Lymphatic mapping and sentinel node harvesting in patients with recurrent breast cancer.

AIMS: To evaluate the feasibility and consequences of lymphatic mapping and a ("repeat") sentinel lymph node (SLN) procedure in patients with breast cancer relapse after previous breast and axillary surgery. METHODS: Review and presentation of a patient cohort. All SLN procedures included lymphoscintigraphy and blue dye injection technique. RESULTS: Twelve cases are described: two patients after a previous SLN procedure and ten after a previous complete axillary lymph node dissection (ALND). Ten patients (83%) had a successful repeat SLN biopsy. After previous ALND, lymphoscintigraphy revealed drainage towards the internal mammary chain in three patients, and contralateral axillary drainage in four. Based on the information from the "repeat" SLN biopsy further treatment strategy was altered in seven of the 12 patients. CONCLUSION: Lymphatic mapping and (repeat) SLN biopsy is possible and can be informative in patients who present with a relapse of breast cancer after previous surgery for primary breast cancer.

Comparison between human pharmacokinetics and imaging properties of two conjugation methods for 99mTc-annexin A5.

Annexin A5 (AnxA5) is a protein with high affinity for phosphatidyl serine, a phospholipid exposed on the cell surface during apoptosis. This phenomenon has been used for determination of cell death after myocardial infarction. To evaluate the potential of (99m)Tc-AnxA5 for in vivo scintigraphy of apoptotic cells, the pharmacokinetics and imaging properties of two radiopharmaceuticals, (99m)Tc-(n-1-imino-4-mercaptobutyl)-AnxA5 (I-AnxA5) and (99m)Tc-(4,5-bis(thioacetamido)pentanoyl)-AnxA5 (B-AnxA5), were studied. I-AnxA5 was administered intravenously to seven patients and one healthy volunteer, and B-AnxA5 was administered to 12 patients. All patients in the pharmacokinetic study had myocardial disease. Additionally, imaging was performed in a patient with acute myocardial infarction, as well as in three patients with different malignancies. The plasma concentration, excretion and biodistribution of (99m)Tc-AnxA5 were measured, as well as levels of AnxA5 antigen. The kinetic data of both radiopharmaceuticals in plasma fitted a two-compartment model. Both preparations had similar half-lives, but a different distribution over the two compartments. Plasma levels of AnxA5 antigen showed a broad variation. Both radiopharmaceuticals accumulated in the kidney, liver and gut. B-AnxA5 was excreted significantly faster than I-AnxA5. Both compounds can be used for imaging of the head/neck region, the thorax and the extremities. B-AnxA5 has a faster clearance and a lower radiation dose. Imaging of apoptosis in the abdomen will be difficult with both radiopharmaceuticals, and especially with B-AnxA5 because of its faster appearance in the gut.

Treatment of 100 patients with sentinel node-negative breast cancer without further axillary dissection.

BACKGROUND: The sentinel node biopsy technique for breast cancer has been validated extensively in phase I and II studies. However, no data from phase III randomized clinical studies are available. It remains controversial whether a histologically negative sentinel node biopsy without further axillary dissection can be considered to be good clinical practice. METHODS: One hundred consecutive patients with breast cancer who had a negative sentinel node biopsy without additional axillary dissection were studied prospectively between 1997 and 2000 in order to identify tumour recurrence and to assess the morbidity of the sentinel node procedure. Special attention was paid to axillary or locoregional recurrence, distant metastases and overall survival. One year after the procedure patients were sent a questionnaire to assess any functional impairment of the arm or shoulder. RESULTS: Median follow-up was 24 (range 16-40) months. One patient had an axillary relapse 14 months after the initial diagnosis of breast cancer. She died after 2 years from metastatic disease. There were no other local axillary recurrences. There was a 94 per cent response rate to the questionnaire. Twelve patients developed mild disabilities, of whom two said that they had to change their hobbies, sports or daily activities owing to the sentinel node procedure. No patient developed lymphoedema or needed physiotherapy after the operation. CONCLUSION: When strict criteria for the sentinel node biopsy procedure are used, the sentinel node biopsy without further axillary dissection after a negative histological investigation is a safe procedure. It may therefore be considered to be the standard of care for the treatment of patients with breast cancer.

Biodistribution and dosimetry of 99mTc-BTAP-annexin-V in humans.

