RESUMEN
BACKGROUND AND OBJECTIVES: Some patients presenting with cutaneous malignant melanoma without palpable adenopathy have regional metastatic disease. The results of a prospective clinical study of gamma probe-directed sentinel lymph node (SLN) biopsy are presented. METHODS: Over a 3-year period, 103 patients with a diagnosis of invasive primary cutaneous malignant melanoma (Breslow > 0.12 mm or > Clark level II) underwent preoperative lymphoscintigraphy with technetium sulfur colloid followed by gamma-probe-guided sentinel lymphadenectomy. There were 46 women and 57 men with a mean age of 55.7 years (range, 19-91). RESULTS: Mean Breslow thickness was 2.3 mm (range, 0.12-10 mm). Primary locations were head and neck in 12, trunk 46, upper extremity 19, and lower extremity in 26. One hundred sixteen lymph node basins were mapped in 103 patients. Axillary, inguinal, and cervical nodal basins comprised 55, 34, and 11% of the total basins evaluated, respectively. Sixty-eight patients (66%) underwent lymphatic mapping of one regional nodal basin, 27 patients (26%) underwent synchronous lymphatic mapping of 2 regional nodal basins, 6 patients (6%) underwent synchronous lymphatic mapping of 3 regional nodal basins, and 2 patients (2%) underwent synchronous lymphatic mapping of 4 regional nodal basins. Seroma or infection did not occur in any patients. Micrometastatic disease was identified in 15 sentinel lymph node biopsy sites in 13 (10%) patients. Of 10 patients undergoing lymph node dissection, 9(90%) had no additional pathological lymph node involvement. We achieved 99% success rate, 1% rate of failed sentinel node procedure, and 8% false-negative rate after median follow-up for 2 years. CONCLUSIONS: We concluded that gamma probe-directed sentinel lymph node biopsy is a straightforward procedure which can be done in the outpatient setting and facilitates management of patients with cutaneous malignant melanoma. It allows the surgeon to identify all basins at risk for metastatic disease and the location of the sentinel node(s) in relation to the basin.
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Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Melanoma/patología , Melanoma/cirugía , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Axila , Femenino , Estudios de Seguimiento , Cámaras gamma , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Metástasis Linfática , Masculino , Melanoma/secundario , Persona de Mediana Edad , Cuello , Cintigrafía , Reproducibilidad de los Resultados , Biopsia del Ganglio Linfático Centinela , Azufre Coloidal Tecnecio Tc 99mRESUMEN
UNLABELLED: This phase I study was initiated to determine the toxicity and therapeutic potential of high-dose 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen monoclonal antibody (MAb) combined with autologous hematopoietic stem cell rescue (AHSCR) in patients with rapidly progressing metastatic medullary thyroid cancer. METHODS: Twelve patients were entered into the study. Dose escalation was based on prescribed radiation doses to critical organs (i.e., kidney, lung, and liver). Starting doses were 900 cGy to the kidney and no more than 1200 cGy to the lung and liver, with dose increments of 300 cGy until the maximum tolerable dose is determined. Tumor targeting was assessed by external scintigraphy, toxicity was assessed according to the common toxicity criteria of the National Cancer Institute, and therapy responses were assessed by CT, serum carcinoembryonic antigen, and calcitonin. RESULTS: One patient received 9.95 GBq 131I-MN-14 F(ab)2, for an initial dose of 656 cGy to critical organs, 8 received 900 cGy (8.69-17.98 GBq), and 3 received 1200 cGy (15.17-17.69 GBq). The MAb scans of all patients showed positive findings. Autologous hematopoietic stem cells were given to all patients 1-2 wk after therapy, when the total body radiation exposure was less than 5.2 x 10(-7) C/kg/h. Dose-limiting toxicity, defined as grade 3 or 4 nonhematologic toxicity, was not seen in the patient who received the 656-cGy dose, and only 1 of the 8 patients treated at the 900-cGy dose level had grade 3 toxicity, which was gastrointestinal and reversible. No dose-limiting toxicity was seen in the 3 patients treated at the 1200-cGy dose level. Except for the instance of grade 3 gastrointestinal toxicity, nonhematologic toxicity was relatively mild, with only grade 1 or 2 toxicity observed in 9 patients. No renal toxicity was seen. Of the 12 patients, 1 had partial remission for 1 y, another had a minor response for 3 mo, and 10 had stabilization of disease lasting between 1 and 16 months. CONCLUSION: The results show the safety of administering high myeloablative doses of 131I-MN-14 F(ab)2 with AHSCR in patients with metastatic medullary thyroid cancer. The antitumor responses in patients with aggressive, rapidly progressing disease are encouraging and warrant further research to optimize the effectiveness of this new treatment.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Medular/radioterapia , Radioisótopos de Yodo/uso terapéutico , Radioinmunoterapia , Neoplasias de la Tiroides/radioterapia , Adulto , Anticuerpos Monoclonales Humanizados , Relación Dosis-Respuesta en la Radiación , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Dosificación Radioterapéutica , Neoplasias de la Tiroides/patologíaRESUMEN
