proportion of pleural versus peritoneal tumors is 10% and 20% re spectively, in tha United States, whereas corresponding filS fSTOOOSGBB i j a I It DOW 07090 * TtfeM 1. Frequency ef Setttaqr VkM Diffuse MeeettietWmee Reference (> (7) (8) (9) (10) (11) (12) Total Total Patients an 37 28 18 16 13 13 12 139 Tumor Type Localized Diffusa *.(%) 6 7 7 8 2 3 1 34(23) M%) 31 21 11 8 13 10 II 103 (73) rates in England are 18% and 12%. This preponderance of pleural mesothelioma is unexpectedly higher than the 2:1 ratio of pleural versus peritoneal disease reported in the older literature (13, 17). The incidence figures for mesothelioma quoted here are most likely to be undent* timated. The true incidence is expected to be higher be* cause until recently mesothelioma was not well accepted and not categorized as such. ETIOLOGY With the possible exception of lung cancer, the role of carcinogenic environmental factors in neoplastic disease is most dearly recognized in diffuse pleural mesothelio ma. An association between exposure to asbestos and subsequent development of malignant mesothelioma of the pleura was first suggested by Wagner, Sleggs, and Marchand (18) when they observed an unusually high number of cases within a short time (1936-1960) among the South African asbestos miners. Since this early report many additional studies have dearly implicated asbestos in pleural and peritoneal mesotheliomas found in miners and other workers occupationally exposed in various trades and industries (4, 3,19-22). Interestingly, evidence generally is lacking for any relation between asbestos ex posure and the development of solitary or localized me sotheliomas (10). Mesotheliomas have been found in all parts of the world but most of the reports have come from areas in England, South Africa, and the United States when as bestos is mined or processed for its many industrial uses. Asbestos is a fibrous silicate of various chemical types such ki chrysotile, crocidolite, amositc, and anthophyilite (23). Chrysotile accounts for about 90% of commercial asbestos followed by crocidolite, amositc, and anthophyi- life in decreasing order. All types of asbestos have proved to be carcinogenic in humans although there is evidence to suggest that crocidolite may be the most potent (24, 23). Further evidence of the etiologic rote of asbestos has been shown in experimental animals where intrapleural injection with asbestos fiber causes mesotheliomas, histo logically identical to the human tumor (26, 27). Under these conditions all varieties of asbestos have been carci nogenic in from 8% to 66% ofthe animals, depending on the dose. The reported frequency of asbestos exposure in me-. sothelioma cases varied from 11% to 91% in 16 separate studies reviewed and summarized by Rubino and associ ates (28). However, a carefol analysis of 168 mesothelio ma cases in England and South Africa by Elmee (23) placed the incidence of asbestos exposure at 70% (117 eases). Only one third (60 patients) of the total cases could be associated with direct occupational exposure in tensive enough to cause asbestosis or lung carcinoma. Another one third (37 cases) were asbestos-related only by trivial contact at work or in the home environment. The remaining 31 cases had no history of contact with asbestos but their exposure could have been forgotten or overlooked (17, 23). Of course, it is possible that un known etiologic factors may induce the neoplasm. In this connection, Chabot and colleagues (29) have shown the induction of typical mesotheliomas in the chicken by strain MC29 avian leukosis virus. Perhaps the most convincing evidence ofassociation of asbestos with mesothelioma is brought out by Selikoff, Chrug, and Hammond (19) who reviewed the post mor tem findings in more than 300 patients who had been exposed to asbestos. They found a frequency of mesothe lioma of 3% in this group, as opposed to a frequency of 0.01 per cent in the general population, thus indicating a 300-fold increase in the frequency of pleural and perito neal mesothelioma in those exposed to asbestos. In sddition, the authors suggested a dose-effect relation by show ing a 13% rate of mesothelioma in a separate analysis of patients dying of asbestosis, a fivefold increase over the rate in insulation workers without asbestosis. Similarly Newbouse and Thompson (17) reported an inverse rela tion between the intensity of asbestos exposure and time to death from mesothelioma, the mesa interval between first exposure and death being 29 years in factory workers and 48 years in subjects living near the factory (17). Most other scrim have reported a similar long interval averag ing 30 years between first exposure to asbestos and dcvel- Teals 2. tncMwwe of Mssemsasma Sy Site and tat Reference Population Sample (millions) Total Mesotheliomas Sex -------- F Site Rate <**** United States (1 () Connecticut* England (4) Canada (3) 210 3.1 33.6 20.0 me. 131 92 39 24 16 8 246 201 43 138 106 32 Fun-iit XT: Comxcucin Sum Dtpeninca el HtsllS. Finenel wmimintine 614 Netmmeer It?