Optimization of radioimmunotherapy interactions with hyperthermia.

The efficacy of radioimmunotherapy (RIT) employing radiolabelled monoclonal antibodies (MAb) is currently limited in most solid tumours. The combination of local hyperthermia (HT) with RIT has the potential to enhance tumour targeting of MAb; moreover, this approach may add an antitumour effect to radioresistant hypoxic and S-phase cells and may inhibit the cells from repairing sublethal damage or potentially lethal damage caused by ionizing radiation. There are distinct types of protocols in this combination. Hyperthermic temperature and timing relative to RIT administration appear to affect the efficacy of the combination therapy. Responses to heating at any particular condition are not always the same among different tumour types. There are many papers describing influence of HT on the biodistribution of radiolabelled MAb, but only limited information is currently available on 'therapeutic' outcomes regarding the dependency of combination protocols. A previous study suggested that the best therapeutic improvement would be achieved when HT was combined immediately after the administration of MAb, which significantly increases the radiation absorbed dose to tumours and produces a uniform intratumoural dose distribution. Further therapeutic investigation should be required to reach the optimal protocol of combining these two modalities.

Hypoxia as a factor for 67Ga accumulation in tumour cells.

Recent reports have demonstrated that hypoxia induces the up-regulation of transferrin receptor expression in tumour cells. Tumour cells take up 67Ga in the form of a 67Ga-transferrin complex via transferrin receptors. As a result, we attempted to determine the influence of hypoxic conditions on 67Ga uptake in tumour cells. B16 melanoma cells and LS180 colon cancer cells were incubated in 95% air/5% CO2 or 95% N2/5% CO2 for 1 h at 37 degrees C. Cellular uptake of 67Ga citrate was subsequently determined at 20, 40, 60 and 90 min. Uptake of the 67Ga-transferrin complex pre-chelated in vitro was similarly assessed. The effect of hypoxia on 67Ga binding to serum proteins was also investigated. Both B16 and LS180 cells displayed increased cellular uptake of 67Ga citrate in N2 gas in comparison to that in air (P < 0.0001). Hypoxia more prominently influenced cellular uptake of Ga-transferrin relative to that of 67Ga citrate (P < 0.0001). Hypoxia did not affect the percentages of 67Ga radioactivity bound to protein in medium supplemented with fetal calf serum, indicating that the results were not caused by the alteration of 67Ga-transferrin formation. These findings suggest the role of tissue hypoxia with respect to accumulation of 67Ga in tumours, which is likely mediated by transferrin receptors.

Estimation of fractional liver uptake and blood retention of 99mTc-DTPA-galactosyl human serum albumin: an application of a simple graphical method to dynamic SPECT.

The objective of this study was to investigate clinical utility of a graphical method for estimating liver uptake and blood retention of 99mTc-DTPA-galactosyl human serum albumin (99mTc-GSA; DTPA is diethylenetriaminepentaacetic acid) using dynamic single photon emission computed tomography (SPECT) data. When considering the kinetics of 99mTc-GSA, if it is assumed that (1) 99mTc-GSA distributes only between blood and liver, and (2) no metabolism of 99mTc-GSA occurs during the observation period, a plot of liver counts versus cardiac blood pool counts should, theoretically, be a straight line. From the slope and y intercept of a regression line, coefficients for converting count based liver and blood pool data to the per cent injected dose (%ID) can be calculated. The applicability of this method was tested on dynamic SPECT data from 30 patients with liver dysfunction. To validate this method, plasma concentrations (%ID/ml plasma) at 6, 15 and 30 min after the injection were estimated by this method and compared with the measured ones. To investigate the clinical significance of the per cent liver uptake, the value obtained by this method was compared with the results of conventional liver function tests, including serum albumin, the hepaplastin test, prothrombin time and indocyanine green clearance. In every data set, a plot of liver counts to cardiac blood pool counts was fitted well by a straight line (P<0.00001). Estimated plasma concentrations by this method showed good correlation with the measured ones at 6, 15 and 30 min after the injection (r=0.748, 0.838, 0.875, respectively; P<0.0001). The liver uptake determined by this method showed good correlation with the results of conventional hepatic function tests (P<0.002). The graphical method could provide an accurate estimate of %ID of 99mTc-GSA in blood without the need for blood sampling. The liver uptake determined by this method could be a simple but useful quantitative indicator of hepatic function.