The pharmacokinetics, dosimetry, and immunogenicity of 131I- and (111)In-/90Y-humanized LL2 (hLL2) anti-CD22 monoclonal antibodies were determined in patients with recurrent non-Hodgkin's lymphoma. Fourteen patients received tracer doses of 131I-hLL2 followed 1 week later by therapeutic doses intended to deliver 50-100 cGy to the bone marrow. Another eight patients received (111)In-hLL2 followed by therapy with 90Y-hLL2 also delivering 50 or 100 cGy to the bone marrow. The blood T(1/2) (hours) for the tracer infusions of 131I-hLL2 was 44.2 +/- 10.9 (mean +/- SD) compared with 54.2 +/- 25.0 for the therapy infusions, whereas the values were 70.7 +/- 17.6 for (111)In-hLL2 and 65.8 +/- 15.0 for 90Y-hLL2. The estimated average radiation dose from 131I-hLL2 in tumors >3 cm was 2.4 +/- 1.9 cGy/mCi and was only 0.9-, 1.0-, 1.1-, and 1.0-fold that of the bone marrow, lung, liver, and kidney, respectively. In contrast, the estimated average radiation dose from 90Y-hLL2 in tumors >3 cm was 21.5 +/- 10.0 cGy/mCi and was 3.7-, 2.5-, 1.8-, and 2.5-fold that of the bone marrow, lung, liver, and kidney, respectively. No evidence of significant anti-hLL2 antibodies was seen in any of the patients. Myelosuppression was the only dose-limiting toxicity and was greater in patients who had prior high-dose chemotherapy. Objective tumor responses were seen in 2 of 13 and 2 of 7 patients given 131I-hLL2 or 90Y-hLL2, respectively. In conclusion, 90Y-hLL2 results in a more favorable tumor dosimetry compared with 131I-hLL2. This finding, combined with the initial anti-tumor effects observed, encourage further studies of this agent in therapeutic trials.
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Anticuerpos Monoclonales/uso terapéutico , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos B/inmunología , Moléculas de Adhesión Celular , Radioisótopos de Indio/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Lectinas , Linfoma no Hodgkin/radioterapia , Radioinmunoterapia , Dosificación Radioterapéutica , Radioisótopos de Itrio/uso terapéutico , Adulto , Anciano , Animales , Anticuerpos Antiidiotipos/sangre , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Radioinmunoterapia/efectos adversos , Recurrencia , Lectina 2 Similar a Ig de Unión al Ácido SiálicoRESUMEN
BACKGROUND: Monoclonal antibodies (MAbs) against carcinoembryonic antigen (CEA) have been recognized as targeting agents for medullary thyroid carcinoma (MTC). This Phase I/II study was initiated to determine the safety, maximum tolerated dose (MTD), and therapeutic potential of (131)I-MN-14 F(ab)2 anti-CEA MAb for patients with metastatic MTC. METHODS: Fifteen patients were enrolled in this study. Dose escalation was based on estimates of radiation dose to the bone marrow, and the radioactive dose given was determined by a pretherapy diagnostic study in which 8 mCi (0.6-20 mg) of (131)I-MN-14 F(ab)2 was administered 1 week prior to therapy. RESULTS: Three patients received an initial dose of 140 centigray (cGy) to bone marrow, 11 received 180 cGy, and 1 received 220 cGy. Myelosuppression was the only significant treatment-related dose-limiting toxicity (DLT), and the MTD appeared to be 180 cGy to the bone marrow. Human antimouse antibodies (HAMA) developed in 8 patients 2-6 weeks after therapy. Seven patients had a median of 55% reduction of tumor markers. One patient showed a dramatic improvement in the mass effect on the airways caused by 3 tumor lesions in the neck, with a 45% reduction of overall tumor burden. The disease has continued to be radiologically stable in 11 of 12 assessable patients for periods ranging from 3+ to 26+ months. CONCLUSIONS: Therapy with (131)I-MN-14 F(ab)2 is well tolerated and shows evidence of biochemical and radiologic antitumor activity. HAMA development suggests that humanized MAbs will be required in trials with repeated dose schedules. Further dose escalation, alone or in combination with other therapy modalities, is indicated for future trials, preferably with humanized anti-CEA MAbs.
