Interferon-induced changes in pharmacokinetics and tumor uptake of 111In-labeled antimelanoma antibody 96.5 in melanoma patients.

The type I interferons [both partially purified human leukocyte interferon (HuIFN-alpha) and recombinant alpha interferon] and the type II interferons have been shown to increase the expression of tumor-associated antigens in vitro. To determine whether HuIFN-alpha could increase tumor acquisition of the antimelanoma antibody 96.5 in vivo, five patients with metastatic malignant melanoma were treated with HuIFN-alpha at a dose of 3 X 10(6) units daily by im administration. Twenty-four hours after the first dose of HuIFN-alpha, 1 mg of antibody 96.5 labeled with 5 mCi of 111In was coadministered with 19 mg of unlabeled 96.5. Five patients matched for metastatic site and lesion size who had not received HuIFN-alpha were also given a dose of 5 mCi of radiolabeled 96.5 at the same total antibody dose (20 mg). In patients treated with HuIFN-alpha, there was a statistically significant increase in the plasma half-life of the 111In label (39.7 +/- 3.3 hr) compared to the untreated control group (29.8 +/- 3.2 hr). In addition, there was an increase in the apparent volume of distribution of the antibody in the HuIFN-alpha group (5.56 +/- 0.67 L) compared to controls (3.15 +/- 0.5 L) suggesting both an increased immediate extravascular distribution of radiolabeled antibody and a decrease in the subsequent rate of clearance of antibody from plasma. These two phenomena result in a 28% decrease in the area under the concentration curve in the HuIFN-alpha-treated group compared to controls. Computer analysis of whole-body scans from patients showed a threefold increase in radiolabeled antibody distributed to tumor relative to blood pool but no change in organ:blood ratios for liver, spleen, bone, or kidney compared to controls. This pilot study suggests that treatment of patients with HuIFN-alpha results in an improved distribution of radiolabeled antibody to tumor target without a concomitant increase of label in normal nontarget tissues. In addition, this change in whole-body distribution of antibody is manifested by changes in the pharmacokinetic parameters measured for monoclonal antibody.

Immunospecific saturable clearance mechanisms for indium-111-labeled anti-melanoma monoclonal antibody 96.5 in humans.

Liver uptake of 111In-labeled monoclonal antibodies (MoAb) remains a significant problem in radioimaging studies to date. To determine if the observed liver uptake of an 111In-labeled anti-melanoma antibody 96.5 (111In-96.5) was dependent on the presence of hepatic antigen or on recognition of circulating murine antibody, escalating doses of an unlabeled nonimmunoreactive MoAb (NIR-MoAb) were administered to 18 patients with metastatic malignant melanoma either 1 or 24 h prior to an infusion of 1 mg of 111In-96.5. The number of metastases imaged, pharmacokinetics, and the ratio of radioactivity (expressed as average counts/pixel) in liver (L), spleen (S), bone (B), and kidney (K) compared to blood pool (heart = H) were examined. Results were prospectively compared with data from six patients who received immunoreactive unlabeled 96.5 prior to 111In-96.5. Increasing dose or changes in the preinfusion time of NIR-MoAb had no significant effect on the biodistribution of 111In-96.5. In contrast, patients who received unlabeled, immunoreactive 96.5 prior to 111In-96.5 infusion demonstrated a significant drop [P less than 0.001] in the liver/heart ratio of radioactivity [2.81 +/- 0.35 (SEM)] compared to patients receiving the identical dose of NIR-MoAb [10.35 +/- 1.33]. Significant decreases in spleen/heart and bone/heart ratios were also observed. Pharmacokinetic studies showed that the volume of distribution (Vd) and the plasma t1/2 both decreased when 96.5 was administered compared to NIR-MoAb. In addition, a 4-fold increase in concentration X time was obtained after 96.5 antibody was administered compared to NIR-MoAb. More metastases were imaged in patients receiving preinfusions of 96.5 (23 of 28) than in patients receiving NIR-MoAb (10 of 18; P less than 0.05). Although tissue distribution of 111In-labeled antibody can be ascribed to nonspecific organ clearance of murine antibodies, a substantial component of tissue disposition of antibody 96.5 was shown to be a consequence of specific clearance of immunoreactive antibody which may cross-react with tissue antigens.