The purpose of this study was to determine the biodistribution and the associated radiation dose of technetium-99m 4,5-bis(thioacetamido)pentanoyl-annexin-V (99mTc-Apomate), a tracer proposed for the study of apoptosis. Eight patients (including two females) with normal kidney and liver functions were included in the study. An activity of 580 +/- 90 MBq of 99mTc-Apomate was injected intravenously, immediately followed by a dynamic study of 30 frames of 1 min each. At about 1 h, 4 h and 20 h p.i., whole-body scans were acquired. All activity distributions were measured using a dual-head gamma camera. Before injection of activity, a transmission scan with a cobalt-57 flood source had been performed to determine patient attenuation. Blood samples were taken every 10 min during the first hour after injection, and at about 4 and 20 h. Urine and faeces were collected during the first 20 h. Organ uptake was estimated after correction for body background activity, attenuation and scatter. Residence times were calculated from the dynamic and whole-body studies and used as input in the Mirdose 3.1 program to obtain organ doses and effective dose. It was found that radioactivity strongly accumulated in the kidneys and the liver [at 70 min p.i., 28% +/- 8% and 20% +/- 4% of the injected dose (ID), respectively]. Uptake in the target tissues (lymphomas or heart) was negligible from a dosimetric point of view. Extrapolating data from the first 20 h, one finds that approximately 73% of the ID will be excreted in the urine, and 27% in the faeces. The biological half-life of the activity in the total body was 16 +/- 7 h. Some organ doses +/- standard deviation (SD) in microGy/MBq were: kidneys 63 +/- 22, urinary bladder 20 +/- 6, spleen 15 +/- 3, liver 13 +/- 3, upper large intestine 12 +/- 6, lower large intestine 8 +/- 4, testes 6 +/- 2 and red bone marrow 4 +/- 0.7. The effective dose was 7.6 +/- 0.5 microSv/MBq, corresponding to a total effective dose of 4.6 +/- 0.3 mSv for a nominal injected activity of 600 MBq. In conclusion, 99mTc-Apomate has a high uptake in the kidneys and liver--in fact a factor of 1.3-1.6 higher than that found for the previously studied 99mTc-(n-1-imino-4-mercaptobutyl)-annexin-V. The biological half-life is shorter, however, but still long compared with the physical half-life of 99mTc. The faster appearance of activity in the intestines may preclude imaging of apoptosis in the abdomen. The effective dose is within the lower range of values reported for typical 99mTc compounds.

Patient dosimetry of intravenously administered 99mTc-annexin V.

UNLABELLED: Annexin V labeled with 99mTc is evaluated as a potential in vivo marker for tissue with increased apoptosis. Promising results in patients have been obtained with 99mTc-(n-1-imino-4-mercaptobutyl)-annexin V (99mTc-i-AnxV). Because information on biodistribution and radiation burden is desired for the application of any radiopharmaceutical, a dosimetric study of 99mTc-i-AnxV was undertaken. METHODS: Eight persons with normal kidney and liver functions were included in this study: six patients with myocardial infarction, one with Crohn's disease, and one healthy volunteer. Approximately 600 MBq 99mTc-i-AnxV were injected intravenously immediately before a dynamic study with a dual-head gamma camera in conjugate view mode. In the next 24 h, two to four whole-body scans were acquired. Patient thickness was determined from a transmission scan with a 57Co flood source. Organ uptake was estimated after correction for background, attenuation, and scatter, using a depth-independent buildup factor and an organ-size-dependent attenuation correction. Residence times were calculated from the dynamic and whole-body studies and used as input for the MIRDOSE 3.1 program to obtain organ-absorbed doses and effective dose. RESULTS: Activity strongly accumulated in the kidneys (21% +/- 6% of the injected dose at 4 h postinjection) and the liver (12.8% +/- 2.2%). Uptake in the target tissues (myocardium or colon) was limited and negligible from a dosimetric point of view. The biologic half-life of activity registered over the total body was 62 +/- 13 h. Of the excreted activity, approximately 75% went to the urine and 25% to the feces. The absorbed dose for the more strongly exposed organs was (in microGy/MBq): kidneys, 93 +/- 24; spleen, 22 +/- 6; liver, 17 +/- 2; testes, 15 +/- 3; thyroid, 10 +/- 6; urinary bladder wall, 7.5 +/- 2.6; and red bone marrow, 5.5 +/- 0.8. The effective dose was 9.7 +/- 1.0 microSv/MBq, corresponding to a total effective dose of 5.8 +/- 0.6 mSv for a nominally injected activity of 600 MBq. CONCLUSION: 99mTc-i-AnxV strongly accumulates in the kidneys and to a lesser degree in the liver. The associated effective dose per MBq is in the midrange of values found for routine 99mTc-labeled compounds. From a dosimetric point of view 99mTc-i-AnxV is therefore well suited for the study of apoptosis in patients.

