REFERENCES 16. Uren NO. Crake T, Leffery DC, Silva R, Gavies GJ, Maseri A. Reduced coronary 1. Goldstein JL. Dana SE, Brunschede GY, Brown MS. Genetic heterogeneity in familial vasodilator function in infarcted and normal myocardium after myocardial infarction. N Engl J Med 1994;331:222-227. hypercholesterolemia: evidence for two different mutations affecting functions of low-density lipoprotein receptor. Proc Nail Acad Sci USA 1975:72:1092-1096. 17. Cohen RA, Zitnay KM, Haudenshild CC, Cunningham LD. Loss of selective 2. Mabuchi H, Tanami R. Haba T, et al. Cause of death in patients with familial endothelial cell vasoactive functions caused by hypercholesterolemia in pig coronary hypercholesterolemia. Atherosclerosis 1986:61:1-6. arteries. Circ Res 1988;63:903-910. 3. Mabuchi H, Koizumi J, Shimizu M, Takeda R, Hokuriku FH, CHD Study Group. 18. Osbome JA, Siegman MJ, Sedar AW, Mooers SU, Lefer AM. Lack of endothelium- Development of coronary heart disease in familial hypercholesterolemia. Circulation dependent relaxation in coronary resistance arteries of cholesterol-fed rabbits. Am J 1989:89:225-232. Physio/ I989;256:C591-C597. 4. Heiberg A. The risk of atherosclerotic vascular disease in subjects with xanthomatosis. 19. Drexler H, Zeiher AM, Meinzer K. Just H. Correction of endothelial dysfunction in Acta MedScand 1975:198:249-261. coronary microcirculation of hypercholesterolemic patients by L-arginine. Lancet 1991:338:1546-1549. 5. Beaumont V. Jacotot B, Beaumont JL. Ischemie disease in men and women with familial hypercholesterolemia and xanthomatosis: a comparative study of genetic and 20. Zeiher AM, Drexler H, Wollschlaeger H, Just H. Modulation of coronary vasomotor environmental factors in 274 heterozygous cases. Atherosclerosis 1976;24:441-450. tone in humans. Progressive endothelial dysfunction with different early stages of 6. Jensen J. Blankenhom DH, Kornerup V. 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Improvement of Radiation Treatment Planning in Squamous-Cell Head and Neck Cancer by Immuno-SPECT
IrenäusA. Adamietz, Richard P. Baum, Frank Schemman, Andreas Niesen, Rainald Knecht, Frank Sarán,Sophia Tieku, Graeme R. Boniface, Gustav Hörand Heinz D. Böttcher Departments of Radiotherapy, Nuclear Medicine and Otorhinolaryngology, Johann Wolfgang Goethe University Medical Center, Frankfurt/Main, Germany; and Biomira Ine, Edmonton, Canada
patients (7.5%), the treatment volume had to be extended. The Previous studies have shown high accuracy for immunoscintigraphy with 99mTc-MAb-174 in patients with squamous-cell carcinoma of therapeutic strategy for seven patients (17.5%) had to be changed due to the detection of metastatic disease beyond the head and the head and neck region compared to CT and MRI. We conducted neck region. RIS of patients with squamous-cell cancers of the head a prospective study to determine if immunoscintigraphy provides and neck region with ""Tc MAb-174H0.64 enabled the detection of additional diagnostic information for radiation treatment planning. tumors that were not depicted by other conventional diagnostic Methods: Radioimmunoscintigraphy (RIS) was performed on 40 imaging procedures. Conclusion: The use of RIS in radiation treat patients (planar, whole-body, SPECT) with histologically confirmed ment planning of advanced tumors of the head and neck region squamous-cell carcinoma (30 primary tumors, 10 recurrences) after injection of the 99mTc(1.1 GBq) labeled monoclonal anti-squamous- appears to yield important diagnostic information that may alter patient management. cell cancer antibody 174H0.64 (murine lgG1). Results were com bined with information obtained by clinical examination, sonogra- Key Words: radiation treatment planning; radioimmunoscintigra- phy, panendoscopy and x-ray CT. The strategy for radiation phy; technetium-99m-labeled monoclonal antibodies; SPECT; head treatment and the required treatment volumes were defined with and neck neoplasms and without immunoscintigraphical findings. Results: Additional J NucÃMed 1996; 37:1942-1946 diagnostically relevant information from RIS was obtained from 10 patients (25%) with advanced tumors or recurrences. In three dancer of the head and neck is a relatively rare form of malignancy, consisting of less than 5% of all human cancers in Received Aug. 29. 1995: revision accepted Apr. 17, 1996. the U.S. (1). Over 90% of these tumors are squamous-cell For correspondence or reprints contact: IrenäusA. Adamietz, MD, Department of Radiotherapy, University Medical Center, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, carcinomas (SCCs) of epithelial origin (2). SCCs of the head Germany. and neck grow in a locally invasive manner and tend to