/ e Unr+U el unemel Mxiem, Ie/umtlf e Mummer $ 112 17 216 113 19 7 30 43 2-2 2.6 2.29 1.0 r ST0005689 079* DOW  t. . r~- -- opment of mesothelioma (3, 4, II, 30). The duration of ohrviM exposure in mesothelioma cam of eouna baa tried from < 1 year to mon than 30 yean. FttAology The variable histologic appearance of pleural mesothe lioma simulates other neoplasias so much to that soma investigators have challenged the existence of the tumor av a pathologic entity. Indeed, many pathologists only mate the diagnosis of "probable mesothelioma,** with confirmation resting on factors like failure to And another primar) tumor or a history of occupational exposure to asbestos The pathologic findings have been detailed in a number of recent papers (11, 30-33). cams ArreAXANCt The solitary mesotheliomas are well circumscribed. usuall> encapsulated, and can arise from perietal or vis ceral pleura. Most tumors are pedunculated and vary in sire from a small mass to one that may occupy the entire hemithorsa (10). Diffuse mesothelioma has a very characteristic macro scopic appearance, which is often of more diagnostic sig nificance than its microscopic features (34). In its earlier stages, the lesions tppear as multiple, small white or gray granules, nodules, or flakes on normal or slightly opaque visceral or parietal pleura (6). The tumor tends to spread along the visceral and parietal pleural surfaces, forming a continuous layer encasing the lung and lending to com pression atelectasis in advanced caste. With advancing disease, the pleural surface becomes progressively thicker and is generally nodular, or papillary, in appearance. The pleural thickening and other changes are generally more marked near the base of the lung. The growing tumor extends in all directions, involving the lung, intercostal spaces, and riba and may even reach the subcutaneous tissues- The diaphragm, liver, pericar dium. heart and other mediastinal structures may be in volved in advanced caeca. In its later stages, the tumor may involve the contralateral pleura and the peritoneum (6. 30. 33). Although diffuse mesothelioma is highly ma lignant. it is predominantly a locally infiltrative tumor with uncommon distant metastases. The regional lymph nodes are the only common site for metastases except in the advanced stages when the tumor may spread to the other lung and distant organs such as Uver, adrenals, brain, and bonce (6,7,30). Mtcaosconc featuku Most of the solitary pleural mesotheliomas are exclu sively fibrous, with a mixture of spindle-shaped cells and collagen fibers. Some have areas of epithelial call ele ments and in rare instances the entire tumor may be of the epithelie! type. These tumors often exhibit considera ble cellular atypia in spite of a generally benign clinical course- The most striking histologic character of diffuse me sothelioma is the remarkable structural variation that Table S. Mrierigfe Feeturae at OHtae WsariMama Reference Patriots 04) (37) m (38) (39) (4) (32) (33) (12) Total as. N 43 31 38 37 31 30 20 12 382 ca.(%> 43 34 22 9 23 14 21 It 3 208(343) Histologic Type Fibromreoraatous *.(%) 28 11 It 2 7 13 0 4 2 S2(21J) Mixed *(%) 24 18 IS 8 3 0 ) 3 92(20 may occur between areas in a single tumor or between different turnon having an Identical gross appearance. This variability probably stems from the fact that mesothelial cells can differentiate into mesenchymal as well as epithelial elements. The cells of the epithelial type may take various shapes, but most commonly they an cuboi ds! and are fairly uniform in size and contain vesicularnuclei. Multinucleatcd forms and occasional mitinri have been observed in some eases but pteomorphism, anapla sia, and atypical mitoses are rare. The cells in mesenchy mal types may vary from oval forms through somewhat elongated to distinctly spindle shapes. The mesenchymal cell type may exhibit-anaplasia and pteomorphism resem bling spindle-cell sarcomas like fibrosarcoma or myosar coma. The proportion of the two mesothelioma cell types is highly variable. The tumor may be purely epithelial or mesenchymal (fibrosarcomatous), or it may contain a mixture of both cell types. The mesothelioma with a par ticular cell type may have a variety of structural patterns. For example, the epithelial type may be arranged in a., tubular or tubulopapillary pattern, or in clefts, solid nests, or sheets. Characteristically, mesotheliomas exhibit more than one pattern and many have a number of petterns. The fibrosarcomatous mesotheliomas consist of sheets of malignant spindle cells or collagenous fiber* re sembling fibrosarcoma. The bimorphic or mixed me sotheliomas are composed of a mixture of epithelial and fibrous elements. The frequency of the three main histologic types varies in different scries, but our compilation of 382 cases from the literature showed a pattern of 34% epithelial. 23% mixed, and 21% fibrosarcomatous (Table 3). The pre dominance of the epithelial type was surprising because McCaughey, who first established histologic criteria for diagnosis of malignant mesothelioma (31), reported the presence of the mixed cellular type in more than 30% of 124 autopsied cases. However, he noted that detection of the mixed pattern would have been impossible using only one or two tissue blocks because widely divergent ele ments usually were not intimately mixed and in most cases occupied adjacent areas or were remou from one another. UFskimw Hwnunueen 615 069SG001Sj DOUJ 07092 V in the chest wall, and rib tenderness may be found in cases of advanced disease (30). In cases with advanced disease contraction of the affected hcmithorax may occur leading to restriction ofchest wall movement and eventu ally a frozen chest, with flattening of the infradavicular region, 'roof tiling* of the riba, and immobility of the chest wall (35). The tumor has a propensity for growth along the nee dle tracks after paracentesis or along the scar of a thoractomy incision (30, 33). Encroachment on the mediastinal structures may lead to neuropathic signs such as vocal cord paralysis or Homer's syndrome (I, 11). The cheat wall invasion affecting intercostal nerves often leads to anesthesia or altered sensation in the skin of the chest wall and abdomen. Congestion and edema may develop m the upper trunk or lower limbs because of compression of the superior or inferior vena cava, or both. Ascitea caused by peritoneal involvement with the tumor is not uncommon in advanced cases (6, 35, 39). The systemic effects may produce a