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Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/inmunología , Antígeno Carcinoembrionario/inmunología , Carcinoma Medular/radioterapia , Carcinoma Medular/secundario , Inmunoconjugados/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Radioinmunoterapia , Neoplasias de la Tiroides/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Antiidiotipos/biosíntesis , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Calcitonina/sangre , Carcinoma Medular/tratamiento farmacológico , Carcinoma Medular/inmunología , Carcinoma Medular/cirugía , Terapia Combinada , Femenino , Humanos , Inmunoconjugados/farmacocinética , Radioisótopos de Yodo/administración & dosificación , Radioisótopos de Yodo/farmacocinética , Masculino , Tasa de Depuración Metabólica , Ratones , Persona de Mediana Edad , Disección del Cuello , Proteínas de Neoplasias/sangre , Dosificación Radioterapéutica , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/inmunología , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/cirugía , Tiroidectomía , Distribución Tisular , Resultado del TratamientoRESUMEN
UNLABELLED: The biodistribution, pharmacokinetics and dosimetry of 188Re-labeled MN-14, an IgG anti-carcinoembryonic antigen monoclonal antibody (MAb), were assessed in patients in advanced gastrointestinal cancer. In addition, the dose-limiting toxicity (DLT) and maximum tolerated dose of fractionated doses of this agent were determined. METHODS: Eleven patients were administered radioactive doses of directly labeled 188Re-MN-14 IgG, ranging from 20.5 mCi to 161.0 mCi (2.0 mg-4.9 mg). Ten of these patients received two or three MAb infusions, given 3-4 days apart, delivering total doses of 30 mCi/m2-80 mCi/m2. External scintigraphy was used to evaluate the MAb biodistribution, and quantitative external scintigraphic methods were used to determine the organ and tumor radiation doses. RESULTS: The biodistribution studies showed enhanced 188Re-MN-14 uptake in the liver, spleen and kidneys, compared to that of 131I-MN-14. The biological T(1/2) values for 188Re-MN-14 in the blood and whole body (in hours) were 8.2 +/- 4.1 (n = 7) and 107.8 +/- 104.2 (n = 9), respectively (mean +/- s.d.). The radiation absorbed doses (cGy/mCi) delivered to the total body, red marrow, lungs, liver, spleen and kidneys were 0.5 +/- 0.05, 3.6 +/- 1.6, 2.0 +/- 0.8, 5.9 +/- 2.5, 7.1 +/- 1.9 and 8.5 +/- 2.8, respectively. Red marrow suppression was the only DLT observed. The maximum tolerated dose of fractionated doses of 188Re-MN-14 was estimated to be 60 mCi/m2. CONCLUSION: Despite its relatively increased renal and hepatic uptake, red marrow suppression is the only DLT of 188Re-MN-14. The feasibility of administering relatively high doses of 188Re on a completely outpatient basis may make this agent a preferred candidate for radioimmunotherapy.
Asunto(s)
Antígeno Carcinoembrionario/inmunología , Neoplasias del Colon/radioterapia , Neoplasias Pancreáticas/radioterapia , Radioinmunoterapia , Radioisótopos/uso terapéutico , Renio/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radioisótopos/efectos adversos , Radioisótopos/farmacocinética , Dosificación Radioterapéutica , Renio/efectos adversos , Renio/farmacocinética , Distribución TisularRESUMEN
UNLABELLED: The aim of this study was to determine, in a Phase I/II clinical trial, the pharmacokinetics, dosimetry and toxicity, as well as antitumor activity, of the 131I-labeled murine anti-carcinoembryonic antigen (CEA) monoclonal antibody, NP-4 (IgG1 subtype). METHODS: A total of 57 patients with CEA-expressing tumors (29 colorectal, 9 lung, 7 pancreas, 6 breast and 4 medullary thyroid cancer patients), mostly in very advanced stages, were treated. The patients underwent a diagnostic study (1-3 mg of IgG and 8-30 mCi of 131I) to assess tumor targeting and to estimate dosimetry, followed by the therapeutic dose (4-23 mg and 44-268 mCi), based on the radiation dose to the red marrow. Imaging was performed from 4-240 hr postinjection (planar and SPECT). Blood and whole-body clearance were determined; radiation doses were calculated by the Medical Internal Radiation Dose scheme. RESULTS: Red marrow doses ranged from 45 to 706 cGy, and whole-body doses ranged from 31 to 344 cGy. Differences in pharmacokinetics were found between different types of CEA-producing tumors: blood T 1/2 was significantly lower in colorectal cancer when compared to all other tumor types (21.4 +/- 11.1 hr versus 35.8 +/- 13.2 hr, p < 0.01), as was also whole-body t 1/2. Myelotoxicity was dose-limiting, and its severity was related to the types of prior therapy and extent of bone marrow involvement. In patients without prior radiation or chemotherapy, marrow doses as high as 600 cGy were tolerated without evidence of dose-limiting toxicity. No major toxicity to other organs was observed. Tumor doses were inversely related to the tumor