1942 THEJOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 12 •December 1996 metastasize to the regional lymph nodes rather than spread TABLE 1 hematogenously to distant sites (3). Site of Primary Tumor and TNM Classification The potential to control SCCs confined to the primary site, LocationOral either by surgery or radiotherapy, is excellent. However, once spread to regional lymph nodes has occurred, the cure rate drops andbasecavity to nearly half. Thus the most important prognostic factor in tongueOropharynxHypopharynxLarynxRecurrentof patients with head and neck SCCs is the status of the neck nodes M. The clinical detection of regional lymph node métastasesis based on palpation, with increased size and firmer than normal lymphnode métastasesTotalT16————6T2621——9T33——1—4T4113—1—15TX————66Total26512640 consistency and/or reduced mobility being risk factors of metastatic involvement. High-resolution CT and MRI are supe rior to palpation, provided that strict interpretive criteria are pharynx (n = 1). Lymph node métastaseswere treated in six used. However, there is still significant room for improvement in the staging of neck lymph nodes (5-13). patients (Table 1). Immunoscintigraphy was performed in all We have previously reported the development of a murine patients in addition to clinical examination, panendoscopy, sonog IgGl monoclonal antibody 174H.64 (MAb-174) which recog raphy and CT. nizes a unique 57,000 dalton cytoskeletal protein, thought to be Monoclonal Antibody Mab-174 a cytokeratin, associated with SCC (14). In immunohistochem- Mab-174 was produced from ascites fluid by injecting hybrid- ical studies, strong staining was demonstrated with MAb-174 to oma 174H.64 cells (2 X IO5)i.p. into pristane-primed Balb/c mice. all SCC tissue, irrespective of the site of origin, and to the basal The mice were bred and housed under VAF conditions. Ascites (stem) cells of mammalian stratified squamous epithelia. Reac were harvested from each mouse 14 days postinjection (p.i.) by tivity of MAb-174 to other normal tissue was restricted to sterile peritoneal lavage and pooled. The antibody containing moderate staining of myoepithelial cells of the breast ducts. ascites was diluted with 25 mM N-Morpholinoethanesulphonic Recently, the use of 99mTc-labeled intact monoclonal anti acid (MES), pH 4.0, centrifuged at 1000 X g and filtered through bodies has been shown to be of diagnostic utility in several a 0.22-/j,m culture capsule. malignant conditions (15,16). Initial clinical studies with 99mTc- The antibody was then purified by a multistep purification labeled Mab-174 had encouraging results in the detection of process including, hydrophobic/ionic exchange preparative HPLC lymph node métastasesfrom SCC of the head and neck (17), (Bakerbond ABx, 22 X 250 mm) and size-exclusion preparative which have recently been confirmed by other investigators (18). HPLC (TSK 3000GW, 2.1 X 60 cm) under sterile laminar flow Radiation treatment planning of the head and neck region conditions. The purified MAb-174 was diafiltered through a demands determinating tumor spread. Pretherapeutic staging of 0.22-/nm filter into 50 mM phosphate-buffered saline (PBS) and head and neck tumors is based on the results of clinical as well stored at —20°C.The purified bulk MAb-174 was tested for murine as histopathological findings, sonography and CT, or MRI. viruses, viral DNA, sterility, mycoplasma and pyrogenicity before Although these diagnostic procedures are routinely established, formulating into labeling kits. the imaging results may be misjudged in 5%-30% of all cases, Radiopharmaceutical Kits which may lead to nonoptimal or inappropriate therapy plan Labeling kits (TruScint* SQ) were prepared and supplied by ning (8,19). Biomira