Intraoperative lymphatic mapping and sentinel lymph node biopsy in patients with papillary carcinoma of the thyroid gland.

We examined the feasibility of sentinel lymph node biopsy for thyroid cancer. Thirty-eight patients with papillary thyroid carcinoma underwent intraoperative lymphatic mapping and sentinel lymph node biopsy. At surgery, we exposed the thyroid gland and used a tuberculin syringe to inject 0.2 ml of 1% patent blue dye directly into the thyroid mass. The lymphatics and the lymph node dyed with blue dyes, was excised as a sentinel lymph node. Modified radical neck dissection was performed following sentinel lymph node biopsy and the diagnostic ability of sentinel lymph node biopsy was examined. A sentinel lymph node was identified successfully in 27 (71%) of 38 patients. Sentinel lymph node biopsy removed one to three lymph nodes (median, two nodes). Eighteen patients had paratracheal sentinel lymph nodes, five patients had jugular sentinel lymph nodes, and four patients had both. Histological nodal metastasis was recognized in 16 of 27 cases. The positive rate of cancer metastases in sentinel lymph nodes was 58%, which was significantly higher than 11% in non-sentinel lymph nodes. Diagnostic ability of sentinel lymph node biopsy showed that accuracy was 89%, sensitivity was 84%, and specificity was 100%. Our preliminary study indicated that sentinel lymph node biopsy was available on detection of non-palpable nodal metastasis in the patients with thyroid cancer; however, further experience and refinement are needed.

A case of double cancers with myocardial metastasis mimicking acute myocardial infarction both on an electrocardiogram and on Tc-99m-MIBI myocardial SPECT.

We report a rare case of double cancers with myocardial metastasis presenting acute myocardial infarction (AMI)-like findings both on an electrocardiogram (ECG) and on Tc-99m-MIBI myocardial SPECT. The ECG showed abnormal Q-waves and ST-segment elevation in leads V1-V4, and Tc-99m-MIBI SPECT showed a photon deficient area in the anteroseptum. These findings were suggestive of AMI, but the patient had been simultaneously suffering from two adenocarcinomas, which were lung cancer and gastric cancer, and consecutive ultrasonic cardiography (UCG) demonstrated a growing mass lesion in the septal aspect of the left ventricle. After a month he died of severe heart failure. The histological diagnosis of a specimen of the cardiac mass lesion was invasive adenocarcinoma infiltrating to the heart, which revealed that the myocardial metastasis had mimicked AMI. This case shows that it is difficult to distinguish between myocardial infarction and myocardial metastasis with myocardial perfusion SPECT. It is necessary to consider the possibility of myocardial metastasis when a patient with malignancy presents AMI-like findings.

Anti-angiogenic therapy and radioimmunotherapy in colon cancer xenografts.