mass and ranged between 2 and 218 cGy/mCi. Modest antitumor effects were seen in 12 of 35 assessable patients (1 partial remission, 4 minor/mixed responses and 7 with stabilization of previously rapidly progressing disease). CONCLUSION: These results suggest that prior chemotherapy or external beam radiation is an important risk factor for the development of hematological toxicity in radioimmunotherapy and that higher radiation doses may be delivered to tumors of patients without prior therapy compromising the bone marrow reserve. The different and, in the individual cases, unpredictable clearance rates suggest the necessity of dosimetry-based treatment planning rather than mCi/m2 dosing. Small tumors seem to be more suitable for radioimmunotherapy because of their favorable dosimetry, but to achieve better therapeutic results in patients with bulky disease, the application of higher, potentially myeloablative doses is indicated.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígeno Carcinoembrionario/inmunología , Radioisótopos de Yodo/uso terapéutico , Radioinmunoterapia , Anciano , Anticuerpos Antiidiotipos/inmunología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Médula Ósea/efectos de la radiación , Femenino , Humanos , Radioisótopos de Yodo/efectos adversos , Radioisótopos de Yodo/farmacocinética , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Radioinmunoterapia/efectos adversos , Radioinmunoterapia/métodos , Dosificación Radioterapéutica , Factores de Riesgo , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Advanced chemotherapy-resistant ovarian cancer has a poor prognosis, thus requiring new therapeutic modalities. A complete clinical remission, using two cycles of 131I-labeled murine MN-14 anti-CEA monoclonal antibody (MAb), given intravenously, is reported in a patient with advanced ovarian cancer refractory to paclitaxel (Taxol) therapy. The patient first received radioimmunotherapy with approximately 74 mCi 131I-MN-14 IgG, followed 4 mo later by a similar dose of radiolabeled MAb. A partial remission was seen by CT 1 mo after the first radioimmunotherapy, and a further objective response was documented after the second radioimmunotherapy. CT scans performed 6 and 11 mo after the second radioimmunotherapy showed stable and minimal residual changes. However, a whole-body PET scan with [18F]fluorodeoxyglucose (FDG-PET) was negative in these regions. The CA-125 also decreased to only 13 U/ml, compared to the baseline value of 7700 U/ml. Based on CT, FDG-PET, serum CA-125 and physical exam, the patient was in complete clinical remission for 8 mo when the CA-125 levels rose. CT also showed a new suspicious lesion, presumably a peritoneal implant. No toxicity was seen after the first injection, and only Grade 1 thrombocytopenia and Grade 2 leukopenia developed after the second injection, both reversing within 6 wk. This is a report of a complete clinical remission with radiolabeled anti-CEA antibodies in a patient with chemotherapy-refractive metastatic ovarian cancer.
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Neoplasias Ováricas/radioterapia , Radioinmunoterapia , Terapia Recuperativa , Anciano , Anticuerpos Monoclonales , Antígeno Ca-125/sangre , Antígeno Carcinoembrionario/inmunología , Desoxiglucosa/análogos & derivados , Femenino , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Humanos , Radioisótopos de Yodo/uso terapéutico , Neoplasias Ováricas/diagnóstico , Inducción de Remisión , Tomografía Computarizada de Emisión , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: This study examined the utility of using radiolabeled anticarcinoembryonic antigen (CEA) monoclonal antibodies (MAbs) as a noninvasive imaging method to aid in the selection of patients for reoperation after operation for medullary thyroid carcinoma (MTC). METHODS: Sixteen patients with persistent or recurrent hypercalcitoninemia since operation or MTC, but had negative or equivocal conventional imaging study results, were given 99mTc-, 123I-, or 131I-labeled NP-4 or MN-14 anti-CEA MAbs. Scintigraphic images were then performed to determine detection of tumor lesions. RESULTS: The MAb scans were positive in 13 (81%) of the 16 patients studied. However, in only three of 13 patients was disease confined to the cervical or mediastinal nodes. In 10 patients, disease was additionally or solely found in distant organs such as liver (five patients), bone (four patients), and periaortic nodes (one patient). On the basis of our studies, only three of the 13 patients with positive scans would benefit from repeat neck exploration, another three would possibly benefit from neck or mediastinal exploration and hepatic resection, and the remaining seven patients would not benefit from any reoperation with curative intent. CONCLUSIONS: MTC imaging with anti-CEA MAbs could be very useful in determining the ideal candidates for repeat neck exploration.
