Imaging infection with LeuTech.

LeuTech is a 99Tcm labelled, anti-CD15, IgM, murine monoclonal antibody shown to have high affinity (Kd = 10(-11) M) for CD15 receptors (5.1 x 10(5)/cell) expressed on human neutrophils. LeuTech was injected directly, intravenously, and its efficacy in imaging infection in 46 consecutive patients was determined. Human anti-mouse antibody (HAMA) response was examined in 30 normal volunteers using a standard LeuTech dose reconstituted with decayed 99Tcm solution. There were 38 true positive, six true negative, and two false negative scans. Of the 38 positive images, 33 (92%) were positive within 10 min after injection of LeuTech. LeuTech accuracy in this group of patients was 96%, sensitivity 95%, specificity 100%, positive predictive value (PPV) 100%, and negative predictive value (NPV) 75%. No elevation of the HAMA titre was observed in any of the 30 normal volunteers and no adverse reaction was noted in any patient. LeuTech is a highly promising agent for rapid imaging of infectious foci.

99mTc labeled VIP analog: evaluation for imaging colorectal cancer.

Early and reliable diagnosis of colorectal cancer continues to be demanding and challenging. Colorectal cancer cells express Vasoactive Intestinal Peptide (VIP) receptors in high density. We have prepared a VIP analog (TP3654), labeled it with (99m)Tc, and evaluated it in experimental animals as an agent for imaging colorectal cancer. The tissue distribution of (99m)Tc-TP3654 has been compared with that of (111)In-DTPA-Octreotide and (99m)Tc-anti-CEA scan in nude mice bearing human colorectal cancer LS174T. Finally, pharmacokinetic and tissue distribution studies of (99m)Tc-TP3654 have been performed in four normal human volunteers. Data suggest that (99m)Tc-TP3654 can be prepared efficiently without loss of its receptor specificity and biological activity. Although the 24 hr tumor uptake of (99m)Tc-TP3654 in the animal model used was modest (0.21 +/- 0.07% I.D./g), the tissue distribution profile was more favorable than that of (111)In-DTPA-Octreotide or (99m)Tc-anti-CEA scan. Human studies indicated that (99m)Tc-TP3654 had no adverse effect in any subject. Within 24 hours, approximately 70% of the injected dose cleared through the kidneys, and approximately 20% through the hepatobiliary system. In these non-fasting volunteers hepatobiliary clearance was slow and in cancer patients tumor uptake was rapid. Data suggest that (99m)Tc-TP3654 is a promising agent for imaging colorectal cancer.

The clinical utility of Tc-99m sestamibi scintimammography in detecting multicentric breast cancer.

The ability to recognize multicentric breast cancer preoperatively would assist in identifying appropriate candidates for breast conservation surgery. Tc-99m scintimammography (SMM) is an adjunct to conventional mammography in identifying selected patients with breast cancer. The purpose of this study is to report the utility of SMM in identifying patients with multicentric breast cancer. Breast cancer patients treated by mastectomy who underwent a preoperative SMM between 1992 and 1999 were identified using the institution's Tumor Registry. The pathology report of each patient was reviewed for multicentric disease defined as an additional focus of cancer within a different quadrant of the breast or greater than 2.5 cm from the dominant tumor mass. Each patient's preoperative SMM was reviewed and compared with the pathologic findings to obtain correlative data. Fifty-eight women treated by mastectomy had preoperative SMM (age range 35-78 years; median 52 years). Pathology revealed infiltrating ductal carcinoma in 49 patients (84.5%), infiltrating lobular carcinoma in five patients (8.6%), ductal carcinoma in situ in three patients (5.1%), and colloid carcinoma in one patient (1.7%). Multicentric disease was present in the specimens of eight patients for a prevalence of 10.3 per cent. SMM was positive for uptake in 36 of 58 patients (sensitivity 62.1%). The sensitivity, specificity, positive predictive value, and negative predictive value of SMM in the detection of multicentric disease were 62.5, 96, 71, and 94 per cent, respectively. Although the overall sensitivity of SMM in the detection of breast cancer is superior to that of conventional mammography and physical examination in identifying multicentric breast cancer it is not an accurate modality for detecting multicentric disease in this study group. However, it may have limited applications in specific cases.

