Copyright ERS Journals Ltd 1994European Respiratory JournalISSN 0903 - PDF document

DOI:10.1183/09031936.94.07010186 Copyright ERS Journals Ltd 1994European Respiratory JournalISSN 0903 - 1936 SSerumumourarker , G. Buccheri, A. Biggi ABSTRACT: The association of biological markers with cancer has been recognized nature, secreted by tumour cells. These substances are nor-nature, secreted by tumour cells. These substances are nor-2] defined the potential clinical applications of a tumourmarker. It should: 1) facilitate the early diagnosis of tumour;2) offer a guide for the evaluation of prognosis; 3) help in The TM should at least: 1) possess constant serumand/or urinary levels (no major fluctuation); and 2) be ofpatients with tumour and in normal subjects in order to REVIEW phosphokinase-BB; CT=calcitonin; ED=extensive disease; GRP=gas- SERUMTUMOURMARKERSINLUNGCANCER molecule, the remaining two thirds being carbohydrate [4].1:5 in CEAs derived from different tumours [5]. CEA istrointestinal tract [6]. An elevation of the concentrationnation of factors: increase in the number of cells producingdecreased ability to use normal pathways of excretion fromthe body. The clearance of CEAs is accomplished pri-the body. The clearance of CEAs is accomplished pri-marker are found in patients with liver metastases fromcarcinoma of the colon. Nonmalignant diseases of thecirculating CEA. The level will decrease when the diseasecirculating CEA. The level will decrease when the diseaseCEA was first identified by GOLDand FREEDMAN[10], in1965 as an antigen specific for adenocarcinomas of thedigestive tract. Early studies showed that serum concen-than in nonsmokers [11, 12]. This was suggested to be theserum [12]. CEA might be an indicator of the small pro-cigarette smoke and, thus, to lung diseases [13]. Severalcigarette smoke and, thus, to lung diseases [13]. Severaljaundice [9], ulcerative colitis [16], bronchitis and emphy-sema [11]. These conditions usually produce transient andthat decrease as the condition improves [17]. The list ofthat decrease as the condition improves [17]. The list ofIn a large study, partially supported by autopsy material,VINCENTet al.[23] concluded that the level of CEA in [24Ð29]. A good relationship between CEA levels and(NSCLC) [23, 24, 27, 29]. Generally, CEA levels vary inprecede their clinical recognition. CEA has been studied asprecede their clinical recognition. CEA has been studied asand NSCLC [23Ð25, 27, 32, 33]. Most studies using uni-CEA and prognosis [23Ð25, 27, 28, 30]. Conflicting resultsCEA and prognosis [23Ð25, 27, 28, 30]. Conflicting results32, 34].In conclusion, CEA assays are moderately useful in lungconference of the National Institutes of Health at Bethesdaconference of the National Institutes of Health at BethesdaTissue polypeptide antigenTissue polypeptide a

ntigen (TPA) is a chemically well-defined substance identified by BJ…RKLUNDand BJ…RKLUND[36],in 1957. It consists of four protein subunits (A1,B1, B2, C) with molecular weights between 20,000Ð45,000Da. The main subunit B1, has been found in foetal tissuesat 10, 17, and 24 weeks [37], and with higher concentration[38]. Increased serum levels of TPA may be present in sev-[39], acute hepatitis [40], pregnancy (with particularly high[39], acute hepatitis [40], pregnancy (with particularly high)autoimmune disorders [43]. High levels of TPA have beenreported in serum and urine of patients with several tumours,lymphoma [44]. TPA is synthesized during the S- to M-the blood stream [45]. Thus, the concentration of the anti-the blood stream [45]. Thus, the concentration of the anti-markers (carbohydrate antigenic determinant 19-9 (CA-19-9), CEA, neuron-specific enolase (NSE), squamous cell(66% and 82%, respectively). Incidentally, this value wasthe highest observed by the authors. In lung cancer patients,the pretreatment serum levels of TPA have been shown, bythe classification into 4 stages of disease [24, 47Ð52]. Inelevated the serum concentration of the marker [48]. Post-elevated the serum concentration of the marker [48]. Post-Table 1. Ð List of reviewed tumour markers in 188 precede them [48] (fig. 1 and table 2). TPA may also beprecede them [48] (fig. 1 and table 2). TPA may also be53]. GRONOWITZet al.