Inc., Edmonton, Canada. Each kit contained 2 mg of Sometimes, even before visible changes in anatomical struc pretreated MAb-174 (IgGl subclass) in a frozen liquid format and tures occur, biochemical abnormalities on a cellular level can be was stored at —20°Cuntil use. Each batch of kit was tested for detected with radiolabeled antibodies (20,21). For this reason, it retained immunoreactivity (inhibition anti-idiotype radioimmuno- is assumed that the results of conventional diagnostic imaging assay and cell line bioassay against bovine SCC tumors), radio- procedures could be supplemented by this new immunologi- chemical purity (size-exclusion HPLC), sterility and pyrogenicity cally orientated imaging modality. The aim of this study was to compare the results of immu- before release for clinical use. Before intravenous injection, each kit was thawed at room noscintigraphy and other diagnostic methods in patients with temperature and reconstituted with the addition of [99mTc]pertech- head and neck tumors, who were scheduled for radiotherapy, netate solution (up to 2 ml/1800 MBq). The kit was incubated at and to analyze if radioimmunoscintigraphy could provide ad room temperature for 20 min before injection. Labeling efficiency ditional information relevant for radiation treatment planning was checked immediately before administration by ITLC-SG with and determine the target volume. 85% methanol as the solvent. Labeling efficiency was always >95%. The injected dose was 1.1 GBq 99mTclabeled to 2 mg of MATERIALS AND METHODS MAb-174. Patients Imaging Procedure Forty patients (31 men, 9 women; mean age 55 yr) with Planar anterior and posterior whole-body imaging was per histologically confirmed head and neck SCC (30 primary tumors, formed 4-6 and 16-24 hr p.i., acquiring 1 million counts per view. 10 recurrent lymph node métastases)who had been referred for SPECT of the head and thorax was peformed 16-24 hr p.i. using primary and adjuvant radiotherapy were entered into the study. The a high-resolution collimator and acquiring 5-15 million counts by study was approved by the Ethics Committee of the University 360°rotation. Reconstruction was done using a modified Shepp- Medical Center, Frankfurt/Main. All patients gave written in Logan filter. The optimal time for SPECT was 16-18 hr p.i. The formed consent. immunoscintigraphic findings were initially evaluated blindly by To determine tumor stage, pretherapeutic diagnostic measures the nuclear medicine physician and were later compared to CT, were taken (16 patients underwent surgery before radiotherapy). sonography, panendoscopy and the histological results obtained at The primary tumors were localized on the tongue and in the oral surgery. MRI and immunohistochemistry on the excised tumor cavity (n = 26), oropharynx (n = 5), larynx (n = 2) and hypo- using MAb-174 were performed in selected cases.
IMMUNO-SPECT AND TREATMENT PLANNING •AdamietZ et al. 1943 TABLE 2 Immunoscintigraphic Findings Beyond the Head and Neck Region 100
Patient no.1234567TumordiagnosisCarcinoma diagnosisMétastasesMétastasesMétastases
oralcavity epistemalregionMediastinumRightand MX)Carcinoma(T4 NO larynx(pT4 MX)RecurrentpN2 lymphnode lungLower orsecondprimary métastases(rN1 MX)Recurrent tumorMétastasesMétastases Treatment of primary tumor Treatment of recurrence lymphnode mediastinumRight
TABLE 3 Corrections of Radiotherapy Planning after Immunoscintigraphy Depending on Tumor Stage T1 T2 T3 T4 TX* TNM category (n = 6) (n = 9) (n = 4) (n = 15) (n = 6) Total
NO (n = 8) N1(n = 11) — — — 1 3/11 N2—N3(n(n = 18) — 215/152 215/61/84/182/310/40 FIGURE 2. (A) Detection of a previouslyunknown rightsupraclavicularlymph =Total node metastasis by planar anterior immunoscintigraphy 18 hr p.i. of 9^JTc- (n3)=40)—0/6—0/9—0/41 labeled Mab-174HO64 in a patient with recurrent oropharynx carcinoma. (B) Transversal SPECT slices show high focal tumor uptake and considerable intravascular activity. (C) X-ray CT scan performed after immunoscintigraphy •Recurrentlymph node métastases. confirmed metastatic nodal involvement.
1944 THEJOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 12 •December 1996 murine IgG. This could be due to the immunocompromised status of the patients.