Angiogenesis is critical to the growth and metastatic process of malignant tumors. An endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), displays anti-angiogenic and anti-tumorigenic effects. The purpose of this investigation was to determine whether exogenously administered 2-ME would enhance the efficacy of radioimmunotherapy (RIT). Experimental RIT with 4.63 MBq of 131I-A7, an IgG1 anti-colorectal monoclonal antibody, was conducted in mice xenografted with LS 180 human colon cancer cells. 2-ME suspended in 0.5% carboxymethylcellulose was administered daily at a dose of 75 mg/kg per day. 2-ME administration suppressed tumor growth and improved the efficacy of RIT in comparison to RIT alone. Tumor volumes on day 13, expressed as a ratio relative to the initial volume, were 12.7 +/- 2.95 in the nontreated control, 4.73 +/- 0.89 with 2-ME, 3.05 +/- 0.37 with RIT and 0.97 +/- 0.20 with RIT+2-ME. Immunohistochemistry of tumor sections stained with an antibody against factor VIII demonstrated a decrease in microvessel number within tumors treated with 2-ME (7.9 +/- 0.8/200x field) as compared with that in control tumors (29.9 +/- 2.5). Cell proliferation assay at increasing concentrations of 2-ME showed direct cytotoxicity of 2-ME in vitro at 5 microM and greater. In conclusion, 2-ME enhanced the efficacy of RIT with 131I-A7 via inhibition of angiogenesis within the xenografts. The direct cytotoxicity of 2-ME appears to have contributed to this improvement. Anti-angiogenic therapy may prolong the dormancy of microscopic metastases while RIT may exterminate this population of cells. Therefore, the combined treatment may improve the therapeutic outcome of patients with disseminated cancer.

Experimental radioimmunotherapy with 186Re-MAG3-A7 anti-colorectal cancer monoclonal antibody: comparison with 131I-counterpart.

A murine IgG1 against a Mr 45 kD tumor-associated glycoprotein in human colorectal cancer, A7, was radiolabeled with 186Re by a chelating method with a mercaptoacetyltriglycine (MAG3). Its specific activity was 119 MBq/mg, which would be high enough for a therapeutic purpose, and its immunoreactivity was preserved well as was 131I-A7 labeled by the chloramine-T method. Growth of human colon cancer xenografts, 9.14 +/- 0.44 mm in diameter, in nude mice was significantly suppressed by an intravenous dose of 4.48 MBq of 186Re-A7. The therapeutic outcome with 186Re-A7 was better than that with 4.63 MBq of 131I-A7. Toxicity of treatments assessed by body weight change was similar with both conjugates. These results are likely caused by the tumor size and more favorable physical properties of 186Re than those of 131I.

Improved response of colon cancer xenografts to radioimmunotherapy with pentoxifylline treatment.

A methylxanthine, pentoxifylline (PTX), has the potential to improve tumour microcirculation and oxygenation in vivo. We aimed to determine whether this agent would enhance the response of tumours to experimental radioimmunotherapy (RIT). Balb/c nu/nu mice with xenografts of LS180 human colon cancer were treated with 4.63 MBq of 131I-A7 anti-colorectal monoclonal antibody. A dose of 50 mg/kg of PTX was administered i.p. immediately after the 131I-A7 injection and daily thereafter for 7 days. The effect of PTX administration on 131I-A7 targeting in tumours was assessed with biodistribution and radioluminography on day 2. Intratumoural pO2 was measured with microelectrodes. The administration of PTX alone did not suppress tumour growth, but the efficacy of RIT with 131I-A7 was significantly improved by PTX: tumour volumes on day 15, relative to the initial volume, were 16.8+/-3.60 in the nontreated controls, 13.9+/-2.17 with PTX, 3.43+/-0.44 with RIT, and 1.86+/-0.59 with RIT+PTX (P<0.05). PTX administration did not alter the biodistribution or intratumoural distribution of 131I-A7. However, intratumoural pO2 was significantly improved by PTX administration: 16.9+/-9.75 mmHg in control tumours versus 25.6+/-11.3 mmHg in PTX-treated tumours (P<0.01). These results indicate that PTX-induced radiosensitisation of tumour cells due to better oxygenation is responsible for the better RIT outcomes, because the net radiation absorbed dose to the tumours did not appear to be changed.

Esophageal hypomotility in systemic sclerosis: close relationship with pulmonary involvement.