99mTc-labeled vasoactive intestinal peptide analog for rapid localization of tumors in humans.

In recent years, imaging tumors with receptor-specific biomolecules has been the focus of increasing interest. Vasoactive intestinal peptide (VIP) has a high affinity for specific receptors that are expressed in high density on a large number of malignant tumors. VIP was modified (TP 3654) without compromising its biologic activity and labeled with 99mTc. Pharmacokinetics and feasibility studies were performed in 3 healthy volunteers and 11 patients with a history of cancer. Imaging was performed for up to 2 h after injection. Within 24 h after injection of 99mTc-TP 3654 (370-555 MBq/5 microg), approximately 70% of the tracer cleared through the kidneys and 20% through the liver. Blood clearance was rapid. No adverse reaction was noted in any subject. All known tumors were clearly delineated within 20 min. Findings were compared with the results of 99mTc-methoxyisobutyl isonitrile, CT, MRI, or histology. There was concordance in 9 patients. In the other 2 patients, only the VIP scan was positive for tumors known to express VIP receptors. The early results of imaging tumors with 99mTc-VIP are promising and warrant further study.

Imaging tumors in humans with Tc-99m-VIP.

Vasoactive intestinal peptide (VIP) was modified at the C terminus with a spacer and four amino acids to serve as a chelating moiety. The modified peptide, TP 3654, was labeled with Tc-99m and evaluated in normal volunteers, as well as in patients with a history of cancer. Renal clearance (67%) was the primary route of excretion, with approximately 20% of the radioactivity clearing through the hepatobiliary system. No adverse reaction was noted in any of the subjects and all, except one small, of the known lesions as seen by CT, MRI, Tc-99m-MIBI, or mammography were correctly identified within a few minutes of an i.v. injection of approximately 10 mCi of Tc-99m-TP 3654 (specific activity 11.3 x 10(3) Ci/m mol). The scans were in concordance in nine patients. In the remaining two, one with a visible mass in the neck from high grade spindle cell sarcoma and the other with a palpable mass in a breast from ductal epithelial hyperplasia, were localized only with Tc-99m-TP 3654, but not with Tc-99m-MIBI. Both malignancies are known to express VIP receptors. The VIP analog promises to be a nontoxic and reliable agent for imaging cancers in humans that express VIP receptors.

Scintimammographic analysis of nonpalpable breast lesions previously identified by conventional mammography.

BACKGROUND: In randomized trials, screening mammography has led to decreased mortality from breast cancer. However, the low positive predictive value of mammography (i.e., the proportion of patients with a positive test result who actually have breast cancer) results in a large number of unnecessary biopsies. We determined whether scintimammography with technetium-99m-sestamibi is a useful supplemental diagnostic tool for women with nonpalpable breast abnormalities identified by conventional mammography. METHODS: Scintimammography was performed preoperatively on 70 women who were 31-66 years of age (mean age and median age = 51 years). These women had nonpalpable breast abnormalities identified by conventional mammography; subsequently, a needle-localization excisional biopsy of each suspicious lesion was performed. Scintimammographic images were interpreted independently by two nuclear medicine physicians who were blinded to all clinical and pathologic data, and an interobserver variation analysis was performed. RESULTS: Interobserver variation analysis of the scintimammographic findings showed an agreement for breast diagnosis of 97% and a kappa coefficient of 0.90. Comparison of scintimammographic findings and histopathologic results revealed that the sensitivity (proportion of patients with breast cancer who had a positive test result), the specificity (proportion of patients without breast cancer who had a negative test result), the positive predictive value and the negative predictive value (proportion of patients with a negative test result who actually did not have breast cancer) of scintimammography were 56% (95% confidence interval [CI] = 23%-85%), 87% (95% CI = 75%-94%), 38% (95% CI = 15%-68%), and 93% (95% CI = 82%-98%), respectively. Four of nine breast cancers were not detected by scintimammography. CONCLUSION: Because of excellent interobserver agreement, scintimammography provides an objective way of detecting primary breast carcinoma. In view of its low sensitivity and positive predictive value, however, scintimammography is not currently recommended as a screening test in patients with nonpalpable positive mammographic findings.

