The role of nuclear medicine in the diagnosis of cancer of unknown origin.

Cancer of unknown origin (CUO) is defined by the absence of any primary tumour in biopsy-proved metastatic cancer. CUO accounts for a 5-10% of all malignancies. These tumors have a specific biology with clinical characteristics of rapid progression and atypical metastases. Diagnostic evaluation is directed at the identification of treatable subset. Accurate diagnostic workup is crucial because both prognosis and survival rates depend mainly on detection of the primary tumor site. Although these patients undergo extensive imaging procedures, nuclear medicine techniques are under-utilized despite their ability of providing molecular information. Positron emission tomography has an emerging role in this clinical challenge along with other nuclear medicine methods including, bone scan, thyroid scintigraphy.

Infecton: a 99mTc-ciprofloxacin radiopharmaceutical for the detection of bone infection.

OBJECTIVE: To evaluate Infecton scintigraphy, with technetium-99m-radiolabeled ciprofloxacin, as a means to detect bone infection, in comparison with other conventional scintigraphic and radiologic methods. METHODS: Forty-five patients with known or suspected bone infection underwent 50 scans with Infecton. Almost all were also subjected to a three-phase 99mTc-methylene diphosphonate bone scan and most of them to a 99mTc-human polyclonal immunoglobulin scan as well as to a gallium-67-citrate scan, plus computerized tomography or magnetic resonance imaging or both. Clinical laboratory criteria for the presence of osteomyelitis were based on the definitions of the Centers for Disease Control and Prevention. RESULTS: Staphylococcus aureus and Pseudomonas aeruginosa were the most frequently isolated pathogens. Based on the CDC clinical laboratory criteria as well as on conventional scan results, Infecton was characterized in 35 studies as 'true positive', in eight as 'true negative', in two as 'false positive', in one as 'false negative', and in four as 'indeterminate'. The sensitivity and specificity of Infecton scintigraphy were found to be 97.2% and 80%, respectively, with positive and negative predictive values of 94.6% and 88.9%. CONCLUSIONS: It is concluded that Infecton is a very sensitive and quite specific marker of bone infection, but care must be taken in cases of excessive new bone formation and primary bone tumors, where false-positive results may be obtained.

Imaging bacterial infection with (99m)Tc-ciprofloxacin (Infecton).

AIMS: The diagnosis of deep seated bacterial infections, such as intra-abdominal abscesses, endocarditis, and osteomyelitis, can be difficult and delayed, thereby compromising effective treatment. This study assessed the efficacy of a new radioimaging agent, Tc-99m ciprofloxacin (Infecton), in accurately detecting sites of bacterial infection. METHODS: Eight hundred and seventy nine patients with suspected bacterial infection underwent Infecton imaging and microbiological evaluation. The sensitivity and specificity of Infecton in detecting sites of bacterial infection were determined with respect to Centres of Disease Control, World Health Organisation, and Dukes's criteria. RESULTS: Five hundred and seventy four positive and 295 negative images were produced. These included 528 true positives, 46 false positives, 205 true negatives and 90 false negatives, giving an overall sensitivity of 85.4% and a specificity of 81.7% for detecting infective foci. Sensitivity was higher (87.6%) in microbiologically confirmed infections. CONCLUSIONS: Infecton is a sensitive technique, which aids in the earlier detection and treatment of a wide variety of deep seated bacterial infections. The ability to localise infective foci accurately is also important for surgical intervention, such as drainage of abscesses. In addition, serial imaging with Infecton might be useful in monitoring clinical response and optimising the duration of antimicrobial treatment.

Diagnostic value of anti-alpha FP antibody levels in a metastatic germ cell tumor of unknown primary site.

BACKGROUND: A 21 year old man with a metastatic germ cell tumor of unknown primary not responding to chemotherapy was scheduled to have a blind bilateral orchiectomy to eradicate the possible primary site although palpation and ultrasonography of the testicles had always been normal. METHOD: The patient underwent a radioimmunoscintigraphy with Anti-alpha FP antibody scan (AFP-Scan). RESULTS: On the basis of the scintigraphic results the patient underwent a left orchiectomy and additionally removal of the lymph node metastases. Histology revealed the presence of an in situ carcinoma in the left testis and a mixed tumor present in the abdominal lymph node metastases. Fluorescent in situ hybridization on tumor cells did not show any abnormalities related to chromosome 12, a finding connected with the somatic type of germ cell tumors. CONCLUSION: Anti-alpha FP antibody scan was helpful in detecting the primary site and saving the life of the patient without resulting in hypogonadism.

Strontium-89 chloride in the treatment of bone metastases from breast cancer.