PURPOSE: Esophageal motility was assessed in patients with systemic sclerosis (SSc) by scintigraphy and compared with (i) extent of scleroderma, (ii) duration of disease, (iii) index of anti-topoisomerase I antibody (topo I), and (iv) pulmonary involvement. METHODS: A multiple-swallow test was performed in 47 patients with SSc in the supine position with 99mTc-DTPA. A region of interest on the entire esophagus was defined and the retention ratio (RR) was calculated from a time-activity curve. RESULTS: Patients with diffuse scleroderma had higher RRs than those with limited scleroderma (48.8% vs. 30.0%; p < 0.05). There was no correlation between the RRs and the duration of disease. Patients with positive topo I had higher RRs than those who were negative (53.8% vs. 29.7%; p < 0.05). Patients with reduced % diffusion capacity for carbon monoxide (%DLCO) had higher RRs than those with normal %DLCO (40.5% vs. 19.6%; p = 0.03). Patients with reduced % vital capacity (%VC) had higher RRs than those with normal %VC (54.6% vs. 25.0%; p < 0.005). Patients with pulmonary fibrosis had higher RRs than those who were negative (58.5% vs. 20.3%; p < 0.00005). CONCLUSION: Esophageal dysfunction in patients with SSc showed a correlation with the extent of scleroderma, positive topo I, and pulmonary involvement. The RR can be an objective clinical marker for the severity of organ fibrosis.

Methylxanthine sensitization of human colon cancer cells to 186Re-labeled monoclonal antibody.

UNLABELLED: Tumor cells lacking the functional p53 suppressor gene may arrest at the G2 phase of the cell cycle after exposure to ionizing radiation, resulting in increased radioresistance. Methylxanthines (MTXs), such as pentoxifylline (PTX) or caffeine (CAF), can inhibit the G2-phase checkpoint arrest of damaged cells and thus radiosensitize them. However, the effect of MTX in cells irradiated with low-dose-rate beta-emission is not well understood. METHODS: A clonogenic assay was performed with LS180 human colon cancer cells lacking the functional p53 suppressor gene. Cells were irradiated with increasing concentrations of 186Re-mercaptoacetyltriglycine (186Re-MAG3)-labeled A7 monoclonal antibody against colorectal cancer (0-925 kBq/mL) at 37 degrees C in 5% CO2 for 24 h in the presence or absence of PTX (0-2 mmol/L) or CAF (0-5 mmol/L). The enhancement ratio (ER) with MTX was calculated as a ratio of 50% cell-killing concentration of 186Re-MAG3-A7 in control cells to that in cells treated with PTX or CAF. The cell cycle distribution was analyzed with a flow cytometer. RESULTS: The concentration of 50% cell kill was 474 kBq/mL 186Re-MAG3-A7. Both PTX and CAF dose dependently enhanced the cytotoxicity of 186Re-MAG3-A7: ERs of 0.5 mmol/L PTX, 2 mmol/L PTX, 1 mmol/L CAF, and 5 mmol/L CAF were 1.50, 2.18, 1.54, and 2.63, respectively. Flow cytometry showed that the percentage nonirradiated cells in the G2/M phase of the cell cycle was 11.3% +/- 1.66%. On the other hand, cells exposed to 186Re-MAG3-A7 accumulated in the G2/M phase of the cell cycle (40.2% +/- 1.46%), which was inhibited by the presence of 1 mmol/L PTX (19.8% +/- 8.12%) or 2 mmol/L CAF (26.9% +/- 6.21%). CONCLUSION: Cellular modulation of the cell cycle with PTX and CAF radiosensitized LS180 colon cancer cells exposed to 186Re radiation.

Technetium-99m-tetrofosmin would be a substrate for multidrug resistance-associated protein (MRP): comparison between a leukemia cell line with high MRP gene expression and its parental cell line.