variable fever, usu ally less than 3S.3*C. Cachexia and cyanosis arc promi nent in advanced cases, and death generally is due to pulmonary infection or to cardiac or respiratory failure. Hypertrophic pulmonary osteoarthropathy has been re ported (7, 33) but less commonly than in benign pleural mesothelioma. Spontaneous pneumothorax happens oc casionally (6) and sometimes may be the first manifesta tion of the disease (9). Diagnosis Diagnosis is generally delayed by an undistinctive clin ical picture in early stages of the disease. Malignant me sothelioma should be a consideration in all cases of pleur al effUsion without obvious cause, particularly when chest pain is a prominent symptom. Unlike the pleuritic pain of inflammatory origin, which usually subsides with effu sion, the pain of malignant mesothelioma gradually in creases despite the effusion (6). History of exposure to asbestos either by occupation or environment, such as by family contact or by proximate residence, is an important guide to investigate for mesothelioma. Particularly vul nerable occupations arc shipyard workers, those storking with asbestos textile manufacturing, and brake Hwiwg, and insulation workers and sack repair workers. The differential diagnosis should include inflammatory pleurisy, primary lung cancer, and the presence of metas tatic disease from a primary tumor elsewhere in the body. Inflammatory pleurisy can be easily diagnosed by the as sociated clinical picture and by pleural fluid analyses in cluding cultures of the sputum and pleural fluid. In lung cancer the cough generally is a more prominent symp tom, often accompanied by hemoptysis, and chest pain is a late feature of the disease. Additionally, the chest roent genogram after thoracentesis will show a parenchymal lesion and the pleura will appear quite normal. Sputum cytology generally shows malignant cells in lung cancer but usually is negative in mesothelioma. In spite of them differences, brochiolar carcinoma of the lung can some times mimic diffuse mesothelioma to closely that differ entiation may be virtually impossible (47). Exclusion of metastatic tumor on clinical grounds alone is most diffi cult. but a systematic search for a primary tumor must be carried out to exclude this possibility. One must especial ly exclude an occult carcinoma of pancreas, gastrointesti nal tract, and ovary. Imrestigationa CHEST ROENTGENOGRAMS The solitary mesothelioma characteristically appeus as a discrete mass, which is of variable size and usually contiguous with one of the pleural surfaces (40). Pleural cflUsion is unusual, and the lungs and remaining pleura are generally normal. The characteristic radiographic n<ip in jb*. sothelioma have been described by Heller, JanoWer, and Weber (45) and others (4*). Unilateral pleural effusion is the most common abnormality (43, 4fi). On removal of the fluid, the pleura may show gross thickening or nodu larity, which is commonly first noted at the bases. In duced pneumothorax after thoracentesis may aid in showing early thickened pleura or small nodular densi ties. Late in the disease tomograms or an overpenetrated film will show compressed lung surrounded on all sur faces by a layer of tumor 2 to 3 cm thick. In addition to the mesothelioma induced changes, signs of aibcstoeis such as interstital pulmonary fibrosis, pleural plaques, and calcification when present are of positive differential- diagnostic value (especially on the contralateral side). Be cause mesothelioma is commonly not associated with as- bestoais, one may need overpenetrated film of the chest to show the characteristic pleura] calcification when gross changes are not present In the later stages, the mediasti num may be widened by involvement of lymph glands. The pericardium may be infiltrated with the tumor and the resulting effusion may enlarge the cardiac silhouette. Extrapleural extension showing as soft-tissue masses or radiologic evidence of rib destruction may occur and are highly suggestive of malignant mesothelioma (4g). Hy dropneumothorax has occurred rarely. THORACENTESIS AND PLEURAL FLUID CHARACTERISTICS One clue to the presence of pleural mesothelioma may be the considerable force needed to enter the pleural space with a thoracentesis needle (34). The pleural fluid is usually straw colored but has been reported to be serosanguineous or frankly hemorrhagic in about 30% to 50% of the cases (6, 7, IS, 49). The effusions generally have a tendency for rapid reaccumulation requiring fre quent aspirations, and the fluid becomes increasingly hemorrhagic with repeated tape. The exfoliative cytology of malignant mesothelioma has been described in detail (50-52). There is considerable difference of opinion concerning its diagnostic value. The pleural fluid generally is very cellular, containing a mix ture of normal mesothelial cells, differentiated and undif ferentiated malignant mesothelial cells, and varying num bers of lymphocytes, histiocytes, and polymorphonuclear leukocytes (50). In these collected observations 20% of the cases showed no clue to the malignant nature of the wwmiiiuiwiiin gi7 i i t / I iI I I I I I I \ \ I lI I ! ST000569I DOW 07093 . 'i . --r. TeWe 4. CtaW Ftalura ef Reference Patients (39) (6) (41) (7) (44) (ID (1) OD (45) (9) Total an 37 31 27 21 19 19 11 10 10 8 191 MwstUrtaw hin *(*) 23 28 13 13 9 18 10 8 4 4 114(69) Dyspnea *.(%) 17 21 22 9 13 18 7 10 6 6 131(68) neural Effusion .(%) 31 27 24 13 13 13 7 7 4 7 130(78) Oinirel Fsanaes Cough Weight Lea *o. (SB 3 10 *>.(%) 4 e 18 1) 11 3 eon 10 72 44 S 0 2 2 62(32) 2 en 40(20) , Fear Others -(%) 2 no* 13 7 *e #n 0 0 1 2601) an Asdics, 4 Honoptysh, 2 ruuakulufu 2 Hancprysk. 