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Anticuerpos Monoclonales , Antígeno Carcinoembrionario/inmunología , Carcinoma Medular/cirugía , Radioinmunodetección , Neoplasias de la Tiroides/cirugía , Adulto , Anciano , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Carcinoma Medular/diagnóstico por imagen , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Reoperación , Neoplasias de la Tiroides/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVES: Epithelial ovarian cancer (EOC) is known to produce carcinoembryonic antigen (CEA), and the plasma CEA level is frequently elevated in patients with advanced stage and bulk of tumor. This study reports the results of a phase I therapy trial with intravenously administered 131I-MN-14 anti-CEA monoclonal antibody (MAb) in patients with EOC. METHODS: Fourteen patients with advanced refractory EOC were given escalating intravenous doses (two received 30 mCi/m2, six 40 mCi/m2, and six 50 mCi/m2) of 131I-MN-14 IgG. All patients received a diagnostic study with 8 mCi (0.6 mg) of 131I-MN-14 IgG 1 week prior to their therapy infusion. Tumor targeting was assessed by external scintigraphy, toxicity according to the Radiation Therapy Oncology Group criteria, and therapy responses by CT and serum CA-125. RESULTS: The MAb scan was positive in all 14 treated patients. Myelosuppression was the only observed treatment-related toxicity. Dose-limiting toxicity, defined as grade 4 leukopenia or thrombocytopenia of any duration, or grade 3 leukopenia or thrombocytopenia of > 2 weeks, was not seen at the 30 or 40 mCi/m2 dose levels. However, 2 of 6 patients treated at 50 mCi/m2 had a grade 4 thrombocytopenia or a grade 3 thrombocytopenia lasting 18 days. Of the 14 patients, 1 with diffuse peritoneal implants of < or = 2 cm had a complete clinical remission by CT and CA-125 for 8 months, following an initial partial remission for 10 months, both at the 40 mCi/m2 dose level. Another patient had a mixed response for 1 month. CONCLUSION: MN-14 anti-CEA MAb is a suitable agent for tumor targeting and may have a therapeutic potential in patients with chemotherapy-refractive EOC, especially those with minimal disease.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Antígeno Carcinoembrionario/inmunología , Carcinoma/radioterapia , Neoplasias Ováricas/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Radioisótopos de Yodo , Ratones , Persona de Mediana Edad , Radioinmunoterapia , Resultado del TratamientoRESUMEN
We present a case of visualization of a clot in the superior vena cava with collateral flow to the liver during a lung perfusion scan. A digital venogram performed after injection through the right central venous line confirmed the presence of a clot in the superior vena cava with retrograde flow into the azygous venous system.
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Circulación Colateral , Hígado/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Síndrome de la Vena Cava Superior/diagnóstico por imagen , Vena Cava Superior/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Angiografía de Substracción Digital , Cateterismo Venoso Central , Femenino , Humanos , Hígado/irrigación sanguínea , Cintigrafía , Síndrome de la Vena Cava Superior/fisiopatología , Agregado de Albúmina Marcado con Tecnecio Tc 99mRESUMEN
UNLABELLED: The clinical feasibility of radioimmunotherapy (RIAIT) was assessed in patients with metastatic, carcinoembryonic antigen (CEA)-producing cancers who had minimal residual or small-volume disease (tumor lesions < or = 3 cm in diameter). METHODS: Thirteen cancer patients (8 colorectal, 3 lung, 1 pancreatic and 1 medullary thyroid cancer) received RAIT with 131I-NP-4 F(ab')2 anti-CEA antibody. The radioactive dose given was based on a prescribed radiation dose to the red marrow. Ten of the 13 patients received initial therapeutic doses delivering 150-450 cGy to the red marrow (70-296 mCi) and six patients had more than one therapy infusion. RESULTS: Targeting of all known tumor lesions < 0.5 cm [corrected] in diameter was possible in nine patients and at least one tumor lesion was evident in all patients. Disease stabilization ranging from 3.5 to 7 mo was seen in 6 of the 13 patients who previously had clear evidence of progressive disease. Four of the six patients with disease stabilization received the presumed maximum tolerated dose of 450 cGy to the red marrow. Red marrow suppression was the only observed toxicity and there was a good correlation between the red marrow dose and myelotoxicity. Red marrow doses < or = 250 cGy resulted in < or = grade 2 myelotoxicity and a red marrow dose of 450 cGy resulted in reversible grade 3 or 4 myelotoxicity in 3 of 6 patients. Human anti-mouse antibodies (HAMA) developed in all but one of the six patients who received multiple therapeutic infusions of the antibody. CONCLUSION: RAIT of patients with small-volume disease is feasible and these patients should be considered for future dose-intensification trials because of their generally poor prognosis.