Sixty-four patients with painful metastatic breast cancer in bone were treated with 2 MBq/kg of strontium-89 chloride as a single intravenous injection. Patients were followed with records of medication, hematology parameters, serial bone and Sr-89 bremsstrahlung images and with a point pain score scale (10-0). The response was assessed during a 6-month period of follow-up. Fifty-two of 64 patients (81%) showed at least a moderate improvement. Eighteen out of the 52 responders showed a dramatic decrease in bone pain (35%), 21 (40%) presented a satisfactory response and in 13 cases (25%) the response was moderate. Only 12 patients (19%) from the whole group did not feel any improvement on pain palliation. A statistically significant decrease of pretreatment levels of platelets and leukocyte counts was observed after 4-6 weeks of therapy in 50 (70%) patients. Although most patients showed no change in their bone scans after 3 months of treatment, an obvious improvement was observed in 3 of them. Furthermore no additional painful metastases on their bone scintigraphic images were observed. The selective strontium-89 local uptake in metastatic sites was also confirmed directly by bremsstrahlung scans which were absolutely comparable to the respective 99mTc bone scans. Precautions have been taken against Sr-89 contamination from the patients' blood or excretions.

Immunolocalization of transitional cell carcinoma of the bladder with intravesically administered technetium-99m labelled HMFG1 monoclonal antibody.

The aim of this study was the immunolocalization of transitional cell carcinoma of the bladder with a radiolabelled murine tumour-associated monoclonal antibody and the measurement of the absolute uptake of the antibody by the tumour. Fourteen patients with transitional cell carcinoma of the bladder received 3-6 mCi (111-222 MBq) of technetium-99m labelled HMFG1 monoclonal antibody intravesically and one patient, 2 mCi (74 MBq) of iodine-131 labelled 11.4.1, which is a non-tumour-specific monoclonal antibody. Four of the 15 patients were evaluated with single-photon emission tomography (SPET) 1 1/2 to 2 h post administration. All patients underwent transurethral resection of the bladder tumour within 12-20 h following intravesical administration of the radiolabelled antibody. The radioactivity of biopsy specimens from normal urothelium and tumour areas were counted in a gamma counter. The mean uptake of the radiolabelled antibodies from normal and tumour sites was expressed as a percentage of the administered dose per kilogram of tissue. Conventional histology and immunohistochemistry using HMFG1 monoclonal antibody were performed on paraffin sections of the biopsy specimens. Although our results are preliminary, it can be concluded that: (a) bladder tumours are well imaged by SPET when using 99mTc-HMFG1; (b) intravesically administered radiolabelled antibody remains on the bladder tissue and does not escape into the systemic circulation; (c) the wide range of tumour uptake values (0%-9.3% administered dose/kg) observed probably can be attributed to heterogeneity of the antigenic expression of the tumour; (d) values of 99mTc-HMFG1 monoclonal antibody uptake by the tumour do not justify future attempts at radioimmunotherapy.

Immunotargeting of urothelial cell carcinoma with intravesically administered Tc-99m labeled HMFG1 monoclonal antibody.

Ten patients with transitional cell carcinoma (TCC) of the bladder received 3-6 mCi of HMFG1 monoclonal antibody (MAb) intravesically. The antibody was labeled with Tc-99m using the 2-Iminothiolane method. All patients underwent transurethral resection of the bladder tumor within 12-20 h following intravesical administration of 99m-Tc-HMFG1. The presence of the radiolabeled MAb in the circulation was studied by measuring the radioactivity in the serum for a period up to 20 h. Three of 10 patients underwent immunoscintigraphy (SPECT) 2-3 h postadministration and cancerous areas could be easily localized. Biopsies were taken from the tumor sites as well as from normal bladder mucosa. Absolute uptake of the administered MAb expressed as percent administered dose/kg of tissue could be evaluated only in eight patients. Multiple specimen taken from various tumor sites in every patient gave a wide range of uptake values ranging from 0 to 9.29% adm. dose/kg, whereas normal tissue uptake values ranged from 0 to 1.63, respectively.

Preliminary results on scintigraphic evaluation of malignant external otitis.

Malignant external otitis (MEO) is a potentially fatal otitis occurring in diabetic and immunosuppressed patients, which may cause cranial nerve palsies and massive thrombophlebitis of the brain. We studied five diabetic patients with the clinical diagnosis of external otitis who were suspected of having MEO and one diabetic patient presumed cured from MEO. All of them underwent methylene diphosphonate, nanocolloid and gallium single-photon emission tomography studies with quantitative analysis on the basis of regions of interest and count profile curves. This combined assessment helped us to diagnose and follow-up soft tissue and temporal bone infection, especially in the case of transsphenoidal extension of the disease, since conventional radiology and computed tomography were of no particular help. On the basis of these results, we consider scintigraphic demonstration of skull base infection as a fourth criterion of MEO given that the classical Chandler's triad (diabetes, granuloma, and Pseudomonas aeruginosa) is not always present.