2 Htaopcpfe, 4 Difsul dubbing, 2 Digital dubbiag, 4 Kotow's syndrome, 1 Hornw*t syndroms, 1 Dysphagta.1 Hosrwiw, 1 Pneumothorax, 1 Clinical Features AOB As in most other neoplasms, the greatest number of mesotheliomas occur between the ages of 40 and 60 yean. Sacconc and Coblenz (34) found that 70% of the patients in a collection of 181 cases were in the 40 to 70 age bracket; Whitewell and Rawcliffe (30) found 74% were between the ages of 30 and 70 in a series of 32 cases. The median age varies between 30 and 60 yean in differ* ent series, but the tumor does occur at all ages (3, 34). In Hochbcrg's (13) report on 192 cases, six cases (3.1%) were found in the first decade of life, a similar number in the second decade, and 21 (6.2%) appeared in the third decade. Fifty percent of the cases were diagnosed in pa* dents 30 to 60 yean of age. SEX In a review of 223 pleural mesotheliomas collected by Hochberg (15), 144 patients were in men and 79 were in women, a sez ratio of 1.8:1. Most series report a ratio of 2:1 but our compilation of 339 recent cases (Table 2) shows a 3:1 ratio. t SYMPTOMS The solitary mesotheliomas are generally asymptomat ic unless the tumor is large and produces localised chest pain and pressure effects (10). Extrathoracic symptoms of pulmonary osteoarthropathy (40) and hypoglycemia are sometimes observed (41,42). In difftise mesothelioma, symptoms may be entirely ab sent or minimal at the onset of the disease. Disease pro gression elicits the common symptoms of chest pain, dyspnea, cough, and gradually increasing weight loss ac companied by pronounced asthenia (6, 7, 13, 34). Chest pain is the most common complaint and eventually be* comes the incapacitating symptom in most patients (Ta ble 4). Because it is caused by infiltration of the chest wall the pain is usually localized over the involved side but may radiate to the shoulder and arm. It commonly has a dun gnawing quality but may vary from mild discomfort to a severe neuralgic pain and tardy has a pleuritic quali ty. Dyspnea is proportional to the disease stage, occur ring with physical exertion in the >Mt<"t"g but later be coming a constant symptom. The cough is a leas common symptom and is not usually present until the disease en croaches on the mediastinum. Then, it may haowna quite persistent, dry, and irritations! although at times there may be slight hemoptysis (6, 11). Some patients have ir regular episodes of low-grade fever. The later stages of disrate are matted by aggravation of all symptoms, poor appetite, and rapid weight loss. In the terminal stages there is marked dyspnea, orthopnea, diaphoresis, <--->--! and severe chert pain that is only"' partially relieved by large doses ofnarcotics. Rarer ya^ toms include arthralgic pain with hypertrophic puhnffd nary osteoarthropathy (6, 33), syncopal attacks from h^ poglycemia (46), and generalized anasarca from perica^ dial involvement or obstruction ofthe inferior and superb or vena cavae (6). Dysphagia (6), hoarseness, and beArl pain have occasionally been reported. ^ PHYSICAL FIHDINOS M The solitary mesotheliomas present few physical signs. Patients usually show signs of a IncaHred chert mass, and, in rare instances, there may be a pleural effbsiott that is sometimes hemorrhagic (7). In diffbse mesothelioma the physical findings vary with the disease stags. Moat patients initially present with signs of fluid in the involved hemithorax (Table 4). In the more advanced disease local chest involvement Is more marked and there may be obvious enlargement of the affected heaithonz, bulging of intercostal spaces, and displacement of the trachea and mediastinum to the unsffeeted side (6). Local tumor growth may also depress the diaphragm and displace the liver and spleen, giving the impression of hepatomegaly or splenomegaly. A pericar dial or pleuropericardial rub is not uncommonly beard after removal of aU the pleural fluid.-Supraclavicular and axillary lymph node enlargement, subcutaneous nodules glC Ammewisrr AnwntwinwriwMieirtM wu--er* *ure 0709* DOW rent tumors, after resection of solitary benign mesothelio ma. arc usually malignant but benign recurrences are oc casionally reported (10). Because solitary mesotheliomas are not always benign, radical excision, perhaps com bined with radiotherapy and chemotherapy, should be used in malignant turnon. Malignancy fas solitary turnon is not uncommon in childhood mesotheliomas (67), and of course the fibrosarcomatous variety of diffuse maaoche lioma may initially present as a localised tumor (6). The therapy of diffuse pleural mesothelioma presants problems that have never been dearly defined The vari ous treatment modalities have included surgery, external radiotherapy, intracavitary radioisotopes, cytotoxic drugs, and various combination of these approaclua. SURGERY Because of the extensive infiltration of adjoining vis cera, the diffuse pleural mesotheliomas pose a difficult problem for complete extirpation. However, fat spite of the technical difficulties, data are available on approxi mately 400 patients who have undergone surgery of vari able extent (61). "Curative" surgery, consisting of pleuropneumonectomy, was attempted in 62 cases by Wont (69), in 17 cases by Bamler and Maaben (70), and in five cases by Schamaun (71). More often these investigators used palliative surgery, generally confined to parietal pleurectomy and removal of the bulk of remaining tu mor. It is difficult to judge whether survival waa pro longed in these uncontrolled scries but ft is dear that a substantial mortality rate (20% la the series of Bamler and Maaben) accompanied the radical procedure. Be cause the survival rate waa no better than that obtained with palliative surgery, parietal pleurectomy alone is the preferred form of treatment A more recent study of Martini, Bains, and Beattie (72) further supports the feasibility of parietal