Immunohistologic assessment of technetium-99m-MIBI uptake in benign and malignant breast lesions.

UNLABELLED: This study was undertaken to assess the relationship between the degree of 99mTc-MIBI uptake in breast lesions and the following histologic factors: neovascularity, desmoplastic reaction, cellular proliferation and mitochondrial density. METHODS: Forty-two patients who previously underwent MIBI breast imaging (4 false-negative, 12 false-positive, 15 true-negative, 11 true-positive) were studied. Immunohistochemical staining was performed for neovascularity (Factor VIII antigen), desmoplasia (alpha-actin antigen), mitochondrial density (mitochondrial antigen) and cellular proliferation (MIB-1 antigen). The degree of microscopic staining was correlated with region of interest measurements of MIBI uptake on scintigraphy. RESULTS: There was a poor correlation between MIBI uptake and the degrees of neovascularity (r = 0.08, p > 0.05) and intracellular mitochondrial density (r = 0.04, p > 0.05) while there was a moderate correlation with cellular proliferation (r = 0.4, p < 0.05) and desmoplasia (r = 0.55, p < 0.001). CONCLUSION: The degree of MIBI uptake in breast lesions is multifactorial, but it appears to be related more to the degree of desmoplastic activity and cellular proliferation than neovascularity and mitochondrial density.

Detection of axillary lymph node metastasis of breast carcinoma with technetium-99m sestamibi scintimammography.

Several investigators have advocated management of breast cancer patients without axillary dissection, obviating the morbidity associated with this procedure. Approximately 30-40 per cent of all patients with breast carcinoma will have lymph node metastasis. Axillary dissection offers no therapeutic benefit to node-negative patients, and it may lead to unnecessary morbidity. It is apparent that a noninvasive test to determine the presence of axillary metastases may obviate the need for axillary dissection. The aim of this study was to determine the role of scintimammography (SMM) with technetium-99m sestamibi in the detection of axillary node metastasis in breast carcinoma. Thirty-one women with the diagnosis of breast carcinoma who had SMM and axillary lymphadenectomy were included. SMM was done following an intravenous injection of 20 mCi of Tc-99m sestamibi. Planar scintigraphic imaging was acquired in a lateral prone and an anterior view of the breasts for the evaluation of the axilla. SMM scans were interpreted by two nuclear medicine physicians blinded to the clinical presentation and histologic results. The correlation of SMM with histologic assessment showed a sensitivity of 75 per cent, specificity of 82 per cent, positive predictive value of 88 per cent, and negative predictive value of 64 per cent. The interobserver correlation of SMM interpretation between the two nuclear medicine physicians showed good agreement, with kappa = 0.49. Consistency in the interpretation of Tc-99m SMM was obtained when two independent radiologists reviewed the studies. Based on these data, we are unable to show that SMM is a reliable test for the detection of axillary metastases in patients with breast cancer. However, a high positive value of 88 per cent is encouraging and deserves further study.

Scintimammography: the new role of technetium-99m Sestamibi imaging for the diagnosis of breast carcinoma.

Technetium-99-Sestamibi scintimammography has emerged as a new procedure for the imaging of breast tumors. Currently, a large clinical experience has been developed and the results published. At the present time, the major drawback of this procedure appears to be its low sensitivity for the detection of breast carcinomas smaller than 1 cm in diameter. There are other biologic and technical issues that remain to be overcome to optimally image the breasts. Some of these include: development of a dedicated breast imager using nuclear medicine techniques, development of stereotactic needle localization of the abnormalities that demonstrate focal increase uptake in women with normal mammogram and breast physical examination, manufacturing of a breast compression device so that we can immobilize the breast in place for more adequate imaging, overcoming the issue of unilateral or bilateral diffuse breast uptake that is noted in 7-10 percent of the cases and finally, determination of optimal dose and imaging factors. This review includes our experience at Harbor-University of California, Los Angeles Medical Center with the use of this agent for breast imaging since 1992.

