The prognostic value of pretreatment 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography scan in women with cervical cancer.

There is substantial risk that prognosis determined with routine clinical staging for cervical cancer may be inaccurate. This is primarily due to understaging due to the lack of detection of nodal disease. This is particularly true for para-aortic nodal metastases. Treatment based on such staging may also be inadequate for the same reason. Positron emission tomography (PET) has been demonstrated to be useful in the staging of cervical cancer and superior to either computed tomography or magnetic resonance imaging in the detection of nodal disease. Our objective was to determine the prognostic value of pretreatment 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) PET scan in women with cervical cancer. We reviewed the records of 56 women with cervical cancer who underwent FDG PET scan prior to treatment. The primary outcome was the effect of abnormal FDG uptake consistent with metastatic nodal disease on 20-month disease-free survival. The pretreatment PET scan demonstrated abnormal FDG uptake in the pelvic nodes alone in 14 (25%) women, in pelvic and para-aortic nodes in 10 (17.9%), and in neither pelvic nor para-aortic nodes in 32 (57.1%). Women with positive pelvic nodes by PET as well as women with positive para-aortic nodes had significantly poorer 20-month disease-free survival compared to women with negative nodes (P= 0.0003 and P= 0.0017, respectively). We conclude that pretreatment FDG PET scan revealing abnormal FDG uptake consistent with nodal disease is a robust predictor of disease recurrence and may alter the therapeutic management of some patients.

Contribution of PET imaging to the initial staging and prognosis of patients with Hodgkin's disease.

BACKGROUND: Positron emission tomographic (PET) scanning utilizing [18F]fluorodeoxyglucose (FDG) is a new method of tumor imaging based on the increased glucose metabolic activity of malignant tumors. In Hodgkin's disease (HD), PET has proven value for the evaluation of residual masses following treatment and for the early diagnosis of relapse. In the initial staging of HD, PET frequently shows a higher stage than conventional methods (upstaging by PET). In the present study, we evaluated the frequency of stage changes by PET in a multicenter setting and determined its prognostic relevance. PATIENTS AND METHODS: A total of 73 patients with newly diagnosed HD were staged with both conventional methods and whole-body PET scanning. All histological types and stages were represented. The median time of follow-up after the initial diagnosis was 25 months (range 1 month to 5 years). The response to treatment was determined by standard clinical and diagnostic criteria. For the purpose of this analysis, data from a PET center associated with a university medical center and a PET center associated with a group oncology practice were combined. RESULTS: A total of 21 patients (28.8%) were upstaged by PET compared with conventional methods. In two cases (2.7%), a lower stage was suggested by PET scanning. With one possible exception, the upstaging had no obvious clinical or biological correlate. Among 12 patients in stage I (A + B) by conventional methods, seven were upstaged by PET (58.3%), four to stage II, one to stage III and two to stage IV. Among 42 patients in stage II, eight were upstaged by PET (19.0%), six to stage III and two to stage IV. Among 12 patients in stage III, six (50%) were upstaged to stage IV by PET. If only early-stage patients and major changes are considered (stages IA-IIB to III or IV), among 49, 10 were upstaged to III or IV, whereas in 39 staging was unchanged following PET. In the former group, three relapsed or were refractory compared with none in the latter group (P<0.006). In advanced stage patients (IIIA or IIIB) a trend toward treatment failure was apparent in patients who were upstaged by PET. CONCLUSIONS: PET scanning is an interesting new modality for the accurate staging of patients with HD and frequently shows a higher stage than conventional methods. PET should be performed at initial diagnosis and should be included in prospective studies of patients with HD. Upstaging by PET may represent a risk factor for a more advanced stage or a biologically more aggressive tumor. Patients with early-stage disease as identified by conventional methods have a significant risk of treatment failure if a more advanced stage is indicated by PET. At present, major stage changes suggested by PET imaging should be confirmed by an independent diagnostic method.

Use of fluorodeoxyglucose-positron emission tomography for the differentiation of cerebral lesions in patients with acquired immune deficiency syndrome.