pleurecto my for controlling pleural effusion without significant op erative mortality. Worn's 1-year survival rate of 70% (140/200) and the 79% (11/14) reported by Martini and colleagues (72) are vastly superior to the generally ac cepted 30% 1-year survival rate after diagnosis of difflise mesothelioma (IS, 34, 33). Postoperative adjuvant che motherapy and radiotherapy of unspecified extent were used in both studies and may-have been influential in the increased survival rate. By comparison, Schuster and Huzly (73) used parietal pleurectomy without supple mental treatment in 98 patients and reported only a 24% 1-year survival rate. external radiotherapy The value of radiotherapy is commonly recognised for controlling pain and pleural effusion in mesothelioma. However, three recent U.S. studies (3, 6, 39) imply that, in spite of the palliative benefits, this modality is relative ly ineffective against the disease, There are also reports indicating that cheat irradiation in mesothelioma is total ly ineffective and may even be detrimental (49). On the other hand, some investigators have reported objective control of the disease by radiotherapy (12, 38, 74. 73). The most impressive data were reported by TaNe S. |unM hi hUOrunt Hnl Htutfulwi Reference Patients Average Survival from Onset of Symptoms Remarks (D (30) (33) (0 09) (43) (33) (44) Total Ms 72* 36 M 31 28 27 20 19 267 IS 12 12 20 12 10 ee 10 list Treated with radiotherapy or chemotherapy, or both One third of patients survived 75b%eydonMd *2ity5ena*n12 months Intensive combination of surgsy, chemotherapy, and ndiothwipy; post-therapy arrival srangtd 14 iw*. Radiotherapy routinriy used Most cases treated suriieaqy 17/20 died within 12 months of onset Only four patients Bend btyeod 1 year TsrlnSei tent cues at fniiemml t Madia m II anerM Schliengtr and hit uiociiia (31, 73) who treated 46 pa tients. There was relatively little benefit with total doeea of < 3300 rad (31), but at a median dote of 4300 rad (ran(e, 3300 to 7300 rad), the median pontimdiation sur vival was 13 months (range, 1 to 37 months). Anatomical regression of tumor was noted in several eases and pa* dents tolerated the therapy without significant complica tions. This group advocated use of irradiation at higher than the commonly used doses and felt that the therapy was definitely beneficial Radioactive Colloidal Sold 0"Au) Colloidal '"Au has been used successfully by some in vestigators for controlling pleural effusion (76-79). Smart and Hinson (76) reported the resolution of pleural effu sion in seven of 10 cases and Strashinin and Chupin (77) achieved similar results in four of six cases treated with intrapleural '"Au. Long-term control has been achieved in some instances (77, 78). The generally recommended dose of 30 to 100 mCi. repeated in 3 to 6 months, has not caused significant toxicity. The treatment is most benefi cial in early cases before the pleural cavity is obliterated by the tiunor. CHEMOTHERAPY The role of cytotoxic drugs in mesothelioma has not been systematically explored but there are well-docu mented reports of definite antitumor effects in some pa tients. Alkylating agents such as cyclophosphamide (80). nitrogen mustard (SIX and thio-TEPA (46) possess some activity and occasionally have induced complete regrealions. Approximately 30% of the patients treated with alkylating agents have experienced some degree of objec tive response (68). Other reportedly active antitumor drugs include doxo rubicin (adriamycin) (82) and 3-fluorouracil (S3). Doxo- IlMnlliltHtMlm 619 j j i I i C69SG001S DOW 07095 7T pleural fluid (30-32X Undifferentiated malignant cefla without mnnthcHal cad characteristic* wart found in an- other 20% of the cases Approximately 30% to 60% of the caaea had typical mreothcHsl ccfts. which could be identified by observers with the wide range of appearance* shown by mmotheiial ceils. Typical m> otbdial calk art rounded, somewhat larger then a histi ocyte, with an abundant dense eoainiphiiic cytoplasm and a small rounded nucleus containing a prominent nucleo lus. Many of the calls an muitinticketed. The g*11* tend to form dusters with knobby outline. The diagnostic value of cytology is limited because of the subtle differences between benign and malignant me- sotheiial oeila. Mesotbails! hyperplasia and hypertrophy is not unoommon in benign pleural effusions, and the cells can be easily mistaken for malignant ceils and vice vena. With those limitations, cytology should only bo a guide to a provisional diagnosis of mesothelioma that should be subsequently oonffrmed by biopsy in all cases. CHEMICAL FlNDINaa The fluid usually is an exudate with high protein con centration ranging from 3.3 to 3.3 g/dl (I, 11). Taryk, I alfthminarayaa. and Saha (I) have reported elevated lactic dehydrogenase level (> 600IU in some cases) and decreased glucose in a proportion of caaea (IX Detection of an deviated concentration of acid muco polysaccharide (AMPX mainly hyaluronic add, in the serous eflUsaou fluid has been considered hdpftil in the diagnosis of diffuse mesothelioma. Harington. Wagner, and Smith (S3) flrst reported hyaluronic add levels of 120 to 7900 jtg/ml of fluid in six biopsy-proven cases of me sothelioma. Similarly, Thompeon, Bromberg, and Amen ta (34) noted elevated concentration in three patients with malignant mesothelioma and undetectable levels in eight patients with pleural effusions of other origin. Cas tor and Naylor (33) in a series of 100 cases of pleural effusion of diverse causes showed that the concentrations of AMP were increased in many benign and malignant cffUsions but were generally below 120 pg/ml in benign conditions and above this level in malignancies including mesothelioma. Similar results were obtained by Rasmus sen and