[34] evaluated five tumour markers(i.e. lactate dehydrogenase (LDH), CEA, serum thymidinekinase (S-TK), NSE and TPA) for assessment of prognosisin 125 patients with SCLC. Tissue polypeptide antigenwas found to be the most powerful independent prognosticdeterminant. In a study of 563 untreated patients with marker are very often associated with shortened survival. Insurvival predictor. Both univariate and multivariate analy-[54). In a more recent study [32], focusing on 360 patientsBUCCHERI S.G.,M.C.,, large cell carcinoma, CT    12345671234567Pattern APattern C Surgery         3691821242730333624681012141618Pattern BPattern DTPA Uá Table 2. Ð Relationships between changes in disease statusHistologyABCDn%n%n%n%Squamous cell carcinoma17212633563240Adenocarcinoma32732719436Small cell carcinoma828144851727Large cell carcinoma1785317533Total29215138129433235%. As in figure 1, consistentmodifications in TPA profiles were grouped on the basis of whetherchanges, or were totally absent (Pattern D). (From [48]). Fig. 1. Ð Paradigmatic patterns of serial tissue polypetide antigen (TPA) measurements in four patients. Concordant changes A), be concurrent with (Pattern B) or follow (Pattern C) the clinical recognition of disease status change (PD). In the last eof TPA after disease progression. CT: chemo

therapy; RT: radiation therapy ; CR: complete response; MR: minor regression; PD: progressive disease. (From the uterine cervix [55Ð57]. Elevated serum SCC-ag levelsthe uterine cervix [55Ð57]. Elevated serum SCC-ag levelsIn 1988, MINOet al.[59] found high serum levels ofSCC-ag in 59% of 76 patients with SCC of the lung, and inonly 20% of patients with other cell types. The mean lev-els of the marker was 3.6 times higher in patients withSCC of the lung, than in healthy subjects and patients suf-diseases. Preliminary data suggest that serum SCC-ag maybe useful in evaluating therapeutic effectiveness in SCC. In SERUMTUMOURMARKERSINLUNGCANCER cells [77]. This property has stimulated the recent renewalof interest in immunotherapy of cancer [78]. IL-2 actsupon a specific surface receptor [IL-2R], absent in resting Tcells but appearing within hours of activation [79]. Activatedcapability of binding the lymphokine [80]. Serum levels ofcapability of binding the lymphokine [80]. Serum levels of82], sarcoidosis [83], Grave's disease [84], organ transplants[85, 86], lymphoproliferative disorders [87, 88], and solidtumours [89, 90].. [91] reported increased levels of sIL-2R inserum samples of patients with untreated lung cancer. Inserum samples of patients with untreated lung cancer. InRecently, our group performed 326 sIL-2R serum assays inbenign disease, and 63 healthy volunteers [92]. We founddisease. Pretreatment sIL-2R correlated neither with thestage of disease nor with the cell type [92]. On the contrary,a shortened survival [92]. Ga shortened survival [92]. Gpatients with lung cancer (squamous cell carcinoma (SCC)or adenocarcinoma (AC)) have high values of sIL-2R. Incorrelate with the extent of the disease, as in our study. Indisease. In fact, the highest levels were found in patientsChromogranin A is a 68,000 Da protein, that has beentumours [94, 95]. O'C[96]observedtumours. N a recent study on 291 patients (129 with SCLC and 162with NSCLC, including 36 with