A preliminary study of brain gliomas with H17E2 monoclonal antibody: immunoscintigraphy and pharmacokinetics.

Ten patients with relapsing high grade brain gliomas and one patient with low grade glioma were studied with a monoclonal antibody (H17E2) against placental alkaline phosphatase. In addition 2 patients with relapsing high grade glioma were studied with a non specific antibody (4D513/2118). 1 mCi of Iodine-131-labelled H17E2 was administered intracarotidly (i.c.) in two, and intravenously (i.v.) in 9 patients. Immunoscintigrams were taken at 0, 2, 24, 48 and 72 hours. Radioactivity was monitored in blood and urine. Tumour/non-tumour ratios were estimated (max. 2.45). All high grade gliomas receiving specific antibody irrespective of the route of administration, gave a positive immunoscintigraphic pattern, increasing in intensity with time. Disappearance of radioactivity in blood was biexpontential with a long component over 30 hours. Urinary excretion of radioactivity ranged from 3.7-21.7% of administered dose/day. The patient with low grade glioma and the patients receiving non specific monoclonal antibody showed a negative pattern, a fast blood clearance and a high urinary excretion. We conclude that a) Iodine-131 labelled H17E2 proved to be stable in vivo and produced satisfactory tumour localisation and b) i.v. route was as good as i.c.

Intracavitary use of two radiolabeled tumor-associated monoclonal antibodies.

Six patients with metastatic breast cancer and malignant pleural effusions and 13 patients with known or suspected ovarian cancer, underwent immunoscintigraphy after intracavitary (intrapleural or intraperitoneal) administration of iodine-131-(131I) or indium-111-(111In) labeled tumor associated monoclonal antibodies HMFG2 and H17E2. This method proved to be sensitive and specific with a true-positive result in 13 out of 14 patients with tumor and a true-negative result in five out of five patients without tumor. At any one time, 65%-80% of the whole-body radioactivity was closely associated with the cavity into which the radiolabeled antibody was administered while the radioactivity in the blood was always low, (approximately 4 X 10(-3) of administered dose/ml of blood). Concentrations of radiolabeled antibody (per gram of tumor tissue) ranged from 0.02%-0.1% of the injected dose in intracavitary tumors, but only 0.002% in a retroperitoneal metastasis. The specificity of this approach was documented in four control patients with benign ovarian cysts and in two patients who were imaged using both specific and nonspecific radiolabeled antibody. We conclude that the intracavitary administration of 131I- or 111In-labeled HMFG2 and H17E2 is a favorable route of administration and offers significant advantages over previously reported intravenous administration for the localization of breast or ovarian metastases confined to the pleural or peritoneal cavities.

Monoclonal antibodies in ovarian tumor imaging.

Immunoscintigraphy of ovarian tumors by intraperitoneal administration of I131 HMFG2 monoclonal antibodies (mabs) was used in this study. The purpose was to evaluate the diagnostic potential of this non-operative imaging technique in detecting ovarian tumor nature and spread. Sixteen patients that received 500-1000 microCi of I131 labelled HMFG2 mabs were evaluated. The scans obtained were compared mainly with the macro and microscopic operative findings of the subsequent laparotomy. Immunoscintigraphy accurately scanned tumor spread in 7 out of 9 patients with known ovarian cancer. It also successfully revealed the malignant or benign nature of pelvic masses in 6 out of 7 patients examined.

Chromium 51 EDTA/technetium 99m MDP plasma ratio to measure total skeletal function.

A method is described for the quantitation of total skeletal activity during bone scans. The method requires a single plasma sample only, taken at the time of imaging. The ratio of % injected dose of 51Cr EDTA to that of 99Tcm MDP is calculated from this sample following combined injection of the two radiopharmaceuticals. The 51Cr EDTA level corrects for the glomerular filtration of 99Tcm MDP. Using this method, which only requires a gamma counter, significant differences from normal controls have been shown in patients with osteomalacia, renal osteodystrophy, Paget's disease and hypercalcaemia. The method provides routine quantitative data to add to the imaging information in the bone scan.

Use of radionuclide labelled microspheres to show the distribution of the pulmonary perfusion with multifocal pulmonary blood supply.

In pulmonary atresia with a ventricular septal defect and similar congenital heart disorders the pulmonary blood supply is often multifocal. The relative distribution of pulmonary perfusion from individual sources is usually demonstrated by selective angiography. A new technique using a selective injection of radionuclide labelled human albumin microspheres was performed in four patients with a complex pulmonary blood supply. In these cases the physiological distribution of each of the multiple sources of pulmonary perfusion was demonstrated. This is a useful additional technique in the assessment of such patients.