Father (36) in 247 cues of pkural effusion. Hya luronic add was present in many caaea of transudelive cffUsions but the level was generally km than 0.2 mg/mL Values of 0.2 mg to 0.1 mg/ml occurred in fluids from different types of inflammation and malignancy (includ ing some eases of mesothelioma) but those greater than 0.1 mg ware found only in mrsotheliomai However only seven of 19 mesothelioma cases bad hyaluronic add level higher than 0.1 mg/ml; the ren had levels between 0 to 0.1 mg distributed fairly uniformly. Therefore devated AMP is far from being a specific and is only moderately sensitive teat for the differential diagnosis of mesothelio ma. When the concentration of AMP it very high, the fluid is characteristically viscous and the appearance should lead one to consider the possibility of an underly ing mesothelioma (56). Some investigators have used histochemical methods of detecting AMP in the pleural biopsy tissue of mesothe lioma (32. 37, SIX Aldan blue and Halt's uuMt fag stains produce a characteristic metachromatic reaction to AMP in the mesothelioma. These reactions era consider ably reduced or abolished by previous digestion with byaluronidate (32X Because AMP may occur in any rapidly growing connective tissue, its presence has diagnostic sig nificance only when associatnd with epithelial aasothdi- In contrast to adenocarcinomas, mesothdiomM do not stain with the periodic add Schiff (PAS) reagent or with mudearmina (39X The intracellular or intrmtubular mu cin of adenocarcinomas usually will taka the PAS or mudcarmine, but not invariably. Although they an often useftU. histochemical teets lack consistency and should be interpreted with caution (7,60X THOBACOTOMY An open thoracotomy is generally required to ftirnish sufficient material for a correct diagnosis by the patholo gist. Multiple biopsies from different pkural areas should be taken because of the variabk histology seen in various parts of the tumor. The gross pathology at thoracotomy is usually characteristic and suggests the diagnosis to the experienced ciinirian. Final diagnosis rests on detailed histologic examination aided by histochemical studies. * Electron microscopy recently has been used in me sothelioma and may have additional diagnostic value in difficult cafes (61-62). There studies can be especially hdpAtl in differentiating diffUre mesotbeXoma from bron chioloalveolar carcinoma, which sometimes resembles it (61.63X Demonstration of asbestos bodies in the sputum or biopsy material has been an additional diagnostic aid in suspected mesothelioma (37,64). They can be best shown in touch preparations made from the fluid squeezed from the fresh tissue (63). Although this finding is usefrtl. it simply implies probabk exposure, in that asbestos bodies have been observed in the sputa of many healthy individ uals throughout the United States (64). . other studies Scalene node biopsy has been used when the lymph nodes are palpable, which may occur in advanced cases <>* , Thoracoscopy is difficult because of the frequent sym physis of pkural surfaces, but it is possibk to visualize the pkural surface in early disease. When the pleura is thin and (ffVtstco is ckar, discrete pkural nodules can be seen overlying the still elastic lung. The nodules are usu ally cherry colored and cither smoothly rounded or warty in appearance. Later, the discrete nodules coalesce sad the underlying lung is obscured. The growth then *P* pears as a grey opaque membrane with localized excres cences of variabk size. The lung becomes completely in* mobile and inenreereted at the later stages of disea** Treatment Surgical excision is generally curative in moat pati" with solitary mesothelioma but local recurrence place in a small percentage of there eases (10,66X R*^* (II M.aclw tWWwtar * Mumttrg r S TOO Ob S ilt DOW 07096 rubicin therapy induced two complete and three partial responses in Bve patients treated by Kucuksu, Thomas, and Exdinli (12). Similarly, Center and Moore (13) treat* cd three patients with 3-fluorouraciI and reported two complete regressions lasting II months in each case. Combination chemotherapy has not been extensively studied but regimenscontaining doxorubicin appear to have quite consistent effectiveness. Gottlieb and associates (14) have reported that doxorubicin plus 5-(3.3-dimethyl-ltnsxeno) imidaxolc 4 carboxamide (DTIC or DIQ was useful in some cases ofmesothelioma. Gottlieb and associ* sics (13) also reported that a combination of cyclophos phamide. vincristine, doxorubicin, sad DTIC known as CY-VA-DIC exhibited good activity. Another four-drug combination termed "COMF," consisting of cyclophos phamide, vincristine, methotrexate, and 3-Duoroursdl also is reported active against mesothelioma (12). These reports are encouraging and indicate the need for properly evaluating the role of chemotherapy in pros pective trials. Whether combinations of drugs are superi or to single agents remains to be proved. gressive forms of chest irradiation. In general optimal rspoase to various therapeutic modalities is most likely when the tumor is tiagau*^ and treated early. Most exact of mesothelioma unfortu nately are fhr advanced at the time of diagnosis, and the patient is physically in a poor condition. Mesothelioma should be considered a possibility in all cam of pleural cffUsion without obvious cause. A history of exposure to asbestos should make ooc suspect the presence of this tumor, especially when pleuraJ effUsion is accompanied by severe chut pain. In the future, increasing recognition of this entity and a more aggressive approach to early diagnosis and to therapy may improve the survival in thil not uncommon type of cancer. ACKNOWLEDGMENTS: Tho Mtbon dusk Mx Koldip K. tuba tad Mr. Wfflaa Sopor fee tbdr vohnMo