SCC), Bwith NSCLC, including 36 with SCC), Bmeasured both CEA and SCC-ag, and reached the followingconclusions: 1) the use of SCC-ag is inappropriate fordisease; 3) SCC-ag serum levels, in contrast to CEA, arenot determined by smoking habits; 4) SCC-ag has lowersensitivity but higher specificity than CEA in SCC; and 5)nosis. Another study by Mnosis. Another study by Mthese results.Other polypeptide antigensFerritinFerritin is an iron-storage protein with a molecular weightof approximately 450,000 Da. Trace amounts of ferritin areof approximately 450,000 Da. Trace amounts of ferritin areFerritin is present in high concentration in the cytoplasmof reticuloendothelial cells, liver cells, spleen cells, anddeveloping precursors of red cells in bone marrow. Extrac

ts[62Ð64]. Increased ferritin concentration in the serum or in[62Ð64]. Increased ferritin concentration in the serum or inmultiple myeloma [68], breast cancer [69], and testicular can-cer [70]. Several mechanisms are responsible for thecer [70]. Several mechanisms are responsible for the[72], and hepatocellular necrosis caused by liver metas-tases.Conflicting results have been obtained concerning thepossible clinical utility of this substance in lung cancer.GROPPet al. [73], demonstrated that ferritin levels weresignificantly higher in metastatic disease, irrespective of thehistological type. In their study, serial measurements of fer-histological type. In their study, serial measurements of fer-considerably higher in 39 SCLC patients than in normal indi-viduals, but no relationship was found with the diseaseextent and the clinical course. In the same study, patientslonger median survival time. From 1988 until 1990, weserum ferritin in lung cancer patients [75, 76]. The com-concentrations of CEA and TPA, was studied. We were,serum levels of ferritin and histological type, clinical stageof disease, or response to treatment. Patients with ferritin[74]. In addition, ferritin was selected as an independent 190 AIDet al. [95] failed todemonstrate any positive histochemical reaction in 12 casesof SCLC [35]. SSpatients with SCLC: 52% of those patients with limiteddisease (LD) and 72% of those with extensive disease (ED)had elevated levels of chromogranin A. In the same study,had elevated levels of chromogranin A. In the same study,EnzymesNeuron-specific enolaseEnolase molecules in mammalian tissues are dimers com-posed of three immunologically distinct subunits [98, 99].The subunit of enolase (-enolase) is widely distributed invarious tissues. The in the heart and other striated muscles. The cells [100], and in neurogenic tumours [101, 102]. Signi-cells [100], and in neurogenic tumours [101, 102]. Signi-[105]. Recently, H. [106] have found patients with bronchogenic carcinoma. Elevated serum70% of 450 cumulated patients with SCLC [107Ð112], and70% of 450 cumulated patients with SCLC [107Ð112], andHigh pretreatment values of NSE were noted in 38Ð71% of(table 3) [107Ð112]. Like few other markers, NSE levelsagain during tumour progression or relapse. Sequentialdetection of relapse [109, 111]. Daily serum determinationsof NSE, performed immediately before and after cytotoxicBUCCHERI lower or normal values [110, 112, 113]. Several reportshave assessed the prognostic capability of NSE. A signi-has been found at univariate analysis [30, 34, 114Ð116].has been found at univariate analysis [30, 34, 114Ð116].RONOWITZet al. [34], using multivariateanalyses.Recently, VIALLARDet al. [117] suggested that theNSE/nonneuronal enolase (N