Radionuclide-guided stereotactic prebiopsy localization of nonpalpable breast lesions with normal mammograms.

UNLABELLED: Scintimammography with 99mTc-sestamibi can be used as a complementary technique to improve the mammogram's sensitivity and specificity for detection of breast carcinoma. We have observed in some patients focal areas of increased 99mTc-sestamibi uptake with no corresponding abnormalities on physical examination or mammogram. A phantom device and a special needle were designed to stereotactically localize these lesions before biopsy. METHODS: After intravenous injection of 30 mCI (1110 MBq) of 99m Tc-sestamibi, a prone lateral image of the abnormal breast was obtained. With the patient in the prone position, the breast was compressed with two fenestrated plates in the prone position. The x and y coordinates of the abnormal hot spot of the breast were determined. The z coordinate of focal 99mTc-sestamibi uptake was determined by advancing a localizer needle through a selected predetermined hole of the fenestrated plate using real-time visualization on the persistence monitor. The tip of the opturator inside the needle is welded with 57Co to determine the depth of the hot spot in the breast. RESULTS: Three women, all of whom had normal mammogram and breast physical examinations, were studied using 99mTc-sestamibi prone breast imaging. Pre-excisional biopsy needle localization of abnormal focal uptake was performed. Two women demonstrated infiltrative ductal carcinoma, and the third had proliferative fibrocystic disease of the breast. CONCLUSION: Our initial experience demonstrates that nuclear medicine guided stereotactic needle biopsy of the breast in patients with positive scintimammograms is technically feasible. In the future, this technology will enable us to detect breast carcinoma in the absence of clear-cut clinical and mammographic findings.

Breast Cancer Imaging: Can Tc-99m Sestamibi Scintimammography Fit In?

Mammography and physical examination are currently the most frequently used screening tests for breast cancer. Considering the 85% sensitivity associated with combined mammography and physical examination and a low positive predictive value of 20% to 30% for the diagnosis of breast carcinoma, there is a critical need for a more accurate noninvasive imaging test to improve the sensitivity and specificity of mammography. This study evaluates the role of Tc-99m sestamibi scintimammography as a complementary procedure to conventional mammography for the detection of breast carcinoma. A sample of 157 women (mean age 47.9 years +/- 10.2 years) with 164 lesions appropriate for histologic and cytologic analysis on the basis of suspicious findings on a mammogram and/or physical examination underwent scintimammography. Subsequently, excisional biopsy and/or fine-needle aspiration were performed. There were 52 primary cancers (8 different histopathologic types) and 112 benign breast lesions (6 different histopathologic types). The sensitivity of Tc-99m sestamibi scintimammography for detecting primary breast cancer was 92.3%, and its specificity was 87.5%. Percent-positive and -negative predictive values associated with Tc-99m sestamibi scintimammography in this cohort were 77.4% and 96.0%, respectively.

Scintimammography with Tc-99m sestamibi.

Mammography and physical breast examination are currently the most frequently and recognized screening tools for detection of breast carcinoma. These methods have been proved successful for early detection of breast cancer. Considering the 85% sensitivity associated with combined mammography and physical examination and a low positive predictive value of 20%-30% for diagnosis of breast carcinoma, there is a critical need for a more accurate, noninvasive imaging test to improve the sensitivity and specificity of mammography (7, 19, 20). Since early 1992, we have studied over 1200 women with clinically and/or mammographic abnormalities prior to breast biopsy and/or fine needle aspiration cytology of the breast. We have evaluated the role of Tc 99m Sestamibi as a complimentary procedure to conventional mammography in detection of breast carcinoma. The preliminary results of our studies have been published elsewhere (14, 17, 18). DuPont Merck Pharmaceutical Company in the USA on that basis, determined to conduct a multicenter clinical trial for the role of this radiopharmaceutical for the diagnosis of breast carcinoma in women with mammographically and/or clinically palpable abnormalities. This study was conducted at 42 institutions throughout the United States and Canada enrolling 673 women who where otherwise scheduled for breast biopsy and/or mastectomy. The preliminary results of this trial in both palpable and nonpalpable breast abnormalities are encouraging (24). Our most recent study on 157 women (mean age 47.9 years +/- 10.2) with 164 lesions with indications for histologic and cytologic analysis who underwent scintimammography with Tc 99m Sestamibi demonstrated the sensitivity of 92.3% and the specificity 87.5% (15). We have concluded that Scintimammography with Tc 99m Sestamibi can be used in conjunction with mammography to improve its specificity.