aUtina is On pnponooa of ito Rarivod t Doea^w 1*7* rrhla lapiM Uloaary I>77. a tuies far rvprian *oaM bo addraad a Srat I. lapba. M.D.; Otvol. opoatol Tbtnpadn M. D. Aarknon Hoapiial tad Toaor laabniu; 4TU law Awe Hi)--. TX 77030 COMBINED MODAUTTO The available data for therapeutic results do not indi cate the superiority of any individual treatment modality, and complete eradication of tumor is infrequent with any of them. The studies that have produced above-average survival rates have used combinations of therapies such as surgery followed by external radiotherapy and, when possible, by systemic chemotherapy (6, 69, 72). In the only study reporting 3-year survival (9%), the therapeu tic approach constated of surgical resection plus radio therapy and chemotherapy (69). Martini and colleagues (72) recently were encouraged by their use of surgery, external irradiation, and chemotherapy in obtaining a post-treatment median survival duration of 16 months in a small group of patients. Although none of the studies were controlled, they strongly support the need for evaluating combined-mod ality approaches in well-designed prospective trials. In general, the lack of success in altering the fatal course of diffuse mesothelioma through single modalities of treat ment. and the recent progress using combined modalities against resistant tumors like osteosarcoma (16,17), favor exploration of multimodality treatment approaches in malignant mesothelioma. Conclusion Diffuse pleural mesothelioma is a highly malignant dis ease with an average survival from onset of symptoms of 12 to 13 months (Table 3). There is usually a delay of 6 to 8 months before the diagnosis is established (6, 7, 39), and most of the patients (approximately 73%) are dead within 1 year after diagnosis. The average survival after diagnosis is to 10 months. The delay in diagnosis is responsible for the advanced disease stage at the time therapeutic intervention is sought. In the put. treatment has been generally unsuccessful in altering the course of the disease. More recently, there appears to be some opti mism with the use of chemotherapy u well u more ag 1. Kumtsxu P. Xasm CB: Prloiiry atoplaaa tfifct ptoun a upon 0flitaM.AASMgMIJIMa 1*31 2. Stout AP, Muixat MIL LeoaiuM pltunl iwnrtrBnn iaiari|t boa of ia chtncttriobct tad Munpnait bp iht aatad of a-- tai- tun. Ant Httei MtSI4U, 1*42 J. Booow M. Constcn A. UvusMtu L Seuairr N: llontMioi fattonif upomn to aboore t rroev of 7} coax Oar *4441.444, irn 4. Oiiixkm M. Loyd Davia TA McncMHoas minor UPT-di. Kr/tatMajl.41-104, 1*74 5. McDonald AD, Kxxnx A. El Attax OA. McDonald K: tpida- ioio(p of priaarp saHpnoa aaiuhiliil naan is Caadx Caseor 2M14-1*, 1*10 1 Raru EX. Pool JLMslamsd MX: Plant ataothoBoaa:cliaical iiporioaca *4th thirty-aroo potaati. Am / Bnatponot **442-110. IMI 7. Ubscmbl HC Paulson DL MmcMIioma oftho piwn. Am Thane Stug l:3S*.S7A IMS S. TaxTLX DA Lasshmsoaxavam 1 Sann SA Pteuril mawhdioaa Aa oaolpao of It eaao tad nrbow of tbo Utarttun Nwtmm (Kalu- oan^JMJVlil IP7S f. EMXtMHArr IU StNStmo DM. Lawixncs MS: Maaholioao of tho plain. / rtonc (Mime Stiff 40:3*2-40*. IMO 10. Smabanan FH. SatSOM SF: Sotitup (locthrad) plounl maocMicaa. Report oftwo coao and mUw of tbo Bunnn. Chau 40.331-343.1M3. It. Sims O: Difua oali(nAM atMdaliomx A diaieopoihotockol itudp of 10 tool caoL Asm Ctit Scaag 124.2MI. IMS 12. Poarxx JM, Cmssx JM: Ploinl aomhotioax. Rcriov oftuna koto- |naa tad upon of It earn. I Tiara Catgmac Saag 334*2-4*0. IMS IJ. Mouth. CO: Pnhonal aawMHnaix Otatnmnra/agjr JJ44-330, 1*71 14. ocKtUX DP. Nimi P: Adoaoaaiatd luaon (oiaorbotiowo) of iat>cular and pontaiieutar daoc. Vmtogf M23-441,1*73 13. ' Hocmoxac LA EadotMHono (ataibtlieaa) of da pitas. Am Km tatan 43:130-173. 1*31 IS CUTLU S3. Youno JL- Third Ntbooal Coaoa Savor iaridaa data. Nat/ data far Naaagr 41.441,1*73 17. Nswmouss ML Thounon K: MaocMioas of plain oad puiioor uai fcaowtaf npoain a oobom hi iht Loadoa ax Mr J lag Nag 21.241-24*. IM3 15. WAOHtl JC SLteu CA MaSCNaNO P: DUtat plowol aaoihiliiaii oad abaia txpooan ia da North Waant Copt pnviacx Mr J lag Nat 17:240-271, IMO I*. SiLixorr U, Cmue I, Hammond EC. Rdtboa bti npaon a abaia ind notoihdiomA. N tag!JNag 272J40.343, IMS 10. Elmu PC Wam OL: Rdortoabip btraota upooiro a oObtMa tad plain! ouli|noacp a BtUax Am NYAcatU I22J44.337, IMS 21. McEwtM J, FinlayWN A Maix A CtaOH AAM: Maocbtbooa ia Sealtad. 4bMM/4:37S-37S, 1*70 11. ASMCXOTT T: rpidnaiolopinl tad eoaabudvt roiatioathipi boraoa momlaliemt ud abaia oa Tpsaidi ldm HttN 24 l324Aa 1*7] 620 Hatatanar ItTT Annan at atonal Maditma *btaarntf Numaar t r ST0005695 DOW 07097 . b mu PC TV epiiaaiaeieBp ft ctacal him af nbmrraia Mi rtlaiai IMi McDohalo 1C McDonau AO. Otau OW, Shmutvcci 1. h CS. Morality m tba etrpeadk aabamae Mm Mi Vile af Qaabaa. Are* Eerirae HmKk 22.4T7-444 |TI a )C AjOmub aimniHM R f rvrar Tt T7* TIT 1*TS 24 WAOM(aSCBaaavO.Taaauu.V:Mmoibdkmaiaramafkmtaeo- taboo itk HhHitH Mi s(Mr aoeriaii JPSCVear2t:l7J.|ll 1*71 V. Smut LM. Prill LN. KiMMlivi LV, Kuiamma IT. Na- minko BA; tiiiwwil led* m Btan caedoofMitefep. /AM CVcer tar 72:1173-1147. IT4 ZB Buano OP. ItAim rii 0. Dohka a. Palzztho O: FpMmlnlwp af pkunl wnartirtiama m Hortti Min help (HMmeal). hi tat Mot 2*414441. 1*71 9. Cmarqt JF. Iiaio 0, Lawoum Al. >(aao IW: Maaotbattomat Ot pemntwuM, epicuriiam. Mi partntiim iaiacei V ataia MO* trka bukOM rirue. Otar Mm 30:1247-1 JOB 1910 ]B Wwnwiu F. lUwcurra IX. Piiime mi Mi n>f upaaun. Thom MM1, 1*71 SI. McCauckit WTR Criteria far rliijAnaU ttiMbea mmadVkl mu Atm NYAftSt! 