Radioimaging of melanoma using 99mTc-labeled Fab fragment reactive with a high molecular weight melanoma antigen.

Twenty patients with metastatic malignant melanoma were studied with 99mTc-labeled monoclonal antibody (MoAb) Fab fragment (NR-Ml-05) reactive with a high molecular weight (Mr 240,000) melanoma associated antigen. Patients received 40 mg unlabeled irrelevant MoAb (NR-2AD-IgG) and 7.5 mg unlabeled NR-Ml-05 (whole IgG) prior to infusion of 10 mg 99mTc-labeled (10-25 mCi) NR-Ml-05 Fab. Unlabeled MoAb were given to block nonspecific and specific binding sites. Gamma camera scans and single photon emission computed tomography were performed at 8 and 24 h postadministration. Of 172 preexisting lesions, 136 were imaged for a sensitivity of detection of 79%. Imaging was site and size dependent with the greatest sensitivity for liver lesions (100%) and the least for bowel (0%). Six sites (2 skin, 1 lung, 3 liver) were detected by single photon emission computed tomography that were missed on routine planar images. Forty-one additional unconfirmed sites were seen. Of these, 7 (17%) have been confirmed as tumor after a median follow-up time of 6 months. False positive scans included scar tissue, areas of chronic inflammation, an infected femoral aneurysm, and septic emboli. Nonspecific uptake of radioactivity occurred in kidney, gallbladder, bowel, thyroid, and myocardium. Human anti-mouse antibodies were detected in up to 69% of patients. In summary, radioimaging with 99mTc-NR-Ml-05 is a sensitive test, especially for detecting liver lesions. It is safe, simple to administer, and convenient for the patient. Biodistribution and imaging sensitivity differ significantly from studies in which 111In-labeled anti-melanoma MoAb have been used.

Improved tumor localization with increasing dose of indium-111-labeled anti-carcinoembryonic antigen monoclonal antibody ZCE-025 in metastatic colorectal cancer.

Monoclonal antibodies (MoAbs) against carcinoembryonic antigen (CEA) react with human colorectal cancer cells, and when labeled with a gamma-emitting radioisotope, may help to localize known and occult metastatic disease. We tested ZCE-025 (Hybritech, Inc, San Diego), a high-affinity immune gamma globulin1 (IgG1) MoAb anti-CEA that does not react with normal granulocyte glycoproteins in a phase I/II trial to determine the reagent's toxicity and its maximum efficacy in detecting metastatic colorectal cancer. Increasing doses of unlabeled ZCE-025 were mixed with 1 mg of Indium-111 (111In)-radiolabeled MoAb and administered intravenously (IV) to 34 patients who had metastatic colorectal cancer. Planar nuclear or single photon emission computed tomographic (SPECT) scans were performed 48 to 72 and 120 to 144 hours later. Total dose of MoAb and scanning sensitivity (number of imaged lesions/number of known lesions) were correlated up to 80 mg. At doses of 2.5 to 20 mg, a mean of 22% of the lesions were imaged; at 40 mg, 77% were imaged (P less than .01). Liver metastases were detected as areas of increased activity ("hot") at the 40 mg dose but showed decreased MoAb uptake at lower doses. At the 40 mg dose normal liver parenchymal uptake of the labeled MoAb was lower with respect to blood pool compared with the other doses. At 80 mg, however, sensitivity of detection declined to 21%. One milligram of 111In-labeled ZCE-025 antibody coinfused with 39 mg of unlabeled antibody appeared optimal for detecting metastatic colorectal cancer, particularly in the liver. Although the exact mechanism(s) for this dose effect is currently unknown, a partial "blocking" effect of unlabeled antibody with a change in MoAb biodistribution may be occurring.

Imaging with indium111-labeled anticarcinoembryonic antigen monoclonal antibody ZCE-025 of recurrent colorectal or carcinoembryonic antigen-producing cancer in patients with rising serum carcinoembryonic antigen levels and occult metastases.