Visualisation of cell death in vivo in patients with acute myocardial infarction.

BACKGROUND: In-vivo visualisation and quantification of the extent and time-frame of cell death after acute myocardial infarction would be of great interest. We studied in-vivo cell death in the hearts of patients with an acute myocardial infarction using imaging with technetium-99m-labelled annexin-V-a protein that binds to cells undergoing apoptosis. METHODS: Seven patients with an acute myocardial infarction and one control were studied. All patients were treated by percutaneous transluminal coronary angioplasty (six primary and one rescue), resulting in thrombolysis in myocardial infarction (TIMI) III flow of the infarct-related artery. 2 h after reperfusion, 1 mg annexin-V labelled with 584 MBq Tc-99m was injected intravenously. Early (mean 3.4 h) and late (mean 20.5 h) single-photon-emission computed tomographic (SPECT) images of the heart were obtained. Routine myocardial resting-perfusion imaging was also done to verify infarct localisation. FINDINGS: In six of the seven patients, increased uptake of Tc-99m-labelled annexin-V was seen in the infarct area of the heart on early and late SPECT images. No increased uptake was seen in the heart outside the infarct area. All patients with increased Tc-99m-labelled annexin-V uptake in the infarct area showed a matching perfusion defect. In a control individual, no increased uptake in the heart was seen. INTERPRETATION: Increased uptake of Tc-99m-labelled annexin-V is present in the infarct area of patients with an acute myocardial infarction, suggesting that programmed cell death occurs in that area. The annexin-V imaging protocol might allow us to study the dynamics of reperfusion-induced cell death in the area at risk and may help to assess interventions that inhibit cell death in patients with an acute myocardial infarction.

Correlative 201Tl SPECT, MRI and ex vivo 201Tl uptake in detecting and characterizing cervical lymphadenopathy in head and neck squamous cell carcinoma.

UNLABELLED: The value of SPECT with 201Tl chloride, in combination with MRI (particularly short inversion-time inversion recovery [STIR] sequences that suppress fat signals) to detect and characterize cervical lymphadenopathies (nodes > or = 1 cm), and ex vivo lymph node 201Tl uptake were studied in patients with squamous cell carcinoma of the head and neck. METHODS: Preoperative SPECT and MRI, displayed in similar planes, were compared with the histologic findings in 15 neck dissection specimens from 12 patients with squamous cell carcinoma of the head and neck (9 with unilateral and 3 with bilateral neck dissection). Results were evaluated topographically with regard to the lymph node compartments (levels) of the neck. In addition, in 8 of these patients, the 201Tl activity of dissected lymph nodes of 10 neck sides was measured immediately after surgery in a gamma counter and expressed as percentage of the injected dose per gram tissue (%ID/g). RESULTS: Sixty-two lymph node levels were evaluated histologically. The high sensitivity of MRI (92% versus 71% for 201Tl SPECT), which correctly detected lymph node involvement in 22 of 24 levels, and the high specificity of 201Tl SPECT (92% versus 71% for MRI), which correctly characterized as negative 35 of 38 lymph node levels without metastasis on histology, led to a combined 201Tl SPECT/MRI accuracy of 92%. 201Tl SPECT was particularly effective in excluding involvement in 9 tumor-free neck levels with pathologically enlarged lymph nodes on MRI but failed to confirm involvement in 5 other tumor-positive levels. Mean 201Tl uptake in 53 lymph nodes with confirmed histologic involvement was significantly higher than uptake in 145 tumor-free lymph nodes (0.0043+/-0.0022 %ID/g versus 0.0023+/-0.0014 %ID/g, P = 0.0001), muscle and fat tissue but clearly lower than salivary gland uptake. CONCLUSION: Although 201Tl SPECT is not sensitive enough to be used as an independent imaging modality for staging of the neck, its correlative application with MRI appears to be an accurate method for the assessment of regional spread in head and neck squamous cell carcinoma. The ability of 201Tl SPECT to characterize neck lymphadenopathies detected by MRI appears to be based on the difference in 201Tl concentration found in lymph nodes with and without tumor involvement.