DISCUSSION Radiation treatment planning in patients with head and neck tumors requires exact determination of the tumor spread for pretherapeutic staging. The requirements for primary and adju vant radiation treatment are equally high. The accuracy of physical examination of the head and neck region ranges FIGURE 3. SCO of the floor of the between 70%-96% (3,7). Comparable data (80%-96%) have mouth without lymph node métas tases (questionable enlargement in been reported for US (22). Diagnostic imaging with CT and/or CT scan). Anterior planar scan 24 hr nuclear magnetic resonance is presently the diagnostic standard p.i. revealed significant uptake in the for tumor staging. The accuracy of both procedures is compa primary lesion. rable and ranges from 70% to 96%, depending on the study (5-7,10,12,23). Conventional procedures therefore need to be tion cytology confirmed the cervical immunoscintigraphic find supplemented. ings of tumor lesions. The determination of the radiation treatment volume is highly In all patients in whom additional lesions were detected by demanding. When individual irradiation techniques are used, a immunoscintigraphy (n = 10), the target volume or the treat precise description of tumor infiltration of the head and neck ment scheme had to be altered. Due to cervical lymph node region is mandatory (24). This individualization was first made métastases,target volumes had to be changed in three patients possible by CT. Compared to the technique of simulator (7.5%) with advanced primary tumors of the oral cavity (pT4 planning, the use of CT resulted in therapeutically relevant pNl and T4 N2) and larynx (pT4 pN3). These lesions had not modification of the target volume in 40% of the patients been previously diagnosed due to ambiguous US and CT (24,25). Radiation planning with the help of CT is a matter of findings. In one patient, the target volume had to be extended; recognition of anatomical structures. Difficulties in establishing in the others, the total dose of the treatment volume was the treatment volume arise when micrometastases are present. It increased. is particularly difficult to differentiate between normal and Alternative strategies of treatment had to be selected in seven tumor-involved lymph nodes with diameters of less than 15 mm patients (17.5%) with positive immunoscintigraphic results (26). MRI may also be unable to detect lesions of such small beyond the head and neck region: patients with primary tumors dimension (23,27). of the oral cavity (T4 NO) and oropharynx (pT4 pN2) as well as SPECT immunoscintigraphy opens new perspectives five patients who had recurrences of lymph node métastases (17,27,28) by three-dimensional display of radiolabeled anti (Table 2). body distribution. The sensitivity and specificity of SPECT The presentation of métastasesand the corresponding immu imaging in head and neck cancers using 99mTc-labeled MAb- noscintigraphic findings in the study group showed that radia 174 appears high. The smallest lesion detected was only 1 cm tion therapy planning had to be corrected in 33% (5/15) of T4 in diameter and, more importantly, additional lesions were tumors (Table 3) unlike Tl, T2 and T3 tumors. Corrections in visualized in several patients that were not revealed by other radiation therapy planning in a patient with lymph node staging methods but were confirmed by subsequent surgery. On recurrences were as high as 83.3% (5/6). For the N-category, the other hand, there are several problems limiting the diagnos the frequency of changes in treatment volumes or therapeutic tic effect of this procedure (20,29), e.g. problems arise in terms strategies ranged from 12.5% (1/8) in NO patients to 66% (2/3) of exact spatial resolution. Differentiation of lesions less than in N3 patients. In comparison to primary tumors, corrections in 10 mm is generally not possible (17), although it has been radiation treatment planning were more frequent in patients described. Technical improvements are based on multihead with recurrent lymph node métastases(Fig. 1). SPECT systems and PET as recently reported (30,31). Cur Surprisingly, all HAMA samples tested negative for anti- rently our group is reviewing comparative studies between isotypic human antimouse antibodies despite the use of an intact [18F]FDG PET and immuno-SPECT in the same patient to obtain data as to superiority of method. Future improvements may also be obtained by using antibodies labeled with positron emitters (31). False-positive findings present a severe problem. Although our studies have shown a false-positive rate of less than 5%, further studies are required to determine the specificity of this method (17,18).