Intracranial mass lesions comprise approximately half of all acquired immune deficiency syndrome (AIDS)-related neurological complications. Although toxoplasmosis and lymphoma are the most common causes of these lesions, diagnosis and treatment can be delayed because computerized tomography and magnetic resonance imaging studies cannot accurately differentiate between them. The authors retrospectively studied nine patients with AIDS in whom, after a 6-hour fast, [18F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scanning demonstrated intracranial mass lesions. The FDG uptake within each lesion was classified as either increased or not increased. In six patients there was no increase in FDG uptake, which suggested a diagnosis of toxoplasmosis, and lymphoma was suggested in two patients in whom increased FDG uptake was demonstrated. In a patient with two lesions, one lesion was shown to have increased FDG uptake whereas the other was shown to have no increased FDG uptake. All patients in whom a diagnosis of toxoplasmosis was made were started on antimicrobial therapy. Two patients died of other AIDS-related complications before repeated neuroimaging could be performed to assess treatment response, one patient refused to undergo further treatment or follow up, and two patients responded well to treatment. One patient with toxoplasmosis did not respond to the drugs. Analysis of a biopsy sample of the lesion confirmed the diagnosis; however, the patient died shortly thereafter. The two patients with FDG-PET-diagnosed lymphoma began corticosteroid therapy and improved considerably. In the patient in whom PET demonstrated two different FDG uptakes, a biopsy sample was obtained that confirmed the diagnosis of lymphoma; this patient was started on corticosteroid therapy and improved. A safe and reliable diagnostic tool, FDG-PET scanning can be used to differentiate causes of human immunodeficiency virus-related intracranial mass lesions. When available, this diagnostic study should be conducted before initiating empirical treatment or obtaining a stereotactically guided brain biopsy sample.

The use of FDG-positron emission tomography for the evaluation of colorectal metastases of the liver.

Each year at least 130,000 people in the United States are diagnosed with colorectal carcinoma. Approximately 14,000 of these patients will have liver metastases, and 20 per cent of these patients will die from these metastases. Surgical resection is the only possible chance for cure in patients with only intrahepatic metastases, and extrahepatic disease is a contraindication to glucose metabolism. Positron emission tomography (PET) allows the in vivo study of the uptake and use of glucose in human cells. Here, we review our experience with the use of PET imaging for the diagnosis and management of colorectal metastases of the liver. We conducted a retrospective chart review of 14 patients undergoing PET imaging for known or suspected hepatic metastases from colorectal carcinoma. Results of CT, magnetic resonance imaging, and PET images were compared with pathological specimens. CT scan identified 7 lesions, and PET identified 31 intrahepatic lesions. Of the 6 patients who underwent surgery, CT identified 4 (20%) and PET identified 17 (85%) of the 20 intrahepatic metastases histologically confirmed. The accuracy (number of lesions) of CT and PET was 20 per cent and 85 per cent, respectively. CT scans had a sensitivity (number of patients) of 50 per cent, and PET had a sensitivity of 100 per cent in patients undergoing surgical resection. PET imaging altered the management in 49 per cent of patients. Twenty-one per cent of patients had their surgery cancelled due to previously undiagnosed extrahepatic metastases. Twenty-one per cent of patients had negative CT scans and underwent surgery on the basis of their PET images, and all had histologically proven disease. One patient avoided a second-look laparotomy when PET revealed a lesion seen on CT to be false positive. PET is an ideal imaging modality to detect intra- and extrahepatic metastases from colorectal carcinomas and would aid in the surgical management of these patients.

A novel, simple method of functional spleen volume calculation by liver-spleen scan.