Imaging inflammatory diseases with neutrophil-specific technetium-99m-labeled monoclonal antibody anti-SSEA-1.

UNLABELLED: Imaging inflammatory diseases with a 99mTc-labeled neutrophil-specific agent that can be injected directly intravenously continues to be a challenge. METHODS: The antibody, anti-SSEA-1, chosen from studies of 10 neutrophil-specific MAbs, recognizes CD-15 antigens (5.1 x 10(5)/human PMN) with a high association constant (kd = 10(-11) M). One hundred micrograms of MAb labeled with 10-20 mCi 99mTc either by a direct or DTPA conjugation method were injected intravenously into 12 patients (9 men, 3 women, aged 19-48 yr) with clinical evidence of ongoing inflammatory processes. Vital signs of all patients were recorded before and up to 3 hr following administration of the MAb. HAMA was determined in two patients. Anterior and posterior spot views and whole-body images were obtained. All patients except one underwent biopsy, US or CT examinations and/or surgical procedures. Blood samples collected from five patients were analyzed. In nine patients, quantitative organ distribution was determined and radiation dosimetry was calculated. RESULTS: Labeling yields were 94.8% +/- 1.4% and 95.8% +/- 3.5%, respectively. All patients had unequivocally positive images within 3 hr of the MAb injection. Eleven of these were confirmed by other modalities. One patient recovered on antibiotics and was sent home without surgery or other procedures. The lack of radioactivity in the thyroid or gastrointestinal tract indicated that the in vivo stability of the agent was excellent. At 3 hr postinjection, bladder activity in six patients was 1.3% +/- 0.4% of the administered dose. At this time, splenic uptake (7.7% +/- 1.0% ad. dose) and red marrow uptake (14 +/- 1.8%) were lower than those of 111In-WBC. At 49.0% +/- 3.2% administrated dose, liver uptake was at the upper limit with 111In-WBC uptake. Renal uptake was only 2.4% +/- 0.03% administered dose. At 2 hr postinjection, 14% to 51% of the radioactivity was associated with PMN. Radioactivity with lymphocytes was 0.7% to 10.9%, 1.2% to 4.3% with platelets and 1.1% to 2.4% with RBC. No HAMA were detectable in either patient, and no adverse reaction was detectable in any patient. CONCLUSION: Results are highly encouaging and have prompted us to prepare a kit for instant preparation and to initiate clinical trials.

Design and assessment of a scintigraphy-guided biplane localization technique for breast tumours: a phantom study.

The aim of this study was to design and assess a scintigraphy-guided stereotaxic localization technique for breast phantoms. We wished to develop and validate scintigraphically aided biopsy of non-palpable breast masses identified only by sestamibi scintimammography. A biopsy table was built for patients to lie prone with the breast in a dependent position. The breast can be compressed in the cranial and caudal directions by fenestrated paddles. Three freely adjustable radioactive reference lines, placed along the x, y and z axes, each containing about 30 MBq (800 micro Ci) 99Tcm, were mounted on sliding rules on the external frame which surrounded the phantom. The breast phantom was a semi-square-shaped sponge. Background activity was provided by a sponge cloth containing 37 MBq (1 mCi) 99Tcm solution. Non-palpable lesions were carved out of the same sponge and wrapped in thin plastic film, and labelled with about 11 MBq (300 microCi) 201T1. The lesions, 3-15 mm in size, were placed at random at phantom depths of 2-6 cm by an individual different from the person performing the localization. Scintigraphy-guided three-dimensional localization of the lesion was performed by acquiring two orthogonal images and superimposing the reference bars over the lesion image and thus identifying the exact x, y and z coordinates of the lesion. Using these coordinates, a 22 gauge needle, containing about 37 MBq (1 mCi) 99Tcm within its lumen, was stereotactically placed into the phantom, and the tracer contained in the needle injected into the lesion. Needle placement was primarily guided by the exact coordinates, but also by real-time visualization of the radioactive needle. Pre- and post-localization images were acquired and regions of interest (ROIs) defined. Also after the tracer was injected into the lesion, images of the phantom with and without the lesion were obtained to calculate the percentage of tracer injected outside the lesion. The results of 30 consecutive localization attempts included 25 exact localizations with less than 20% tracer injected outside the lesion, 2 "near misses' with 37-44% injected outside the lesion, and 3 "misses' with 60, 85 and 100% of the tracer being injected outside the lesion. The missed localizations were all in lesions at least 4 cm deep, and all had partially superimposed ROIs, which indicates the needle came very close to the lesion. To conclude, our scintigraphy-guided biplane localization technique for breast phantom lesions successfully localized 90% of all lesions.