Does the cellular bronchoalveolar lavage fluid profile reflect the severity of sarcoidosis?

The aim of this study was to assess whether the cellular bronchoalveolar lavage fluid (BALF) profile, particularly the number of polymorphonuclear neutrophils (PMNs), is associated with disease severity of sarcoidosis and its usefulness in determining remission. Twenty-six nonsmoking outpatients with sarcoidosis were included in this study. The patients were divided into two subgroups according to the absolute number of PMNs in BALF: < or =0.2x10(4) cells x mL(-1) (group 1; n = 15) and >0.2x10(4) cells x mL(-1) (group 2; n = 11). The radiographic stage, high-resolution computed tomography (HRCT) findings, 67Ga lung uptake as well as lung function tests differed significantly between group 1 and 2. Follow-up revealed that 14 (93.3%) patients of group 1 compared to four (36.4%) of group 2 recovered spontaneously without the help of corticosteroids. In contrast, no differences were found in the number of lymphocytes in BALF nor in the serum angiotensin converting enzyme (sACE) level between both groups. The number of PMNs, the transfer factor of the lungs for carbon monoxide (TL,CO), the forced expiratory volume in one second (FEV1) and one of the HRCT subscores discriminated between patients with different disease progression. Of these parameters the PMNs appeared to be the only one which differentiated patients who demonstrated remission and those who deteriorated. In conclusion, these results indicate that the number of polymorphonuclear neutrophils in bronchoalveolar lavage fluid distinguish between sarcoidosis patients who demonstrated remission and those having a more severe course of the disease. Whether polymorphonuclear neutrophils may be considered as markers of disease activity and/or prognosis in sarcoidosis needs further investigation.

Intense muscle uptake of gallium-67 in a patient with sarcoidosis.

Sarcoidosis has been associated with muscle involvement. In general, this involvement remains asymptomatic. The following case report demonstrates a patient with a 4-mo history of sarcoidosis who reported severe fatigue and slight muscular complaints at a regular checkup. Gallium scintigraphy indicated unexpected and unusually extensive muscular localizations of the disease. The latter findings were confirmed by examination of biopsy specimens. The importance of gallium scintigraphy lies in the possibility of wholebody screening for inflammation localizations, particularly when physical, laboratory, lung function and radiographic examinations fail to provide convincing evidence of active sarcoidosis. Furthermore, it can be helpful in the follow-up of the effect of supportive treatment.

Validation of gamma probe detection of the sentinel node in melanoma.

UNLABELLED: In melanoma, the presence or absence of metastasis in the first lymph node (sentinel node, SN) has a predictive value for the entire lymph node basin. This study explores the efficacy of lymphoscintigraphy with 99mTc-nanocolloid and a gamma-ray detection probe in tracing SNs. METHODS: Sixty patients with clinically localized melanoma were studied. Lymphoscintigraphy was performed after intradermal injection of 60 MBq 99mTc-nanocolloid at the primary tumor site. Scintigraphy included early dynamic images and a body scan 2 hr postinjection. The following day, a gamma detection probe (Neoprobe 1000) was used intraoperatively to trace the still radioactive SNs. The number of counts of the nodes and the surrounding tissues was measured before, during and after excision. Excised nodes and normal tissue samples were measured in a gamma well counter. The uptake of 99mTc-nanocolloid was calculated. RESULTS: Lymphoscintigraphy showed 122 SNs distributed over 73 drainage basins. Use of the probe led to retrieval of all nodes that were searched for. The SN-to-background ratios were high: a median of 36 in vivo (range: 2-722) and a median of 274 ex vivo (range: 6-2,985). Counts in vivo correlated well with counts ex vivo. The mean percentage of the injected dose per SN was 0.69 (range: 0.0013-6.82), versus 0.23 (range 0.0004-2.59) in 23 measured second-echelon nodes (non-SNs). Mean percentage of uptake per gram tissue in SNs was 2.1 (range: 0.003-17.4), in skin 0.01 (range: 0.00-0.22) and in subcutaneous fat 0.0035 (range: 0.00-0.081). CONCLUSION: Average uptake of 99mTc-nanocolloid in SNs is substantially higher than uptake in non-SNs, skin and subcutaneous fat. The resulting high SN-to-background ratios facilitate the intraoperative detection of these nodes using a gamma detection probe.