CONCLUSION SPECT imaging using 99nTc Mab-174 in patients with advanced and recurrent SCCs of the head and neck region can supply relevant additional diagnostic information for the radio therapist. The inclusion of this procedure in planning radiation therapy and determining treatment volume needs to be consid ered, particularly in patients with advanced head and neck cancers and those with recurrent lymph node métastases. FIGURE 4. Large SCO of the left alveolar process (without lymph ACKNOWLEDGMENTS node involvement) demonstrating high Mab-174HO64 uptake (coronal We are grateful to Biomira Inc., Edmonton, Canada for provid SPECT slices 7 hr p.i). ing the 174HO64 antibody.
IMMUNO-SPECTANDTREATMENTPLANNING•Adamictz et al. 1945 REFERENCES 17. Baum RP. Adams S. Kiefer J. et al. A novel technetium-99m-labeled monoclonal 1. Silverberg E, Lubera JA. Cancer statistics, 1989. Cancer I989;39:3-20. antibody ( 174H.64) for staging head and neck cancer by immuno-SPECT. Acta Oncol 2. I .u ñu.MI-GE. Head and neck cancer: a general overview. In: Laramore GÈ. ed. 1993:32:747-751. Radiation therapy of head and neck cancer. New York: Springer-Verlag; 1989: 18. Schomburg A, Hotze AL, Walther EK, Alberty J, Bender H, Herberhold C, Biersack 1-11. HJ. Radioimmunoimaging of head and neck cancer. Onkologie 1993:16:465-469. 3. Myers EM. Head and neck oncologi: Diagnosis, treatment and rehabilitation. Boston: 19. Amdur RJ, Parsons JT, Mendenhall WM, Million RR. Stringer SP, Cassisi NJ. Postoperative irradiation for squamous-cell carcinoma of the head and neck: an Little. Brown and Co.; 1991. 4. Shear M. Hawkins DM. Fair HW. 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Ictal Cerebral Blood Flow in Seizures Originating in the Posterolateral Cortex
R. Duncan, S. Rahi, A.M. Bernard, A. Biraben, A. Devillers, J. Lecloirec, J.P. Vignai and P. Chauvel Neurology Clinic, University of Rennes Regional Medical Center, and Department of Nuclear Medicine, Centre Eugène Marquis, Rennes, France
ictal EEG onsets. Ictal SPECT may be useful in distinguishing such In selecting patients for epilepsy surgery, it is important to distin seizures. guish mesial temporal seizures from seizures originating in the Key Words: cerebral blood flow; epilepsy;temporoparieto-occipital posterolateral cortex. We studied ictal cerebral perfusion in five junction seizures; localization patients with complex partial seizures with clear posterior EEG ictal onsets and clinical seizure semiology suggesting seizure origin in the J NucÃMed 1996; 37:1946-1951 posterolateral cortex. Methods: Ictal SPECT was performed during video EEG monitoring using 99mTc-HMPAO as a cerebral perfusion Actal HMPAO-SPECT has been used as a localizing investi tracer and a rotating gamma camera to acquire images. Results: Three patterns of ictal hyperperfusion were seen: pattern A = gation in partial epilepsies, particularly those of mesial temporal temporoparieto-occipital junction extending into the lateral temporal lobe origin, where studies have shown accurately localizing cortex, involving the mesial temporal cortex and basal ganglia to a changes in a high proportion of cases (1-19). The pattern of lesser degree and a small area of hyperperfusion in the contralateral perfusion change seen during seizures originating in the mesial parietal cortex (two patients); pattern B = pattern A but with no temporal lobe (2,3,8,11,13) shows hyperperfusion of the entire hyperperfusion of the mesial temporal cortex (one patient); and anterior temporal lobe, including the mesial and lateral cortices. pattern C = localized hyperperfusion in the area of the temporopa This hyperperfusion could extend into the ipsilateral basal rieto-occipital junction (two patients). Conclusion: Our results sug ganglia and involve the contralateral temporal lobe. The rest of gest distinct patterns of ictal perfusion in seizures with posterolateral the ipsilateral hemisphere is hypoperfused. Fewer data exist on postictal patterns of perfusion in extratemporal seizures Received Dec. 5, 1995; revision accepted Apr. 10, 1996. (15-19), but it has been suggested that early injection of For correspondence or reprints contact: R. Duncan, MD, PhD, MRCP, Dept. of Neurology, Institute of Neurological Sciences, Southern General Hospital, Glasgow G51 HMPAO can detect changes in rCBF, which can produce useful 4TF, Scotland. localizing information (79).
1946 THEJOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 12 •December 1996