Technetium-99m-sestamibi scintimammography of breast lesions: clinical and pathological follow-up.

UNLABELLED: Mammography and physical examination combined have a sensitivity of 85% for the detection of breast carcinoma. Mammography also has a positive predictive value of 15%-30%. The aim of this study was to evaluate the usefulness of scintimammography using 99mTc-sestamibi as a complementary technique to mammography for the detection of breast carcinoma to improve mammography's sensitivity and specificity. METHODS: We studied 100 consecutive patients (mean age 48.3 +/- 10.8 yr) who had 106 lesions warranting biopsy (67 lesions) or fine needle aspiration cytology (FNA) (39 lesions) of the breast. There were 85 palpable and 21 nonpalpable lesions. The size of the lesions on the mammograms were moderate (2.3 +/- 1.8 x 1.9 +/- 1.5 cm). Each patient received 20 mCi 99mTc-sestamibi intravenously. Five and 60 min postinjection, planar breast images in the lateral prone position were obtained. An anterior erect projection was then obtained to visualize the axilla and, if needed, a posterior oblique prone projection. RESULTS: Scintimammography was true-positive in 30 lesions with biopsy-confirmed breast carcinoma; it was true-negative in 65 lesions subsequently proved to be benign. There were nine breast lesions with benign findings in which the scintimammography result was positive (false-positive scintimammography) for cancer. Finally, two lesions with pathologically proven carcinomas demonstrated a negative scintimammographic result. Therefore, in this group, the sensitivity of scintimammography was 93.7% with a specificity of 87.8%; the positive predictive value was 76.9%. The negative predictive value was 97%. CONCLUSION: Scintimammography is a highly sensitive test that improves the specificity of conventional mammography for the detection of breast carcinoma.

Scintimammography: the complementary role of Tc-99m sestamibi prone breast imaging for the diagnosis of breast carcinoma.

PURPOSE: To evaluate the complementary role of technetium-99m sestamibi scintimammography in improvement of the sensitivity and specificity of mammography in detection of carcinoma of the breast. MATERIALS AND METHODS: At 5 and 60 minutes after intravenous injection of Tc-99m sestamibi, scintimammograms were obtained in 147 women (age range, 18-73 years; mean age, 47.9 years +/- 10.2 [standard deviation]) with 153 lesions that warranted breast biopsy (102 lesions) or fine-needle aspiration cytologic analysis (51 lesions). There were 113 palpable and 40 nonpalpable lesions. Lesion size on mammograms was 0.8 x 0.6 cm to 15.0 x 11.0 cm (mean, 2.82 cm +/- 1.71 x 2.39 cm +/- 1.56). RESULTS: Scintimammographic findings were true-positive in 47 biopsy-confirmed carcinomas, true-negative in 91 benign lesions, false-positive in 11 lesions with benign histopathologic findings (fibrocystic disease [n = 8] or fibroadenoma [n = 3]), and false-negative in four lesions of infiltrating ductal carcinoma. The sensitivity of scintimammography was 92.2%; specificity, 89.2%; positive predictive value, 81.0%; and negative predictive value, 95.8%. CONCLUSION: The authors conclude that scintimammography is a sensitive test that can improve the detection of breast carcinoma.