We tested whether nuclear imaging with indium111 (111In)-labeled murine monoclonal (MoAb) anticarcinoembryonic antigen (anti-CEA) ZCE-025 antibody could detect recurrent disease in patients with a rising serum CEA level but negative findings for computed tomographic (CT) scans of the abdomen and pelvis, chest radiograph, and colonoscopy or barium enema. Twenty patients with a history of completely resected CEA-producing adenocarcinoma (18 with colon cancer, one with breast cancer, and one with Hodgkin's disease) and a rising serum CEA level were given an intravenous infusion of 2 mg of 111In-labeled ZCE-025 mixed with 38 mg of unlabeled ZCE-025. Planar and single-photon emission CT (SPECT) scans were acquired at 72 and 144 hours, and in 19 of the 20 patients these were positive. Of those 19, 13 underwent exploratory surgery, and cancer was found in 10, and two had a diagnostic biopsy, which confirmed cancer. Three patients who had negative laparotomies and all four patients who did not undergo surgery or biopsy were followed radiologically. In all seven, cancer was subsequently detected at the sites suggested by the ZCE-025 scan. Thus, tumor was confirmed in all 19 patients with positive scans. Five of 13 patients who were explored benefited from the study and the exploratory laparotomy, as disease was entirely resected in four or was subjected to definitive radiation therapy to the pelvis in the fifth. In two additional patients who were not explored, MoAb imaging resulted in definitive therapy to regionally confined recurrent disease. 111In-labeled anti-CEA MoAb ZCE-025 scanning in patients with rising CEA successfully imaged metastatic colorectal cancer that eluded detection by other methods and affected the care given to some. These results suggest an important role for 111In-labeled ZCE-025 scanning among patients with rising CEA and otherwise occult metastatic cancer.

Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients.

Twenty-eight evaluable patients with metastatic cancer refractory to standard therapy received escalating doses of muramyl tripeptide phosphatidylethanolamine (MTP-PE) (.05 to 12 mg/m2) in phosphatidylserine (PC):phosphatidylcholine (PS) liposomes (lipid:MTP-PE) ratio 250:1). Liposomal MTP-PE (L-MTP-PE) was infused over 1 hour twice weekly; doses were escalated within individual patients every 3 weeks as tolerated for a total treatment duration of 9 weeks. Routine clinical laboratory parameters, acute phase reactants and various immunologic tests were monitored at various time points during treatment. Toxicity was moderate (less than or equal to grade II) in 24 patients with chief side effects being chills (80% of patients), fever (70%), malaise (60%), and nausea (55%). In four patients L-MTP-PE treatment was deescalated due to severe malaise and recurrent fever higher than 38.8 degrees C. The maximum-tolerated dose (MTD) was 6 mg/m2. Significant (P less than .05) increases in WBC count, absolute granulocyte count, ceruloplasmin, beta 2-microglobulin, c-reactive protein, monocyte tumoricidal activity, and serum IL-1 beta were found. Significant decreases in serum cholesterol were also observed. Clearance of intravenously (iv)-infused technetium-99 (99mTc)-labeled liposomes containing MTP-PE in four patients was biphasic; gamma camera scans revealed uptake of radiolabel in liver, spleen, lung, nasopharynx, thyroid gland, and tumor (two patients). No objective tumor regression was seen. In view of its definite immunobiologic activity and lack of major toxicity, additional phase II and adjuvant trials of L-MTP-PE are warranted.

Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography.

OBJECTIVE: To determine if previously hypertensive patients with acute ischemic stroke should be treated with antihypertensive medication in the immediate poststroke period. DESIGN: Randomized double-blind, placebo-controlled trial. SETTING: Sixteen consecutive hypertensive patients (four men and 12 women; mean age, 66 years [age range, 46 to 83 years]) with middle cerebral artery infarction within 72 hours of onset and blood pressure between 170 and 220 mm Hg(systolic) and 95 and 120 mm Hg (diastolic). INTERVENTION: Placebo (n = 6), nicardipine hydrochloride (20 mg [n = 5]), captopril (12.5 mg [n = 3]), or clonidine hydrochloride (0.1 mg [n = 2]) given every 8 hours for 3 days. MAIN OUTCOME MEASURES: Decline in blood pressure, change in cerebral blood flow as measured by single photon emission computed tomography, and clinical change as determined by the National Institutes of Health Stroke Scale. RESULTS: Blood pressure fell significantly in both the drug-treated group as a whole and in those patients receiving placebo (P < .001). There was no difference in blood pressure levels between these two groups throughout the study period. Patients receiving nicardipine had a consistently lower pressure than the other groups. A significant negative relationship was noted between the maximum blood pressure fall and improvement in cerebral blood flow. There were four patients whose blood pressure dropped by more than 16% of the baseline value on any 24 hours in the first 3 days. All either failed to increase or actually decreased their cerebral blood flow to the affected area. Three of these patients were treated with nicardipine. There was no significant difference in clinical course between the placebo-and drug-treated groups as a whole. CONCLUSIONS: Hypertensive ischemic stroke patients with a moderate elevation of blood pressure in the first few days may not require antihypertensive therapy. Nicardipine and possibly other calcium channel blockers may cause an excessive fall in blood pressure and impair cerebral blood flow in these patients and should therefore be used with caution.