UNLABELLED: Spleen enlargement is commonly associated with portal hypertension from cirrhosis and may cause thrombocytopenia. Thus, accurate assessment of spleen size may be helpful in the clinical evaluation. Spleen length is not a precise estimate of spleen size because of the variation in spleen configuration, and spleen volumes measured by edging techniques can be tedious. We present a new method of measuring the functional spleen volume by liver-spleen scan (LSSs), validation experiments and some clinical data. METHODS: The method involves measurement of the total spleen counts by SPECT and dividing by a representative voxel concentration on a single frame to obtain the organ volume. Validation included phantom studies and clinical evaluation in 443 consecutive patients, including 216 with histologic assessments of chronic liver disease (CLD) and 11 healthy volunteers. RESULTS: A calibration factor determined from phantoms was used to convert the calculated volume (CV) to the "true" volume (V): V = CV (0.956) - 66.5 (r = 0.9991; P < 0.001). The volume calculations were validated in a second group of phantoms (r= 0.981; P < 0.0001). Spleen volumes were expressed as volume (cm3) and as volume per pound ideal body weight (IBW) (cm3/lb) (the conversion factor to convert cm3/lb IBW to cm3/kg IBW is 2.2). Clinical studies of reproducibility included demonstration of a significant (P < 0.0001) linear correlation between volumes calculated from repeat LSSs within 9 mo of the initial LSS in 11 healthy volunteers and 32 patients with CLD: y = 1.02x - 25; r = 0.968. The correlation with spleen volumes from autopsy or splenectomy was significant: y = 0.766x + 57; r = 0.845; P < 0.001. The normal spleen volume in 11 patients was 201 +/- 77 cm3 and 1.43 +/- 0.68 cm3/lb IBW (upper limits of normal: 335 cm3 or 2.5 cm3/lb IBW). In 443 consecutive LSSs over 15 mo, half of the patients had spleen volumes above the upper limits of healthy volunteers, and CLD was present in 90.9% of these patients. In 216 patients with histologically proven liver disease, a progressive increase in the percentage of spleen volumes above the upper limits of normal was noted from no fibrosis (10%) to mild to moderate fibrosis (36.7%) to early cirrhosis (52%) to advanced liver disease (75%). The correlation of spleen volume with platelet count was excellent (r = 0.7635; P < 0.005). CONCLUSION: This novel spleen volume measurement detects serious liver disease and correlates with splenic hyperfunction.

PET and [18F]-FDG in oncology: a clinical update.

Positron emission tomography (PET) has become a very useful adjunct to anatomic imaging techniques, adding unique information to the characterization of disease. The whole-body PET FDG technique developed over the last few years has surpassed most expectations with respect to its utility in clinical oncology. The large spectrum of neoplasms that now can be studied with this approach makes it an essential clinical imaging tool in diagnosis and management for many patients with cancer. The metabolic information provided by this technique is complementary to results from standard clinical and morphological examinations. It may be anticipated that through application of the multi-modality imaging approach, significant advances in medical care will come.

A study of the pharmacologic control of blood flow to acute skin flaps using xenon washout. Part I.

This study was undertaken to understand the control mechanisms differentiating circulation to normal skin and acute skin flaps. The approach was to compare the effects of systemic vasoactive drugs on skin blood flow in rats in acute skin flaps and identical areas of control skin. With this model it was felt that systemic changes would affect both areas equally and any difference in response would be due to vascular control mechanisms unique to the flap. Xenon washout by percutaneous injection was chosen to measure blood flow. The results of over 8000 observations in these studies were: 1. Vasodilation enhances blood flow and flap survival. 2. Vasoconstriction decreases blood flow. 3. Depletion of sympathetic nerve terminals enhances blood flow and flap survival. 4. The acute flap is less sensitive to systemic alpha-agonists than control skin. 5. The acute flap is less sensitive to vasodilators acting at the receptor-site level than control skin. 6. Total sympathetic denervation does not occur. 7. Biologic increases in area of flap survival did occur in drug dose ranges predicted by xenon washout measurements in this model. These findings indicate that the vessels in an acutely raised skin flap have a greater vasospastic tone than is optimal for maximum nutrient blood flow. One explanation consistent with these findings is offered in which the mechanism responsible for this tone is the release of catecholamines from the sympathetic nerve terminals after the flap has been raised.

A study of the pharmacologic control of blood flow to delayed skin flaps using xenon washout. Part II.

These experiments indicate that there are two components to the delay phenomenon. The first component is passive vasodilation owing to loss in the acute flaps originating from the sympathetic nerve terminals. The second component is active vasodilation not involving loss of a second vasoconstrictor mechanism or sensitization of the beta-receptors. Overall, the increase in blood flow associated with the delay phenomenon was seen to begin near the base of the flap and proceed distally. While the second component could not be identified, its characteristics suggest that its site of action is directly at the smooth-muscle or vascular-architecture level without involving the beta-receptors for vasodilation.