NE) ratio increases the abilityof the test to separate SCLC from NSCLC patients. In fact,the NSE/NNE ratio misclassified only three out of 57NSCLC (5.3% of false positive). Its sensitivity was 76respectively). This index could represent a better approach[118] found abnormal concentra-growing in tissue culture. Creatine phosphokinase is andiphosphate (ADP). CPK levels are 10Ð100 times higher in[119]. Interestingly, "variant" SCLC cell lines that lose[120]. In two recent clinical studies, CPK-BB was elevat-but in only 2% of patients with LD [118, 121]. A directlation with survival were also described [118, 121]. Blation with survival were also described [118, 121]. BCPK-BB, 82 and 50% in untreated SCLC patients withED and LD, respectively. High concentrations of the isoen-between meningeal spread and parenchymal cerebral metas-between meningeal spread and parenchymal cerebral metas-GlycosyltransferasesThe glycosyltransferases constitute a group of enzymeswhich catalyses the transfer of individual sugars fromnucleotide-sugar precursor molecules into appropriate accep-tors [124]. An increase in serum glycosyltransferase activ-tors [124]. An increase in serum glycosyltransferase activ-The a-(1-3)-L-fucosyltransferase is one of the glycosyl-transferases thought to be responsible for the synthesis oftumour-associated antigens [128Ð130]. The accumulation ofsera of patients with lung cancer [131Ð133]. Recently,sera of patients with lung cancer [131Ð133]. Recently,()L-fucosyltransferase. They observed higher serum levels of Table 3. Ð Raised levels of NSE in serum of untreat-Study [Ref. No.]LDED[107]15/3849/56[108]6/1324/27[109]25/3834/39[110]34/4854/55.[111]23/3945/54[112]6/1622/27LD: limited disease; ED: extensive disease. SERUMTUMOURMARKERSINLUNGCANCER the enzyme in patients with lung cancer, compared topatients with benign pulmonary diseases and healthy controls.with the clinical stage and with the size of the primaryity among the histological types [134]. Follow-up studiesdisease [134]. The utility of the enzyme as a diagnosticdisease [134]. The utility of the enzyme as a diagnosticHormonesBombesin/gastrin releasing peptideBombesin (BN) is an amphibian skin peptide of 14 aminoacids [135]. Gastrin releasing peptide (GRP), the mam-able to release gastrointestinal hormones [136]. Cellsregularly found in the foetal and infantile epithelium ofthe lung [137]. A bombesin-like immunoreactivity hasnerves, and neuroendocrine bronchial cells [136, 138, 139].[140], which has a growth promoting activity in SCLC[141]. Unfortunately, increased concentrations of GRP in theserum are rare, because of the very short half-life [142Ð144].serum increase [139]. Recently, a radioimmunoassay for a72% of 71 SCLC patients [145]. In a study by

P72% of 71 SCLC patients [145]. In a study by Ped in the fluid of patients with meningeal carcinomatosisfrom SCLC, independent of a positive cytology. Combiningtion rate of patients with central nervous system (CNS)metastases to 67%. Importantly, 93% of patients with in-creased BN or calcitonin had CNS metastases. However,with regard to meningeal carcinomatosis, BN alone waswith regard to meningeal carcinomatosis, BN alone wasAdrenocorticotropic hormone and related moleculesEctopic secretion of adrenocorticotropic hormone (ACTH)was initially observed in 1928 by BROWN[147] in a patientwith Cushing's syndrome and small cell carcinoma of thelung (SCLC). Ectopic ACTH production has been describedthymoma, islet cell cancer of the pancreas, medullary cancerthymoma, islet cell cancer of the pancreas, medullary cancerElevated serum levels of ACTH have been reported in25Ð30% of patients with SCLC [150Ð152]. The clinical pic- out obesity, striae and osteoporosis. Its frequency ranged[153Ð157]. Conflicting results have been reported con-vival of patients with lung cancer [150, 151, 155, 158].adeno- and small cell type [159]. A significant differencetumour [159]. The NHcancer in 1938 [160]. In 1957, Scancer in 1938 [160]. In 1957, Stulated inappropriate secretion of