UNLABELLED: The kinetics of cellular accumulation and retention of technetium-99m-tetrofosmin (99mTc-TF) were investigated in wild type HL60/WT cell line and in its doxorubicin-resistant HL60/DOX cell line with multidrug resistance-associated protein (MRP), but without P-gp overexpression, to determine whether 99mTc-TF is a substrate for MRP. METHODS: The accumulation and washout of 99mTc-TF were observed in both cell lines at 37 degrees C. The effect of verapamil on the kinetics was also assessed. RESULTS: 99mTc-TF net accumulation was significantly lower in HL60/DOX (1.35 +/- 0.23%) than in HL60/WT (12.79 +/- 0.47%) at 60 min (P < 0.001). Three minutes after exchanging the incubation solution to the tracer-free medium, only 18.20 +/- 0.34% of 99mTc-TF remained in HL60/DOX, whereas 84.74 +/- 0.65% did in HL60/WT (P < 0.001). In the presence of 10 microM verapamil, 99mTc-TF net accumulation in HL60/DOX was 302% of the control and the washout was significantly delayed. CONCLUSION: 99mTc-TF would be a substrate for MRP and 99mTc-TF may be used as a functional imaging agent of MRP in vivo.

Prevalence of deep venous thrombosis in the lower limbs and the pelvis and pulmonary embolism in patients with positive antiphospholipid antibodies.

BACKGROUND: Antiphospholipid antibodies (AA) are immunoglobulins that cross-react with phospholipid on cell membrane, and are therefore associated with a hypercoagulable state manifested by arterial/venous thromboses. We aimed to determine the prevalence of deep venous thrombosis in the lower limbs and the pelvic region (DVT) and pulmonary embolism (PE) in patients with positive AA. METHODS: Sixty-six patients (48 female, 18 male) with positive lupus anticoagulant (LA) and/or positive anticardiolipin antibody (aCL) underwent radionuclide (RN) venography with 370 MBq of 99mTc-MAA. Pulmonary perfusion scintigraphy was performed in 58 patients. Fifteen patients had positive LA and positive aCL (LA+/aCL+), 33 patients had positive LA only (LA+/ aCL-) and 18 patients had positive aCL only (LA-/aCL+). 43 patients were diagnosed with primary antiphospholipid syndrome (APS) and 19 were diagnosed with APS associated with SLE. RESULTS: DVT was detected in 21 of 66 patients (32%). Patients with LA+/aCL+ showed higher prevalence of DVT (53%) as compared to LA+/aCL- (27%) and LA-/aCL+ (22%). PE was found in 13 of 58 patients (22%). The prevalence of PE was higher in patients with positive aCL (33% in LA+/aCL+; 36% in LA-/aCL+) than in patients with negative aCL (10%). CONCLUSION: Because of the high prevalence of DVT and PE in patients with AA, RN scintigraphy must be recommended in screening for these clinical troubles. These results indicate that the prevalence of DVT and PE may vary in subgroups of AA.

Sentinel lymph node biopsy in breast cancer using blue dye with or without isotope localization.

BACKGROUND: The purpose of this study was to determine the feasibility of sentinel lymph node (SLN) biopsy using blue dye with or without isotope localization to predict the presence of axillary and internal mammary lymph node (IMN) metastases in patients with breast cancer. We also investigated whether multiple sectioning of the SLN could improve the accuracy of frozen section examination. METHOD: One-hundred twenty-six patients underwent dye-guided or dye- and gamma probe-guided SLN biopsy followed by complete axillary lymph node dissection (ALND). No ALND was performed in the 14 patients with small tumors and a negative SLN. In addition, 69 patients underwent IMN biopsy. RESULTS: The axillary SLN was identified in 123 of 140 (88%) patients. An accuracy rate of 90% was obtained by frozen section examination of the SLN, which increased to 100% in patients examined with a greater number of sections. Lymphatic flow to the IMN and/or a radioactive hot spot in the IMN was found in 9 of 102 (9%) patients, while a hot node was detected using a gamma probe in only 2 of these patients. No involvement of the IMNs was found histologically in these 9 patients. IMN involvement was found in 7 of 61 (11%) patients without lymphatic flow to the IMNs or a hot spot by lymphoscintigraphy or who did not undergo lymphoscintigraphy. CONCLUSION: ALND can be avoided in patients with small breast cancers and a negative SLN. SLN biopsy guided by lymphatic mapping is unreliable for identifying metastases to IMNs.