112.401411. IMS SB Oruec 1. Roma SH. MootTIN B KVolefka! eVneurWce ef aa> othdioma amneiarai with aeb MM Am NY Amt AN 131414422. IH1 IS. Bourn OH: Oita ptant moiMom A dhiol pjlnihVI mix Atl Da Ckcct <001411,1*70 14 Saccomi A. CoeuKX A FailrebaHnma at dM plaun M npai at rrocmm. Am JO* Add 13:144-207. IMI ft. Scicoi CA Maacmano P. Waohiz 1C DifiM pleunl nemVHeum Souk Aftka. SA&MttJiSJt-M. IMI SB MaOwu D. McPokau AO. Mellinaat raMnOuSel turnon Hietdoo icl type Mi eabearoa eapoean N tafU Not 217:170-371. 1*72 ST. HouaiMAMt DO: A Mop* toia at itinmhcBnitnta ui ertempa to Meanly eabeerca Utkin tout of the rumen Am NYAettSd 1)1447- *7). IMS a Scmuihqu M. Ezcirwaot F. Olacmi A odnui It MmotV- bomm pitunu miUm flak ia 3* cu iom a amnpiiM Ml CVaer 34 24530t. 1*4* 1*. Oku HC bum) IO. Cam DT. Bumatz ft Difbee mII|mu meewheiiome Ot the plena. A nna a137 cmm Os 40344-3701 1*71 40. Hurcmioow WB. Ftnatwatoo Ml: Utmhrnerir eiMnrhelinuia Mo- tmtegr 40*37*43, IMS. 41. Nujok R. Burmam SO. Kum A CMutow IS. Stun 1. Camtav* I: Hppoglpeeaiie 0004 Mtrriareri vfch >IH'U pkunl MMiMhiinnH / none Certiorate Sort 4*304-314 1*73 41 lm CIF. WaUAMMN OK. Iamm ML: Pkunl mwkrtinon Mi kypopirenuA. Ptae A Joe Varf 41:1103-1107. IMS 41. Fauuim T. Soiuaui I: Pkunl aeotheHcoia Aea Kctmt (Stocks) IU(wppl):2l4-221.1*40 44 SutAtiN 1C JaCUOn O: MAlipnul pleunl uiMnrtetlnna Ropon *t 1 cama 2 Thom Certiorate Sort 71421427, in* 43. Hiuii RM. Iamowu ML. Wmm Al. Th* ndinlnpinl ita non of --Kp-- pleunl manilHliooM Am J Aomttfmoi 104.51-3*. 1*70 44 Caktaiohi O. Rioon C Saviuj L. Almbu T. Matua N. Nam C: PWunl mnnihdioiiir e ilovtp prepnMn cue. Mtano Mot 441300.1107. 1*73 47. Haiwooo TR. OkACtr OR. Yocoo H: PieielnuMnrttflwo'etnio ear- emona el the hta*: * nriau of paraphanl In* cuaar. Am i Clip fathot <3:139-147. 1*7* 41. SOkOaiOH A: Raiinlii0nl hm of Mtae uaaothaioau Eooitoo Km 1)30.114.1*70 4*. Etaa PC Tke patunl Mena* af iUtae orhilnsio. Ip *ofcj*c Mt- Acs of Atbouat Lpoa. Fraace. TV laisuitinnel Apaacjf Far Re- aoarek On Cuear. 1*71. pp. 24A272 50 HtuWAa t TV efnliaiip 1710I0U tttUtm ptaipl piMOtkaHopu. Cancer 13.4*1-704. IMS SI. Norma B TV aaMtothp ryaplnp efiiflM eieUfuea oHaodHliooM. 1 Talbot Banana/ *42*1-297. IMS 51 Roeetra OH. Caw*pph OM: bdbBarlap cyaolop afditae tanka boon. J dm HUm! iiJT7-SO. 1*71 SX Kapincton ft. Wash** 1C Smith M: TV taaeiiM af kialpwla tat ia pleunl iuiia af caaaa aritk iihee pleunl ptaaaiWIioniM tr / EttHtho! 44:1141. IMS 34 Tmomnon ME. Bpomauo FA AM4HTA ft: Adi utopoli'iearkar- ie ieierauMUM. A uaeM adjunei for the dlapaoM of oiaHppau an- auhdiama with eiliaioa. Am 1 Cbo HtM 32.3)3-33*. 1*4* S3. Captou CW. Natloa B. Adi aueopolTMeehafid* oooipoaitioo afear- Snip af 1001 mem S0441A4O IMT 34. Ramumn KN. FAaaaa V: HpaMreed aaU la S4T plaanl ScootJ Kafir Dm 44J4AS7L IMT r. Aaaj H. Emoo M. Sa*ai Y. Yobobava A Sato H. MffraaaiiA M. Konwo K: Hinorkaiaital iM-aiimrloa af kpalanuic adi h a aaaeef pleunl ataaoikeiioaM. Am Kn KmfirDk II14M-70L 1*73 WacmuIC Mumoa* PE. Haaiwotow ft: HjwnrkMieal tanoaa^ boa af kpalureaic adi ia plaanl waoiVtaBM / Mai Raramfaf *471-71. IMS s*. Koaaooowui RA Boaarr Bft I m m aiaeul au Jbal* MV/444143. I*TS 40 Fsmu EA Hakimoaa ML TV 1 aaiia ike iintiEcailMaf aiTikiliMa Ctaaar DJ37-441. IMS I. WaM N: DaeirM aucrana** ia tka 1 ana. Oaoar 11:1044-1034,1*71 41 Kat 1 Savuaaao SO: UVumacanl andaa af 1 aaaothdioM af iV pleun Attk Mi *2j44MJ3. 1*71' 41 Kunm C Ftae acracnn aft sou ioT-1 in. i*n <4 SnnafMia I, Mrru ft . Oocmf H*t 1 lltl-2*!. 1*44 43. Captlmah B. SCVU.T RX. McKiait BU: Cm ranata aftV 1 ckuaaoa Oaoenl lloapiral NE4pf/Ma41*OIS2-lS7,1*74 44. VlTl-ir IK Fapbib/C Ham Rl Bsmim Valp tkrou add eaaa af dn piaan. / TVne CMVau Skat 43il04K l*7S 47. lUumaAN SL Stout AP: MaaoAdioau ia aUMnak CVaar 17Jl*> 344 IM4 B Lioha SR Muooia FM: TVnpaorit appnarkaa ia nalpau mm toikafiaue. Qatar TiaaKee41141 IfTt 4*. ibe plaun. TSonirkiniBd 2UH-1911*74 70. Bamlu K), Maamn W: TV panaatapa af Valia aai anScaau plaun nann anon* padaaae af a diate af ha* ausary moM roniilaiaiina af tV --uj-- plaun nnoiVlieaa aai In ndad uaaianu. joclaiiap reads af a <iap>n|M apkaioaioa af prnanai ion antar. TVnactawBk 22J44-1*!. 1*74 71. SchamaUK M: Ok FniMMaik 4ar chinriiadiea Bakaoitaf in 44 Aaaa Maawhaliaaii 4ar Fkan 4arah naurgpaauuoaUtania. Bctc OurArm 2* 7-211*42- 71 Maitiki N. Bam Ml Burns ES: tataatas kr pkaraeuanr la malipiMt abaiea. CVaar 11.714.7H 1*73 71. SCNWTta O. Hwlt A Opandra I cry difuaa plaural nooon. ^ 74. Brihit WF: Tnainaat afplaanl 1 r 22JM-177.1*74 . IAHA 229:141.1*74 73. EacHwtoa F. SCMUtitoaa M: La i plaunu aalfaia. A pwpaa it 14 o Boar* 34:233-13*. 1*71 74. Smart 1. HodOM KFW: Plaanl 1 , */7Wan3ldlA3Sl 1*37 77. Stbapminoi AL CMM I: I >4fpA naqr nakpaMt pleunl won. Ycjr Octet 14J0-14 1*70 74. RiCMart A ShiIMAk CO: Frokilioail turrrnl lo 4i4Ve ak awhelionn maud wiik "A*. CVaar 12:7** 403.1*3* 7*. BoOAaou* OM. Xiwm KF. MlU *H; Fkanl 1 Rapon of tar aai Am Hoc TMara 7IHMK 1*33 40 Ot Fitrao 1 Oinkam L: SuaeaaaM rpekpknepkiiRlik ranaa ia a cue of diflM pleunl Biaaorkiinaia Tcmori 4*4*-71.1*41 41. Cay FW. Tom BCR: DiFim pleunl aiMiHkiima A amrlral afaua paur follaviac aioaaao nuaaaii Oaatfp. / TVnr OetOmtcm Sect 44:71-77. IMS 42. Kucuuu N. TaoaaA* W. Ezsou Ckaaiaftnapp af ailpua dtttaa --Caaear 17-.I14S-IS74 1*74 (S. Oirnu RE. Mooaa OR CVnorhanop af allpaau aaoOatak _ 30:132-113. I*M Oottuso 1A Baus UC Quaouaha 1M. Luca IK. WamcAa IF Ji Swaovia SO. Wur SR BaowHua A FBsi E HI: 1 pp of aanonaa anlk a rnuikiiirina af aifknpda aai 1 imidazole urPouiuiie. CVaar 30:1412-14111*72 u. Oottliu IA Booar OF. Sonouia JO. Rooauoua V. I MA: Ae dTacdra tco 4-in( coiakinarta ra|hBU (CY-VA-OIC) In (abatneO- hoc Am Amoc CVaar Km IS;!*! 1*74 I*. Iapps N. Flat B tlL TBaom O. Bmio Y: At)amm medMUuoM Mi dnoraram-taMr tnaraiuu af Miauaaianma N toN i Mai 2*l:*M-**7.1*74 17. CoaTU EF. Houano IF. Wamo ft. Soraa LF. Bum J. Sam H. Bank k Oiiocwtu. O: Aaipuadu aai Akkmpaio ia primary aa- taoaaraomA N SogH Net 2719*4-1000.1*74 raf1 ampqm ~ run----- 21 PST000569G DOW 07098