vasopressin, also known asantidiuretic hormone (ADH), as the cause of persistenthyponatraemia in two patients with bronchogenic carcinoma.Subsequently, GEORGEet al. [162] demonstrated in vitroin vitroInappropriate ADH secretion has been demonstrated inSCLC patients, with rates depending on the method used forthe hormone identification [164]. The concentration ofthe hormone identification [164]. The concentration ofdrome was quite low (approximately 10% of 596 patients insix different studies [153Ð157, 169]). Elevated serum levelssix different studies [153Ð157, 169]). Elevated serum levelswith the response to treatment [158]. Tumour-producedADH may be bound to neurophysin, as in the posteriorADH may be bound to neurophysin, as in the posteriortrations of ADH-neurophysin were elevated in 65% of 103patients with SCLC. In patients with initially high values,patients with SCLC. In patients with initially high values,CalcitoninCalcitonin (CT) is a 32 amino acid peptide, with a mol-ecular weight of 3,419 Da synthesized by the thyroid C cells[171]. Normally, CT is secreted by the thyroid in responsethe stimulation of certain gastrointestinal hormones. The BUCCHERI hormone inhibits the release of calcium and phosphate fromhormone inhibits the release of calcium and phosphate fromMarked elevations of serum calcitonin are usually foundin familial medullary thyroid carcinoma [173]. Elevated lev-in familial medullary thyroid carcinoma [173]. Elevated lev-Calcitonin was elevated

in 59% of 425 SCLC patients[151, 175Ð180]. Elevated concentrations are rare in othertypes of lung cancer [177, 181]. Serum concentrations ofand in only 56% of 71 patients with LD [151, 175, 181].Conflicting reports about the use of calcitonin in monitoringtreatment response have so far been published. Wtreatment response have so far been published. Wpatients responding to chemotherapy, and an increase inprogressive diseases. Mprogressive diseases. Mtrary, showed no such effect.In conclusion, the assay of serum calcitonin seems tobe a general indicator of the course of SCLC disease, but itis not sufficiently reliable for evaluating the response totreatment.Insulin-like growth factorsThe insulin-like growth factors [IGF], or somatomedin, arepolypeptides of about 7.5 kDa, having a structural similar-ity to pro-insulin [183]. Insulin-like growth factors I and II(IGF-I, IGF-II) share a 62% sequence homology. Theircharacteristics [184, 185]. IGF-I is mitogenic for both clas-characteristics [184, 185]. IGF-I is mitogenic for both clas-IGF-I may be an autocrine growth factor for human SCLC.There are contrasting reports concerning the utility ofIGF as a tumour marker. MMserum IGF-I concentrations in 42 SCLC patients, and con-cluded that IGF-I levels do not correlate with the tumourbulk, or with the therapeutic responsiveness of SCLC.REEVEet alet althe serum of patients with both SCLC and NSCLC, and acourse. Further studies are needed for a better evaluation ofcourse. Further studies are needed for a better evaluation ofIts devastating incidence and clinical seriousness have stim-ulated innumerable research studies, with any possibleapproach.Historically, NSCLC and SCLC were considered to havedifferent origins (ectodermal and endodermal, respectively),thus, accounting for the many differences observed in theirclinical behaviour. However, in more recent years, it has and NSCLC. Several data suggest a common stem for allcers reveals that about 15% of SCLC tumours containsNSCLC subtypes. In 13Ð28% of autopsy specimens fromhistology was proved [190Ð194]. Thistology was proved [190Ð194]. Treported that changes of the culture medium may, in somecases, induce chances in SCLC morphology from smallcell to squamous cell and vice versa. The expression of. The expression ofThe above data on the clonal heterogeneity of lungcancer may explain the several limitations in the clinical useof serum tumour markers. Indeed, none of the serum com-of lung cancer. The most fruitful application at present ismonitoring of tumour activity. During active therapy, atreatment. Earlier detection of relapse may allow a modi-NSCLC; NSE, BN/GRP and CPK-BB in SCLC patients.NSCLC; NSE, BN/GRP and CPK-BB in SCLC patients.to new therapeutic strategies for each tum