Asunto(s)
Neoplasias Colorrectales/radioterapia , Radioisótopos de Yodo/uso terapéutico , Neoplasias Pulmonares/radioterapia , Radioinmunoterapia , Adulto , Anciano , Anciano de 80 o más Años , Antígeno Carcinoembrionario/inmunología , Relación Dosis-Respuesta en la Radiación , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dosificación RadioterapéuticaRESUMEN
BACKGROUND: The initial clinical experience with the second-generation, high-affinity, MN-14 immunoglobulin (IgG) anticarcinoembryonic antigen (CEA) monoclonal antibody (MoAb) in patients with CEA-producing tumors was reported previously. A bivalent fragment of this MoAb, MN-14 F(ab)2, was prepared, and its pharmacokinetics, targeting properties, dosimetry, and immunogenicity were investigated. METHODS: MN-14 F(ab)2(0.6-29 mg) was labeled with 131I(7.7-269 millicuries and injected into 28 patients with CEA-producing cancers. External scintigraphy was used to evaluate tumor targeting. Quantitative external scintigraphy methods were used to determine the organ and tumor radiation doses. RESULTS: The overall sensitivity of tumor targeting on a lesion basis was 86%, similar to that reported previously for MN-14 whole IgG. The biologic T1/2's for the fragment in the blood and total body (in hours) were 16.8 +/- 4.1 and 59.4 +/- 9.4, respectively, compared with 27.3 +/- 15.7 and 69.6 +/- 32.2 reported for MN-14 IgG. Depending on the protein dose given, high plasma CEA levels (>100ng/ML) resulted in a significant alteration of MoAb pharmacokinetics and organ dosimetry. Individual tumors received an average dose of 10.7 +/- 7.3 centigray [cGy]/mCi, and the tumor-to-total body, red marrow, lung, liver, and kidney dose ratios were 16.8 +/- 11.1, 5.6 +/- 3.6, 5.1 +/- 3.9, 6.0 +/- 3.8, and 3.1 +/- 2.0, respectively (mean + standard deviation [SD]). Only 9 of 18 patients (50%) injected with >4 mg (range: 4-52.1 mg) of MN-14 F(ab)2 developed significant levels of human antimouse antibodies, suggesting that the F(ab)2 may be less immunogenic than the intact IgG. CONCLUSIONS: MN-14 F(ab)2 exhibits a similar targeting sensitivity and tumor dose as reported previously for the IgG form. The lower red marrow doses combined with lower immunogenicity expected for this agent, may make it a suitable alternative for future imaging and therapeutic applications.
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Anticuerpos Monoclonales/metabolismo , Antígeno Carcinoembrionario/inmunología , Fragmentos Fab de Inmunoglobulinas/metabolismo , Inmunotoxinas/metabolismo , Neoplasias/sangre , Adolescente , Adulto , Anciano , Anticuerpos/sangre , Anticuerpos Monoclonales/uso terapéutico , Complejo Antígeno-Anticuerpo/sangre , Antígeno Carcinoembrionario/sangre , Femenino , Semivida , Humanos , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Inmunotoxinas/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , CintigrafíaRESUMEN
UNLABELLED: This study evaluates the pharmacokinetics, dosimetry, toxicity and therapeutic potential of radiolabeled NP-4 and MN-14 anti-CEA antibodies in medullary thyroid cancer (MTC). METHODS: Eighteen patients with advanced MTC entered exploratory clinical studies with therapeutic doses of 131I-labeled NP-4 and MN-14 murine monoclonal antibodies (MAbs) reactive with carcinoembryonic antigen (CEA). Doses administered ranged from 46 mCi for 131I-MN-14 lgG to 195 mCi for 131I-MN-14 F(ab)2 in patients negative for human anti-mouse antibodies (HAMA). RESULTS: The radioconjugate blood half-life (T1/2) for the whole lgG was 42.5+/-5.0 hr compared to 18.8+/- 4.1 hr for the bivalent fragments. Tumor doses of 17.5+/-11.0 and 11.4+/-6.3 cGy/mCi were estimated for 131I-MN-14 lgG and F(ab)2, respectively. Tumor/red marrow dose ratios exceeded 3:1 for most lesions. Red marrow doses of up to 350 cGy generally could be delivered with < grade 4 toxicity. Seven of 14 evaluable patients showed evidence of anti-tumor effects lasting up to 26 months, based on physical exam, tumor markers or computed tomography. CONCLUSION: This study demonstrates that anti-CEA MAbs may be suitable for radioimmunotherapy of metastatic or recurrent MTC.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígeno Carcinoembrionario/inmunología , Carcinoma Medular/radioterapia , Radioisótopos de Yodo/uso terapéutico , Radioinmunoterapia , Neoplasias de la Tiroides/radioterapia , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Carcinoma Medular/diagnóstico por imagen , Femenino , Humanos , Radioisótopos de Yodo/efectos adversos , Radioisótopos de Yodo/farmacocinética , Masculino , Persona de Mediana Edad , Radioinmunoterapia/efectos adversos , Dosificación Radioterapéutica , Neoplasias de la Tiroides/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