Performance evaluations of recent wide field scintillation gamma cameras.

Performance characteristics of four recent wide field scintillation gamma cameras were evaluated for 140-keV gamma imaging. Parameters measured included intrinsic spatial resolution, energy resolution, uniformity and linearity distortion, and count-rate capability and its influence on the spatial resolution. The system performance of the cameras was compared with representative parallel-channel collimators in terms of spatial resolution and relative sensitivity. Visual imaging comparisons of each camera system were performed by taking images of Rollo phantom containing four different lesion sizes, with four different contrast ratios, for equal imaging time.

Bone scanning in lymphoma.

The results of bone scanning with the newer technetium-99m complexes were correlated with clinical, laboratory, and radiographic findings in 26 patients with malignant lymphoma (10 with Hodgkin's disease and 16 with non-Hodgkin's lymphomas). Abnormalities on bone scan compatible with lymphomatous involvement of the skeleton appeared to occur more commonly in patients with diffuse lymphomas than in patients with nodular lymphomas and were generally observed in the setting of advanced disease (15 of 23 patients). Twenty-seven (73%) of the 37 scans obtained were abnormal. Although abnormal scans were observed with the greatest frequency in patients with bone pain (11 of 11), bone marrow involvement (11 of 12), abnormal skeletal radiographs (11 of 11), and elevated serum alkaline phosphatase levels (5 of 6), bone scanning also detected lymphomatous involvement in patients free of pain or with normal laboratory tests. Moreover, conventional radiography was entirely normal in six (35%) of 17 patients with abnormal scans and revealed only nonspecific osteopenia in another two patients (12%). Serial bone scans in nine patients reflected their response to chemotherapy. Of the 37 scans, only one was judged falsely positive and one falsey negative. Bone scanning with 99mTc complexes is a safe, simple, and sensitive screening procedure for detecting both extensive and focal lymphomatous involvement of the skeletal system and is a useful means of following such involvement in response to treatment.

Splenic artery ligation in selected patients with hepatic cirrhosis and in Sprague-Dawley rats.

The effects of splenic artery ligation were studied in Sprague-Dawley rats and in eight selected symptomatic patients with hepatic cirrhosis. In rats, this maneuver induced splenic infarction, reduced functional splenic mass, transiently raised platelet and reticulocyte counts and was without local complications. In seven selected patients with cirrhosis and prominent splenomegaly, the splenic artery was markedly enlarged, splenic arterial flow was greatly increased and splenic artery ligation partially lowered portal pressure. In three patients with varying cytopenias secondary to hypersplenism splenic artery ligation uniformly improved peripheral blood elements, although varying degrees of hypersplenism later recurred necessitating splenectomy in one. In five other patients, splenic artery ligation in conjunction with coronary vein ligation in four was performed for bleeding esophageal varices. Two patients later required portacaval shunting, and one other in whom operation was undertaken in desperation died of hepatic failure. Celiac-mesenteric arterioportography, operative portography, hemodynamic measurements and examination of peripheral blood elements in these eight patients suggests that splenic artery ligation in conjunction, where appropriate, with coronary vein ligation has several potentially beneficial effects. Hypersplenism may be sufficiently controlled to alleviate clinical symptoms. Arterial inflow into the portal system is reduced tending to lower portal pressure. Transheptic portal flow from the mesenteric bed is preserved. Venous anastomotic channels still functioning around the splenic pedicle and no longer draining a hyperdynamic splenic circuit may be converted into an escape route for mesenteric venous blood entering the portal system under high pressure. Nonetheless, each of these effects and their interrelationships require further study before this operation assumes a larger role in the treatment of complications of portal hypertension.

A clinical evaluation of indium-111 bleomycin as a tumor-imaging agent.