Localization of indium-111 leukocytes in noninfected neoplasms.

Indium-111-labeled autologous leukocyte studies in general carry a high sensitivity, specificity, and accuracy for the investigation of infections and abscesses. However, past studies have described sporadic cases in which 111In leukocytes localized in tumors. Our experience using 111In leukocytes for the investigation of fever of unknown origin in cancer patients, however, indicates a relatively high incidence of 111In leukocyte localization in noninfected neoplasms. Out of the 61 patients studied for fever of unknown origin, 21 patients (34%) manifested abnormal localization of 111In leukocytes in neoplasms without clinical evidence of infection. These included patients with abnormal localization in: (a) lymph nodes, (b) soft-tissue tumors, and (c) bone neoplasms. The tumors included both primary and secondary lesions, and hematologic as well as solid tumors. The mechanism of 111In leukocyte localization in tumors is still not completely explained. Interpretations of 111In leukocyte studies in cancer patients with fever should take into consideration the possibility that localization may occur in neoplastic tissue per se and does not always indicate the presence of infection.

Indium-111-labeled B72.3 monoclonal antibody in the detection and staging of breast cancer: a phase I study.

Sixteen patients with primary breast cancer were studied with a pancarcinoma monoclonal antibody B72.3, an IgG1 molecule directed against tumor-associated glycoprotein (TAG-72) present in several tumors. Five millicuries of 111In was used to label 0.2 mg (six patients), or 2 mg (six patients), or 20 mg using the site-directed bifunctional DTPA method (at carbohydrate moiety). Digital, planar, and SPECT images were obtained at 2, 48, 72 and 96 hr when possible. HAMA levels were obtained before the Mab infusion and at 1, 3, and 6 wk postinfusion. Fourteen of 14 known primary breast lesions were detected by imaging (100% sensitivity). Two fibrocystic lesions were negative. Seven of 14 patients had lymph node metastases by histologic methods, but all were missed by radioimmunoscintigraphy. Tumor uptake of Mab ranged 0.00054%-0.0038% of the ID/g. The tumor-to-normal breast tissue ratio was 4.3 +/- 0.91 (mean +/- s.e.m.). Lymph nodes localization of 111In-B72.3 by tissue analysis was similar for tumor-bearing and normal nodes (0.0039 +/- 0.0023 versus 0.0025 +/- 0.0019). Pharmacokinetics revealed mean plasma half-life of 33.3-41.2 hr for the different doses. There was no statistical difference between any of the pharmacokinetic parameters of different doses. HAMA was positive only in 17% of the patients. The study suggests that this antibody has 100% sensitivity for primary breast cancers, but very poor detection rate of metastatic lesions in axillary lymph nodes; thus making it of questionable value in the initial staging process of this disease.

Radioimmunoscintigraphy of prostate cancer.