PURPOSE: This investigation was undertaken to assess the targeting of established and occult medullary thyroid cancer (MTC) with radiolabeled monoclonal antibodies (MAbs) reactive with carcinoembryonic antigen (CEA). PATIENTS AND METHODS: Twenty-six assessable patients with known (n = 17) or occult (n = 9) MTC were studied with radiolabeled anti-CEA MAbs. Scintigraphic images were collected to determine targeting of tumor lesions. RESULTS: The targeting results of technetium 99m (99mTc)-,iodine 123 (123I)-, and iodine 131 (131I)-labeled anti-CEA antibodies (all directed against the same epitope of CEA) indicated that all these reagents were capable of detecting established and occult MTC. The sensitivity for detection of known sites of disease ranged from 76% to 100% for the various anti-CEA MAbs used, when compared with computed tomography (CT), magnetic resonance imaging (MRI), bone scan, or other imaging modalities. Moreover, the antibody scan was positive in seven of nine patients with occult disease (patients with negative conventional imaging studies, but who had elevated calcitonin and/or CEA levels). Three of seven patients underwent surgery and the disease was confirmed by histopathology in all three. CONCLUSION: Anti-CEA MAbs are excellent agents for imaging recurrent, residual, or metastatic MTC. The high lesion sensitivity in patients with known lesions, combined with the ability to detect disease, may make these agents ideal for staging patients, monitoring disease pretherapy or posttherapy, and especially for evaluating patients with recurrent or persistent hypercalcitonemia or CEA elevations after primary surgery. Analogous to radioiodine in the evaluation of patients with differentiated thyroid cancer, radiolabeled anti-CEA MAbs may achieve a similar role in diagnosing and monitoring patients with MTC.
Asunto(s)
Antígeno Carcinoembrionario/inmunología , Carcinoma Medular/diagnóstico por imagen , Carcinoma Medular/inmunología , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/inmunología , Humanos , Radioisótopos de Yodo , Valor Predictivo de las Pruebas , Cintigrafía , Sensibilidad y Especificidad , TecnecioRESUMEN
LL2 is a murine IgG2a anti-CD22 monoclonal antibody found to react with virtually all non-Hodgkin's lymphomas (NHLs). Twenty-one patients with chemotherapy-resistant NHL received nonmyeloablative doses of 131I-labeled LL2 IgG and F(ab')2 ranging from 15 to 343 mCi given in cycles of 15-50 mCi, for up to seven treatment cycles. The cumulative protein dose ranged from 1.1 mg IgG to 157 mg F(ab')2. Seventeen patients were assessable for treatment response, and antitumor effects were seen in five (one complete remission, two partial remissions, and two minor or mixed responses). In addition, one complete response was seen in a patient who received only "diagnostic" doses of 131I-LL2 IgG. Thus, a total of six patients had responses according to the defined response criteria. Three additional patients have been treated with potentially myeloablative doses of 131I-LL2 IgG at a starting dose level of 90 mCi/m2 (100 mg). Two patients were evaluable, and both had partial remissions lasting 8 and 3 months, respectively. Chimeric and complementarity-determining region-grafted LL2 have been developed. Initial clinical studies have shown that these agents have targeting properties similar to the murine LL2 and, therefore, may be suitable alternatives to murine LL2 in the treatment of NHL. LL2 is a promising agent for the treatment of lymphoma, particularly when the maximum tolerated dose is given either with or without autologous bone marrow transplantation.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Moléculas de Adhesión Celular , Radioisótopos de Yodo/uso terapéutico , Lectinas , Linfoma de Células B/radioterapia , Radioinmunoterapia , Adulto , Anciano , Animales , Anticuerpos Monoclonales/farmacocinética , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos B/inmunología , Femenino , Humanos , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B/inmunología , Masculino , Ratones , Persona de Mediana Edad , Dosificación Radioterapéutica , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/uso terapéutico , Lectina 2 Similar a Ig de Unión al Ácido Siálico , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
A complementarity-determining region-grafted (humanized) version of MN-14 (hMN-14), a high-affinity, anti-carcinoembryonic antigen (CEA) murine monoclonal antibody (mMAb), was selected from several clones that differed slightly in their framework composition. One clone was selected based on its similar binding affinity to CEA as that observed with mMN-14 MAb and its production yields. Targeting studies, using 131I-labeled humanized MN-14 (hMN-14)/125I-labeled mMN-14 IgG in GW-39 tumor-bearing nude mice, showed excellent tumor uptake and tumor: nontumor ratios, similar to the mMN-14. A pilot clinical imaging trial was initiated to determine the targeting, pharmacokinetics, and dosimetry for 131I-labeled hMN-14 IgG. Nineteen patients with advanced CEA-producing tumors were given 8 to 