our histotype.Acknowledgements: The authors thank A. Cerchietti for1.Coombes RC, Neville AM. Ð Significance of tumor-index2.Coombes RC, Powels TJ. Ð Tumour markers in the man-3.Coligan JE, Henkart PA, Todd CW, Terry W. Ð Hetero-geneity of the carcinoembryonic antigen. 4.Pritchard DG, Todd CW. Ð The chemistry of carcino-Immuno- diagnosis of Cancer. New York, Marcel Dekker,5.Banjo C, Shuster J, Gold P. Ð Intermolecular heterogene-6.Go VLW, Ammon HW, Holtermuller KH, . Ð Quan-7.Thomas P, Zamcheck N. Ð Role of the liver in clearance SERUMTUMOURMARKERSINLUNGCANCER 28.Sculier JP, Feld R, Evans WK, . Ð Carcinoembryonic29.Goslin RH, Skarin AT, Zamcheck N. Ð Carcinoembryonic30.Ferrigno D, Buccheri GF, Cecchini C, Marchetti G. Ð31.Laberge F, Fritsche H, Umsawasdi T, Carr DT, . Ð32.Buccheri GF, Ferrigno D, Vola F. Ð Carcinoembryonicantigen (CEA), tissue polypeptide antigen (TPA), and other33.Dent PB, McCulloch PB, Wesley-James O, . Ð34.Gronowitz JS, Bergstrom R, Nou E, Pahalmam S, et al. Ðsmall cell lung cancer. A multivariate analysis. 35.N.H.I. Ð Carcinoembryonic antigen: its role as a marker in36.Bjšrklund B, Bjšrklund V. Ð Antigenicity of pooled37.Luning B, Redelius P, Wiklund B, Bjšrklund B. ÐBiological Fluids. Oxford, Pergamon Press, 1976; p.513.38.Bjšrklund B. Ð Tissue Polypeptide antigen (TPA). 39.Lundstršm R, Bjšrklund B, Eklund G. Ð A tissue derived-: Bjšrklund B40.Sylvan S. Ð TPA in acute hepatitis. Hogman A, eds. Laboratory Testing in Cancer. Stockholm,41.Bjšrklund B, Bjšrklund V, Wiklund B, . Ð A human: Bjšrklund B, eds. Immunological technique for Detectionof Cancer. Stockholm, Folksam, 1973; p. 133.42.Oehr P, Bellmann O, Hamann D. Ð Measurement of ten-43.Ruibal A, Clotet B, Pigrau C, . Ð Tissue Polypeptide44.Menendez-Botet CJ, Oettgen HF, Pinsky CM, SchwartzMK. Ð A preliminary evaluation of tissue polypeptidebenign neoplasm. 45.Bjšrklund B, Bjšrklund V. Ð Specificity and basis of 8.Moore TL, Ohar P, Zamcheck N, . Ð Carcino-embry-onic antigen(s) in liver disease: I. Clinical and morphological9.Lurie BB, Loewenstein MS, Zamcheck N. Ð Elevated10.Gold P, Freedman SO. Ð Demonstration of tumor-11.Hansen HJ, Snyder LJ, Miller E, Ð Carcinoembry-12.Clarke C, Hine HR, Dykes PW, Whitehead TP, WhitfieldAGW. Ð Carcinoembryonic antigen and smoking. 13.Merril WW, Goodman M, Matthay RA, Naegel GP, Ð Quantitation of carcinoembryonic antigen in lung lining14.Khoo SK, Warner NL, Lie JT, . Ð Carcinoembry-onicantigen activity of tissue extracts: a quantitative study of15. Khoo SK, MacKay IR. Ð Carcinoembryonic antigen in16.Gardner RC, Feinerman AE, Kantrowitz PA, . Ð17.Loewenstein MS, Zamcheck N. Ð Carcinoembryonic anti-18.Stewart AM, Nixon D, Zamcheck N, . Ð Carcino-19.Seppala M,

Pihko H, Ruoslahti E. Ð Carcinoembryonic20.Orjasaeter H, Fossa SD, Schjolseth SA, . Ð Carcino-21.Rimsten A, Adami HO, Wahren B. Ð Carcinoembryonic22.Moore TH, Kupchik HZ, Marcon N, . Ð Carcino-23.Vincent RG, Chu TM, Fargen TB, Ostrander M. Ð24.Buccheri GF, Violante B, Sartoris AM, Ferrigno D, . ÐClinical value of a multiple biomarker assay in patients25.Muller T, Marshall RJ, Cooper EH, . Ð The role of26.Rasmuson T, Bjork GR, Dambe L, . Ð Tumor mark-27.Concannon JP, Dalbow MH, Hodgson SE, et al. Ð 194 46.Mizushima Y, Hirata H, Izumi S, . Ð Clinical signif-47.Buccheri GF, Ferrigno D, Sartoris AM, . Ð