In an evaluation of indium-111-bleomycin as a tumor-imaging agent, 357 whole-body tumor scans were performed in 293 patients. Of 246 studies performed in patients with a variety of active solid tumors, 218 (89%) were true-positive studies and 28 (11%) were false-negative. Of 69 scans in patients thought to be free of tumor after therapy, 32 (46%) were false-positive studies and 37 (54%) were true-negative. The true-positive rates by major tumor type were: adenocarcinoma of gastrointestinal tract origin (95%), lymphoma (88%), melanoma (87%), sarcomas (82%), lung (77%), breast (77%), childhood tumors (71%), gynecologic tumors (70%), and genitourinary tumors (68%). Soft tissue and lymphatic sites of tumor, both above and below the diaphragm, were easily visualized, whereas hepatic and bone marrow sites of involvement were less easily discerned. False-positive uptake with 111In-bleomycin was noted in lungs (6%), gut (3%), mediastinum (2%), normal breast tissue (0.8%), and in occasional inflammatory lesions. In 19 patients with multiple myeloma or leukemia, a pattern of diminished bone marrow uptake associated with abnormal accumulation of 111In-bleomycin in extramedullary sites of involvement was the rule. In another 23 patients in whom scans were performed because an occult tumor was suspected, scanning did not lead to specific diagnosis of tumor in a single instance. We conclude that 111In-bleomycin is a safe, effective, and useful new tumor-imaging agent in the initial staging and followup of patients with a variety of solid tumors. Significant advantages of this agent over other currently available radiopharmaceuticals include: A) a broader spectrum of tumors taking up the radio-pharmaceutical, and B) generally better delineation of abdominal and pelvic disease due to lack of interference from gut uptake.

Study of leukocyte kinetics in acute myelocytic leukemia utilizing chromium-51.

Leukocyte kinetic studies using chromium-51 were performed in four patients with acute myelocytic leukemia (AML). Intravascular leukocyte survival was prolonged in comparision with granulocyte survival in normal subjects. Significant splenic pooling occurred in three patients, none of whom had splenomegaly. In one patient studied, circulating leukemic cells were shown to return to the bone marrow. The prolongation of intravascular leukocyte survival in AML in relapse, as in chronic myelocytic leukemia, probably depends on several factors including the presence of immature leukemic cells and the recycling of these cells from the spleen and bone marrow.

Indium-111 bleomycin tumor scanning in lymphoma.

A new radiopharmaceutical, indium-111 labeled bleomycin (IB), was evaluated as a tumor-imaging agent in 55 patients with lymphoma. Overall disease activity was correctly identified in 79% of 75 whole-body scan obtained 48 hours after intravenous administration of IB. Serial scans in 19 patients accurately reflected changes in their disease status. Lymphatic and soft tissues sites of involvement both above and below the diaphragm were most readily identified by scanning. Bone marrow and hepatic involvements were more difficult to detect because of normal tissue background in the considered organs. Five patients manifested diffuse pulmonary uptake of IB and only in one case was it explained. To determine the accuracy of scanning with IB, we evaluated 731 individual sites of potential tumor involvement with these results: true positives 90%, false negatives 10%, false positives 4%, and true negatives 96%. Thus, tumor scanning with indium-111 bleomycin is an important new technique for the initial staging and serial evaluation of patients with lymphoma.

Chromate transport in human leukocytes.

Chromium is a trace metal of importance in human physiology and, in addition, as 51-chromate, has been extensively used as a label in the study of blood cell pool sizes and intravascular kinetics. The transport characteristics of 51-chromate were investigated in normal human leukocytes. Chromate uptake is unidirectional over a 1 hr incubation with extracellular chromate concentrations up to 200 mumoles/liter. Under these conditions, intracellular 51-chromium is in a form in which it is nonexchangeable. Influx is temperature sensitive with a Q(10) of approximately 2 and may be energy dependent since a variety of metabolic poisons strongly inhibit uptake. The unidirectional influx of chromate follows Michaelis-Menten kinetics; the maximum velocity is 52 mmumoles/g dry weight of cells per min and the chromate concentration at which influx velocity is half maximal is 87 mumoles/liter. This transport mechanism is highly specific for chromate; other divalent tetrahedral anions only slightly inhibit influx at concentrations up to 10 times that of chromate. Metavanadate, however, competitively inhibits chromate influx at equimolar concentrations. Exposure of cells to unlabeled chromate leads to inhibition of subsequent influx of 51-chromate. It is suggested that this is due to a primary inhibitory effect of chromate on cellular energy metabolism.