30 mCi (0.5 to 20.0 mg). Eleven patients also received 131I-labeled mMN-14 IgG for comparison. The biodistribution, tumor targeting, and pharmacokinetic behavior of the hMN-14 was similar to that seen with the mMN-14. The average time required to clear 50% of the radiolabeled hMN-14 from the blood and total body was 32.9 +/- 25.6 h and 109 +/- 73 h, respectively. Patients with elevated plasma CEA (i.e., > 200 ng/ml) had more than 30% of the labeled antibody complexed within 1 h after injection. In some of these patients, increased complexation resulted in enhanced metabolism of the antibody with more rapid clearance from the blood than that seen in patients with lower plasma CEA. The average radiation absorbed dose measured in 20 tumors (average weight, 204 +/- 205 g) in 14 patients was 7.6 +/- 5.3 cGy/mCi. Tumor: nontumor dose ratios were 2.5 +/- 1.6, 9.5 +/- 5.8, and 2.6 +/- 1.8 for the red marrow, total body, and liver, respectively. One patient, with a highly elevated human anti-mouse antibody response from a prior OncoScint study (murine B72.3 IgG), received 3 injections of the hMN-14 without an adverse experience, and showed no evidence of altered biodistribution characteristic of mMAb-human anti-mouse antibody interactions. An antibody response to hMN-14 (HAhMN14) was not detected in patients who received only the hMN-14 (as many as three injections), but in three patients who received two injections of the mMN-14, a HAhMN14 response was detected. With similar, excellent targeting properties as the mMN-14 and the potential for reduced immunogenicity, hMN-14 is an attractive candidate for further clinical imaging and therapy applications.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Región Variable de Inmunoglobulina/inmunología , Radioisótopos de Yodo/uso terapéutico , Neoplasias/radioterapia , Radioinmunoterapia , Adulto , Anciano , Animales , Anticuerpos Monoclonales/inmunología , Antígeno Carcinoembrionario/inmunología , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Neoplasias/inmunología , Neoplasias Experimentales/radioterapia , Proyectos Piloto , CintigrafíaRESUMEN
The targeting potential of 131I-labeled NP-4 and MN-14 anti-CEA (carcinoembryonic antigen) monoclonal antibodies (MAbs) was assessed in 19 patients with metastatic medullary thyroid cancer (MTC). Seventeen of these patients also entered pilot radioimmunotherapy studies with nonmyeloablative doses of 131I-anti-CEA MAbs. Tumor targeting was possible in all 19 patients, with an overall lesion sensitivity of 91%. Tumor dosimetry with 131I-MN-14 IgG or F(ab)2 was very favorable, with tumor doses of 14.3 +/- 8.3 cGy/mCi and tumor:red marrow dose ratios exceeding 3:1 for most lesions. Limited antitumor effects lasting up to 26+ months, based on physical exam, tumor markers, computed tomography, or a followup MAb scan, were seen in 5 of 11 assessable patients given relatively low doses of 131I-labeled anti-CEA MAbs. We conclude that anti-CEA MAbs are excellent agents for targeting metastatic MTC. The high tumor uptake of the 131I-anti-CEA antibodies and evidence of tumor response in some patients suggest that radioimmunotherapy with radioiodinated anti-CEA MAbs may be an effective treatment for MTC, particularly when the maximum tolerated dose is given alone or in combination with autologous red marrow or peripheral stem cell support.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Carcinoma Medular/radioterapia , Radioisótopos de Yodo/uso terapéutico , Radioinmunoterapia , Neoplasias de la Tiroides/radioterapia , Animales , Antígeno Carcinoembrionario/inmunología , Carcinoma Medular/diagnóstico por imagen , Carcinoma Medular/inmunología , Femenino , Humanos , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Masculino , Ratones , Proyectos Piloto , Cintigrafía , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/inmunologíaRESUMEN
The MR features of congenital glenoid dysplasia are described. Osseous changes include both dysplasia of the glenoid and hypoplasia of the glenoid process. In addition, there are cartilaginous changes with hypertrophy of both the articular cartilage and the glenoid labra.
Asunto(s)
Imagen por Resonancia Magnética , Articulación del Hombro/anomalías , Adulto , Cartílago Articular/patología , Humanos , Húmero/patología , Hipertrofia , Masculino , Articulación del Hombro/patología , Tendinopatía/diagnóstico , Tendones/patologíaRESUMEN
Transient bone marrow edema has been thought to be related to other similar entities including transient regional osteoporosis and spontaneous osteonecrosis. Although the findings of three-phase bone imaging have been described in osteonecrosis, scant attention has been paid in the nuclear medicine literature to patients with transient bone marrow edema. The authors report the findings of three-phase bone imaging in two patients with knee pain and a transient bone marrow edema pattern as documented by MRI.