Tumormarkers in bronchogenic carcinoma. Superiority of tissue48.Buccheri GF, Ferrigno O. Ð Usefulness of tissue polypep-tide antigen in staging, monitoring, and prognosis of lung49.De Angelis G, Cipri A, Fiori F, Munno R, Pau F, PigoriniF. Ð Valutazione dei titoli plasmatici dell'antigene carci-50.Luthgens M, Schlegel G. Ð Verlaufskontrolle bei bronchial-51.Schultek T, Wood WG. Ð Tissue polypeptide antigen52.Pau F, De Angelis G, Antilli A, . Ð Valore prognos-53.Volpino P, Cangemi V, Caputo V,. Ð Clinical use-54.Buccheri GF, Ferrigno D. Ð Prognostic value of the tissue. Ð Tumor-antigen TA-56.Senekjian EK, Young JM, Weiser PA, . Ð An evalu-57.Crombach G, Wurz H, Kreienberg R, . Ð Evaluation58.Kato H, Miyauchi M, Morioka M, . Ð Tumor antigenof human cervical squamous carcinoma. Correlation of59.Mino M, Ho A, Hamamoto K. Ð Availability of Tumor-60.Body JJ, Sculier JP, Raymakers N, . Ð Evaluation of61.Clichton RR. Ð Ferritin: structure, synthesis and func-62.Aungst CW. Ð Ferritin in body fluids. 63.Drysdale JW, Kohgo Y, Watanabe N. Ð Radioimmuno-64.Halliday JW, Powell LW. Ð Serum ferritin and isoferritin65.Jacobs A, Slater A, Whittaker JA, et al. Ð Serum ferritinBUCCHERI 66.Matzner Y, Konijn AM, Hershko C. Ð Serum ferritin in67.Parry DH, Worwood M, Jacobs A. Ð Serum ferritin in68.Patel R, Shan PC, Vohra RM, . Ð Serum ferritin lev-69.Jacobs A, Jones B, Ricketts C, Bulbrook RD, Wang DY. Ð70.Wahren B, Alpert E, Esposti B. Ð Multiple antigens as71.Hershko C, Konjin AM. Ð Pathogenesis of impaired iron: Brow E, ed. Proteins ofIron Metabolism. Philadelphia, Grune & Stratton, 1977; pp.72.White GP, Worwood M, Parry D. Ð Ferritin synthesis in73.Gropp C, Havemann K, Lehmann FG. Ð Carcinoembry-and during therapy. 74.Cox R, Gyde OH, Leyland MJ. Ð Serum ferritin levels in1986; 22:75.Ferrigno D, Buccheri GF. Ð Serum ferritin levels in lung76.Ferrigno D, Buccheri GF. Ð Comprehensive evaluation ofLung Cancer77.Dinarello CA, Mier JW. Ð Lymphokines. 78.Oliver RTD. Ð The clinical potential of interleukin-2. 79.Waldmann TA. Ð The structure, function, and expres-80.Rubin LA, Jay G,

Nelson DL. Ð The released interleukin-81.Muller C, Knoflach P, Zielinski C. Ð Soluble interleukin-82.Kloster BE, John PA, Miller LE, . Ð Soluble inter-83.Semenzato G, Cipriani A, Trentin L, . Ð High serum84.Nakanishi K, Taniguchi Y. Ð Increased levels of solubleinterleukin-2 receptors in Grave's disease. Proceeding of the85.Colvin RB, Fuller TC, MacKenn L, Kung PC, IP SH,Cosimi AB. Ð Plasma interleukin-2 receptor levels in86.Stole V, Krause JR. Ð Interleukin-2 receptor levels aretions. 87.Wagner DK, Kiwanuka J, Brenda K, Rubin LA, Nelson DL,Magrath IT. Ð Soluble interleukin-2 receptor levels inpatients with undifferentiated and lymphoblastic lymphomas:88.Chilosi M, Pizzolo G, Semenzato G, Cetto G. Ð Detection SERUMTUMOURMARKERSINLUNGCANCER to therapy of small cell lung cancer. 108.Ariyoshi Y, Kato K, Ishiguro Y, Sato T, Suchi T. Ð109.Cooper EH, Splinter TAW, Broun DA,. Ð EvaluationS. Ð Neuron specific enolase: a useful diagnostic serum111.Johnson DH, Marangos PJ, Forbes JT . Ð Potentialutility of serum neuron-specific enolase levels in small cellHerman DP. Ð Serum neuron specific-enolase. A markerfor disease extent and response to therapy for small cell lung113.Splinter TAW, Cooper EH, Kho GS, Oosterom R, PeakeMO. Ð Neuron-specific enolase as a guide to the treatmentof small cell lung cancer. 114.Jorgensen LG, Hirsh FR, Osterlind K, Cooper EH, LarssonLI. Ð Occurrence of neuron-specific enolase in tumour tis-. Ð Neuron-specific116.Jaques G, Bepler G, Holle R, . Ð Prognostic value ofÐ Enzymatic determination of serum neuron-specific enolasein small cell lung cancers. Utility of the serum neuron-118.Gazdar AF, Zweig MH, Carney DN, Van Steirteghen AC,Baylin SB, Minna JD. Ð Levels of creatine Kinase and itsWeynants P, Humblet Y, Canon JL, Symann M. Ð120.Gazdar AF, Carney DN, Nau MM, Minna JD. Ð Char-121.Carney DN, Zweig MH, Ihde DC, Cohen MH, MaKuchRW, Gazdar AF. Ð Elevated serum creatine Kinase BB122.Bork E, Hansen M, Urdal P, . Ð Early detection of123.Pedersen AG, Bach FW, Nissen M, Bach F. Ð Creatine124.Spiro RG. Ð Glycoproteins. 