The development of hybridoma technology has increased research efforts and clinical applications in the area of radioimmunodetection. Despite the many investigative antibodies directed against prostatic tissue or prostate cancer cell lines, only two have been tested in clinical trials. A 111In-labeled antibody directed against prostate-specific antigen, the best available serum tumor marker for prostate cancer, has shown poor sensitivity in limited clinical radioimmunoimaging trials. Monoclonal antibodies against prostatic acid phosphatase have shown better imaging results, particularly at higher antibody doses (greater than or equal to 40 mg). The limitations of this antibody include the poor results in detecting soft tissue lesions, including the primary lesion; the development of human antimouse antibodies in 50% of the patients at doses greater than or equal to 40 mg; the expense of the antibody; and the fact that better results are currently attainable by other less expensive imaging modalities. If and when a more suitable antibody or fragment is developed, the prospect of improved staging and new treatments using immunologic conjugates carrying therapeutic agents may become realities. Until such time, prostatic cancer will be staged with other currently available imaging modalities and conventional therapies with their limitations will remain state of the art.

Indium-111 labeled leukocytes in evaluation of active specific immunotherapy responses.

Active immunization of patients utilizing viral oncolysates (VO) has been studied in clinical trials. VO are extracts of cultured tumor cells that have been infected with certain types of viruses, particularly surface budding varieties. The objectives of the current studies were to examine the trafficking patterns of Indium (In)-111-labeled leukocytes or lymphocytes in two groups of patients with gynecologic malignancies to determine whether these cells migrate to sites of active immunization after VO. Eight patients with ovarian cancer received VO intraperitoneally followed by In-111-labeled leukocytes or lymphocytes (500 &mgr;Ci) intravenously. In a separate trial, three patients with cervical cancer received In-111-labeled lymphocytes after they had been treated with VO administered by the intralymphatic route. Gamma camera imaging was performed to evaluate the distribution patterns of the labeled cells at several time intervals after injection. Results indicate that metastatic tumor sites exposed to VO therapy show significant uptake of In-111 cells. These sites of malignancies were confirmed by computerized tomography and ultrasound scans. In patients with ovarian cancer no uptake of the radiolabeled cells was observed in metastatic tumors of the liver and lymph nodes. In patients with cervical cancer, lymph node metastases exposed to intralymphatic VO therapy were visualized very well. Other known tumor sites not exposed to VO therapy showed no uptake of radioactivity. These findings confirm that VO induces immune responses. This diagnostic nuclear medicine technique may prove to be a useful method for following-up responses to immunotherapy.

Gallium67 scintigraphy in the diagnosis of acute renal disease.

67Ga scintigraphy was performed in 44 patients with various biopsy proven forms of renal disease and in a further 64 patients, some with clinically diagnosed renal disease and some with non-renal disorders. Renal uptake of gallium at 48 hours was graded by two blinded observers and by tissue ratios determined by computer. All 11 patients with biopsy proven acute drug-induced interstitial nephritis demonstrated intense, diffuse, bilateral renal 67Ga uptake, a phenomenon observed in only five of the other 30 patients with biopsy proven renal disease and in four of the 64 patients with clinical diagnoses only. No patient with acute tubular necrosis demonstrated significant renal gallium uptake. It is suggested that 67Ga scintigraphy is an excellent screening test for the presence of acute interstitial nephritis and helps to identify which patients with unexplained acute renal failure require renal biopsy.

Effect of unlabelled monoclonal antibody (MoAb) on biodistribution of 111indium labelled (MoAb).

We have evaluated immunoscintigraphy in cancer patients using four 111In-labelled murine monoclonal antibodies (MoAb): 96.5 (anti-P97 of melanoma), ZME-018 (anti-high molecular weight antibody of melanoma), ZCE-025 (anti-CEA for colon cancer) and PAY-276 (anti-prostatic acid phosphatase for prostatic cancer). The effect of increasing the doses of unlabelled MoAb (co-infused with 1 mg labelled MoAb) on the relative body distribution of each labelled MoAb was assessed. Localization in the liver decreased significantly in all cases, with increasing MoAb dose, except for ZME-018. Localization in other organs increased significantly as the liver activity decreased. The spleen activity, however, fell in the case of MoAb ZME-018. Blood-pool activity increased with MoAb dose in all four MoAbs. These findings correlated with the rise in the detection rate of metastases, the plasma half-life, and other pharmacokinetic parameters. However, the dose level at which this correlation occurred varied with each antibody. These data demonstrate that co-infusion of unlabelled MoAb with 111In-labelled MoAb could alter the organ distribution, pharmacokinetics and tumour uptake in a favourable manner, though the degree to which this occurs depends on the antibody in question.

Ga-67 uptake by metastatic carcinoma of the penis.