Optimal timing of administration of hyperthermia in combined radioimmunotherapy.

Local hyperthermia (HT) may enhance the efficacy of radioimmunotherapy (RIT). However, the optimal timing of HT relative to administration of antibody is unknown. Human colon cancer xenografts (290 +/- 26 mm3) were treated with 4.63 MBq 131I-A7 monoclonal antibody (MAb) anti-Mr 45,000 glycoprotein antigen on colorectal cancer, and HT at 43 degrees C for 1 h was administered at: (A), 2 days after the 131I-A7 injection at the maximum 131I-A7 tumor accumulation (radiation); (B), soon after the 131I-A7 injection aiming to increase the tumor accumulation of 131I-A7 due to HT vascular effects; or (C), 2 days before the 131I-A7 injection in an attempt at injecting 131I-A7 when increased antigen expression could be expected. Specific growth delay (SGD) of tumors was calculated as (Tqtreat-Tqcontrol)/Tqcontrol where Tq was tumor quadrupling time. The biodistribution and intratumoral distribution of 131I-A7 were investigated to explore the mechanism of tumor response among the different HT regimens. HT alone produced some antitumor effect (SGD 1.90 +/- 0.26), which was less effective than RIT (3.11 +/- 0.50). HT soon after 131I-A7 RIT (B) significantly enhanced RIT efficacy (6.57 +/- 0.51, p < 0.0001) whereas neither HT at 2 days after RIT (A) nor at 2 days before RIT (C) did so. Biodistribution study revealed that HT soon after RIT (B) increased the tumor radiation absorbed dose by a factor of 2.4, while HT after RIT (A) did not increase radiation dose and HT before RIT (C) decreased it. Radioluminograms of tumor sections indicated that HT soon after RIT (B) improved the uniformity of 131I-A7 distribution whereas HT after RIT (A) did not and HT before RIT (C) diminished the uniformity of A7 distribution. In conclusion, the best therapeutic efficacy was obtained when HT was combined soon after the initiation of RIT with 131I-A7. The increased tumor radiation absorbed dose and the uniform intratumoral distribution of 131I-A7 were important factors underlying this improvement, and the additive cytotoxicity of HT is suspected to some extent. HT-induced radiosensitization of tumor was not apparent in this model when HT was given 2 days after 131I-A7 MAb.

Dye- and gamma probe-guided sentinel lymph node biopsy in breast cancer patients: using patent blue dye and technetium-99m-labeled human serum albumin.

BACKGROUND: Sentinel lymph node (SLN) biopsy is a promising method for the diagnosis of the axillary nodal status. We examined the availability of the SLN biopsy using two mapping procedures: the dye- and gamma probe-guided method, and preoperative lymphoscintigraphy by gamma camera imaging. METHODS: We enrolled 48 patients with breast cancer. Technetium-99m-labeled human serum albumin was injected into the subdermal tissue above the primary tumor or biopsy cavity, and preoperative gamma camera imaging was performed. After induction of general anesthesia, patent blue dye was injected into the peritumoral area prior to the surgical procedure. A handheld gamma-detection probe was used to assist in SLN detection. Careful dissection was performed to identify blue-stained afferent lymphatic vessels and nodes. An SLN was defined as any blue and/or radioactive node, and was excised. After SLN biopsy, axillary lymph node dissection of level I, II, and III was completed, in order to confirm the diagnostic ability of the SLN biopsy. RESULTS: Intraoperative SLN identification of axillary lesions was successful in 43 of 48 patients (90%). The dye- and gamma probe-guided method was successful in 25 patients (52%), the dye-guided method alone succeeded in 11 patients (23%), and the gamma probe-guided method alone succeeded in 7 patients (15%). Preoperative lymphoscintigraphy revealed axillary focal accumulations in 29 of 48 patients (60%). All patients who underwent successful preoperative SLN identification by lymphoscintigraphy had successful intraoperative SLN identification. A diagnostic accuracy of 95%, a sensitivity of 89%, and a specificity of 100% were achieved in the diagnosis of axillary metastasis. Internal mammary SLNs were identified in four patients intraoperatively, but we could not detect cancer metastasis in the internal mammary SLNs. CONCLUSIONS: The dye-guided and gamma probe-guided methods were complementary. Preoperative lymphoscintigraphy was useful to predict intraoperative SLN identification. Further study is necessary to assess the role of SLN biopsy of the internal mammary lymph nodes.