125.Podolsky DK, Weiser MM. Ð Galactosyltransferase 89.Rovelli F, Lissoni P, Crispino S, . Ð Increased levels90.Lissoni B, Barni S, Rovelli F, . Ð The biologic sig-91.Marino P, Cugno M, Preatoni A, . Ð Increased levels92.Buccheri GF, Marino P, Preatoni A, Ferrigno D, Moroni G.Ð Soluble interleukin-2 receptor in lung cancer: an indirect93.Ginns LC, De Hoyos A, Brown MC, Gaumond BR. Ð94.NaKajama T, Shimosato Y, Morinaga S, . Ð Immuno-95.Said JW, Vimadalal S, Nash G. Ð Immunoreactive neuron-96.O'Connor OT, Deftos LJ. Ð Secretion of chromogranin A97.Sobol RE, O'Connor DT, Addison J, Suchocki K, RoystonI, Deftos LJ. Ð Elevated serum chromogranin A con

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nkshaw OF. Ð Chloride depletion inconditions other than Addison's disease. 17: 1Ð6.Schwartz WB, Bennet W, Curelop S, . Ð A syndrome162.George JM, Capen CC, Phillips S. Ð Biosynthesis ofcarcinoma. Patient with the syndrome of inappropriate163.Ewing HP, Newsom BD, Hardy JD. Ð Tumor markers.164.Hansen M. Ð Clinical implications of ectopic hormone 197 165.Greco AF, Hainsworth J, Sismann A. Ð Hormone pro-Oldham RK, Bunn PA eds. Small Cell Lung Cancer. NewGropp C, Luster W, Havemann K, Lehmann FG. ÐUhlenbruk G, Wintzer G, eds. CEA und andera Tumor-Haefliger JM, Dubied MC, Vallotou MB. Ð Excretion jour-168.North WG, Maurer H, Valtin H, O'Domell JF. Ð Human169.Hainsworth JD, Workmann R, Greco FA. Ð Management170.Maurer LH, O'Domell JF, Kennedy S, . Ð Humanneurophysins in carcinoma of the lung: relation to histology,disease state, response rate, survival, and syndrome of inap-propriate anti-diuretic hormone secretion. 171.Dilley WG, Wells SA, Cooper CW. Ð Calcitonin radio-: Rose NR, Friedman H, eds. Manual of172.Heynen G, Franchimont P. Ð Human calcitonin radio-173.De Lellis RA, Rule AH, Spiler I,. Ð Calcitonin and174.Coombes RC, Greenberg PB, Hillyard C, . ÐPlasma. Ð Calcitonin in. Ð Plasma calcitoninlung cancer. 177.Luster W, Gropp C, Sostmann H,. Ð Demonstration178.McKenzie CG, Evans IMA, Hillyard CJ, . Ð Bio-. Ð Correlation of180.Wallach SR, Royston I, Taetle R,. Ð Plasma calci-. Ð PlasmaJ Clin Endocrinol. Ð Value of serum calcitonin estimation in clinical oncology.Humbel RE. Ð Insulin-like growth factors, somato-medins,184.Ullrich A, Gray A, Tam AW, . Ð Insulin-like growth185.Morgan OD, Edman JC, Standring DN, . Ð Insulin-186.Macauly VM, Teale JD, Everard MJ, Joshi GP, Millar JL.Ð Somatomedin-C/insulin-like growth factor-I is a mitogen187.Macauly VM, Teale JD, Everard MJ, Joshi GP, Millar JL,Smith IE. Ð Serum insulin-like growth factor-I levels inReeve JG, Payne JA, Bleehen NM. Ð Production of189.Crofton J. Ð Tobacco and third world. 190.Hirsch FR, Ottesen G, Podenphant J, Olsen J. Ð Tumorheterogeneity in lung cancer based on light microscopicfeatures. A retrospective study of a consecutives series of191.Matthewes MJ. Ð Effects of therapy on the morphologyand behaviour of small cell carcinoma of the lung. A: Muggia F, Rozenweig M,Ð Mixed anaplastic small cell and squamous cell carcinomaof the lung. 193.Abeloff MD, Eggleston JC, Mendelsohn G, Ettinger DS,Baylin SB. Ð Changes in morphologic and biochemicalSehested M, Hirsch FR, Osterlind K, Olsen JE. ÐMorphologic variations of small cell lung cancer. A. Ð Reversible196.Carney DN, Gazdar AF, Bepler G, et al. Ð Establishment197.Gazdar AF, Carney DN, Nau M, Minna JD. Ð Character-. Ð Staging andSERUMTUMOURMARKERSINLU