Six patients with metastatic carcinoma of the penis underwent Ga-67 citrate scanning. Intense radioactive uptake was noted in the metastatic inguinal lymph nodes that was not influenced by the presence or absence of infection. There was a correlation between clinical improvement and decrease in abnormal groin uptake. The results reported here suggest the possibility of using Ga-67 citrate scanning in the staging, management, and follow-up of this relatively rare condition, although further experience is needed to establish its precise role.

HIDA and pseudosplenomegaly in hydatid cyst and amebic abscess of liver.

Tc-99m-HIDA and related compounds have been universally accepted for studying the hepatobiliary system. The authors describe yet another use of HIDA documented by three case reports. HIDA is taken up by the hepatocytes and not by the reticuloenthothelial system. Two patients are described, one with hydatid cyst and the second with amebic abscess of the liver, in whom splenomegaly was diagnosed clinically and confirmed by ultrasonography as well as by Tc-99m-tin colloid scan. HIDA imaging proved the spleens to be normal. A displaced right lobe of the liver in one case, and an enlarged left lobe in the other, led to this erroneous diagnosis, which the authors term "pseudosplenomegaly." In the third patient, HIDA not only clarified the extent of the spleen, but also revealed a "cold" area in the left lobe of the liver. This was missed by the colloid scan because of the position of the "cold" area.

Scintigraphic findings of osteomyelitis after intraosseous infusion in a child.

A case of unilateral tibial osteomyelitis in a 20-month-old child after bilateral intraosseous infusion (IOI) needle placement is presented. A review of the indications, potential complications, and scan findings is discussed. This case also shows the lack of significant uptake in the noninfected side, suggesting that a three-phase bone scan is of value in differentiating reactive bone from infected bone in patients with IOI.

Intussusception secondary to Meckel's diverticulum detection with Tc-99m monoclonal antibodies to granulocytes (Leukoscan).

A case of Meckel's diverticulum causing intussusception in an 8-year-old boy is presented. The Meckel's diverticulum was detected by using a Tc-99m-labeled antigranulocyte monoclonal antibody MN3 (Leukoscan; Immunomedics, Morris Plains, NJ), which is under clinical evaluation for the detection of atypical appendicitis at the authors' institution. Pathologic evaluation confirmed Meckel's diverticulitis with ileal-ileal intussusception.

Radionuclide lung imaging in respiratory decompression sickness: potential role in the diagnosis and evaluation of hyperbaric therapy.

Of the more than 3.5 million trained divers in the United States, many will experience various illnesses specific to divers. Most of these illnesses are related to the changes in absolute pressure that divers experience while diving. During and after ascent, a diver is at risk for decompression sickness and pulmonary barotrauma. A very rare casualty is pulmonary decompression sickness from immersion. This is a literature review and case report of a young woman with acute respiratory decompression sickness who had defects on perfusion lung imaging after a diving accident and after hyperbaric oxygen therapy. However, the perfusion defects reverted to normal in less than 24 hours. Possible explanations for the changes in the appearances of the scans are offered and discussed. This case report shows the potential utility of lung scanning in the diagnostic examination of these patients and the evaluation of the adequacy of treatment with hyperbaric oxygen therapy. A greater use of ventilation-perfusion lung scans in the treatment of such patients may establish its role more definitely.

Technetium-99m sestamibi uptake in a maxillary brown tumor.

Brown tumors have been reported to take up TI-201 when dual-tracer parathyroid scintigraphy using TI-201 and Tc-99m pertechnetate was performed. With the change to the more favorable Tc-99m sestamibi parathyroid scanning, similar phenomena of tracer uptake in brown tumors have been reported. The authors describe a 44-year-old man with a left maxillary swelling. Laboratory investigations revealed elevated parathyroid hormone levels. Computed tomography of the head showed a left maxillary expansile mass. Subsequently, a Tc-99m sestamibi scan was performed to rule out a parathyroid adenoma. Left inferior parathyroid retention of the tracer was seen, indicating a parathyroid adenoma. An incidental finding was the uptake of Tc-99m MIBI in the left maxillary brown tumor. This case suggests the utility and possible specificity of Tc-99m MIBI uptake in diagnosing brown tumors.