Evidence for early and persistent impairment of salivary gland excretion after irradiation of head and neck tumours.

Salivary gland scintigraphy with technetium-99m pertechnetate was used to follow changes in the excretion and uptake function of the major salivary glands until 1 year after irradiation. Twenty-five patients who received radiotherapy for head and neck tumours were included in the study. Seventy-nine salivary glands (39 parotid and 40 submandibular) were evaluated in relation to the average received radiation dose. Salivary gland scintigraphy was performed before and 1, 6 and 12 months after radiotherapy. For each gland the excretion response to carbachol, evaluated by calculation of the salivary excretion fraction (SEF), the cumulative gland uptake (CGU) and the absolute excreted activity (AEA) at various intervals after radiotherapy were compared with the baseline values. The excretion response decreased in 20 of 25 patients at 1 month after radiotherapy. One month after radiotherapy both SEF and AEA decreased significantly in relation to the radiation dose. These decreases in excretion parameters persisted during the follow-up period. Parotid excretion was affected significantly more than submandibular excretion. CGU values did not change significantly until 6 months after radiotherapy, but at 12 months a significant decrease related to radiation dose was observed. Xerostomia was assessed during radiotherapy and on the days of the scintigraphic tests. The incidence of xerostomia did not correspond to the effects observed in the scintigraphic studies. It is concluded that radiotherapy induces early and persistent impairment of salivary gland excretion, related to the radiation dose. This impairment is stronger in parotid glands than in submandibular glands.

Reproducibility of lymphoscintigraphy for lymphatic mapping in cutaneous melanoma.

UNLABELLED: One of the indications for lymphoscintigraphy in patients with melanoma is to determine the lymphatic drainage pattern and position of the first draining lymph node--the sentinel node. Metastasis in the sentinel node indicates the need for therapeutic lymph node dissection. The purpose of the present study was to examine the reproducibility of lymphoscintigraphy in assessing the location and number of sentinel nodes. METHODS: Twenty-five patients with clinically localized melanoma were investigated. The same investigator performed two scintigraphic studies with a 2-4 wk interval in each patient, in an identical manner. A 60-MBq dose of 99mTc-nanocolloid was injected intradermally at the primary tumor site. The lymph flow was studied dynamically, complemented by lateral/oblique views. The images were evaluated by a panel of three observers. RESULTS: The sentinel node was visualized within 20 min in all patients. A difference in number of sentinel nodes depicted on the first and second study was noted in three patients (12%). The melanoma was situated on the head (two patients) and arm (one patient) in these patients. Otherwise, the images were identical for number and location of nodes. CONCLUSIONS: Reproducibility of lymphoscintigraphy with 99mTc-nanocolloid was high in this study. However, some sentinel nodes may be missed in lymphoscintigraphy for melanoma.

Iodine-123 metaiodobenzylguanidine in the assessment of late cardiac effects from cancer therapy.

Recognition of adverse late cardiac effects from cancer therapy may enable identification of patients with risk of cardiotoxicity upon cancer retreatment. In this study the feasibility of using iodine-123 metaiodobenzylguanidine (123I-MIBG) heart scintigraphy to detect abnormalities of the myocardial adrenergic neurone function in the late period after cancer therapy was evaluated in relation to the left ventricle ejection fraction (LVEF) in 18 cancer patients: 11 had undergone thoracic irradiation involving the heart, in five cases in combination with anthracycline therapy, 11-228 months (median 60 months) before radionuclide tests, while seven had not received previous anthracycline and/or radiotherapy (controls). The 123I-MIBG cardiac uptake, expressed as a heart-to-mediastinum ratio on planar images after 4h, ranged from 1.21 to 1.76 (median 1.56) in cancer therapy patients, which was significantly decreased (P=0.0006) in comparison with controls (range 1.81- 2.06, median 1.9). The myocardial 123I-MIBG washout, calculated from planar images after 15 min and 4 h, and LVEF also showed significant differences, but with some overlap in individual cases. In cancer therapy patients, cardiac abnormalities seen on planar images and additional single-photon emission tomographic images varied from focal defects to diffusely reduced myocardial uptake. It is concluded that 123I-MIBG heart scintigraphy, which is able to identify cardiac adrenergic neurone abnormalities in the follow-up period after cancer therapy, may help to identify relapsed patients who are at increased risk of developing cardiotoxicity during retreatment with cardiotoxic therapy modalities.