Pharmacologic intervention with angiotensin II and kininase inhibitor enhanced efficacy of radioimmunotherapy in human colon cancer xenografts.

UNLABELLED: Induced hypertension and kininase inhibition can enhance tumor targeting of radiolabeled monoclonal antibody (MAb) by altering tumor circulation. This study investigated the effect of this manipulation on the antitumor efficacy of radioimmunotherapy (RIT). METHODS: Mice bearing human colon cancer xenografts were administered 2.0 microg/kg/min of angiotensin II (AT-II) for 1 h and 30 microg of a kininase inhibitor, enalapril maleate, before the administration of 3.7 MBq (131)I-A7, an IgG1 against 45-kDa glycoprotein on colorectal cancer, and tumor growth was observed thereafter. The mechanism of the manipulation effect was investigated by estimation of the tissue absorbed dose and radioluminography of tumors. RESULTS: The pharmacologic manipulation with AT-II and enalapril improved the tumor quadrupling time (Tq) of 3.7 MBq RIT from 24.3 +/- 2.75 d to 33.1 +/- 2.83 d (P < 0.05). Addition of this manipulation made 3.7 MBq RIT as effective as 9.25 MBq RIT alone (Tq, 37.2 +/- 2.97 d). Dose estimation showed that the manipulation increased the tumor absorbed dose 1.55-fold without affecting the doses to normal tissues. Uniform intratumoral distribution in the manipulated tumors was shown by radioluminography. CONCLUSION: Larger and more uniform tumor radiation produced by this pharmacologic manipulation can benefit RIT with (131)I-MAb.

Increased uptake of 99mTc-HL91 in tumor cells exposed to X-ray radiation.

99mTc-HL91, a hypoxic marker, may be a predictor of tumor response to radiotherapy and an indicator of tumor oxygenation in the course of treatment. In this study, serial changes in 99mTc-HL91 uptake were observed in the normoxic condition in a human bladder cancer cell line exposed to a single dose or a fractionated dose of 10 Gy with an x-ray beam. The uptake per cell increased during cell growth retardation induced by the irradiation. This finding indicates that 99mTc-HL91 uptake is affected by injury to cells due to radiation; it may therefore be difficult to correctly assess the tissue oxygenation status during radiotherapy with 99mTc-HL91.

Enhanced efficacy of radioimmunotherapy combined with systemic chemotherapy and local hyperthermia in xenograft model.

We previously found that the efficacy of radioimmunotherapy (RIT) with (131)I-A7, an IgG(1) against M(r) 45000 glycoprotein on colon cancer, was enhanced by local hyperthermia (HT) or chemotherapy with 5-fluorouracil (5-FU). In this study, we aimed to further enhance its efficacy by combining these three modalities. Human colon cancer xenografts (146 x 12 mm(3)) in Balb / c nu / nu female mice were treated with 9.25 MBq (131)I-A7 i.v. combined with HT (43 degrees C for 1 h) and 5-FU (30 mg / kg / day i.p. for 5 days). Tumor growth delay, (Tq(treated) - Tq(control) )/ Tq(control) where Tq is tumor quadrupling time, in mice treated with RIT + HT + 5-FU was improved to 12.7 from 5.90, 7.55 and 10.1 with RIT alone, RIT + 5-FU and RIT + HT, respectively. Complete response was observed in 4 out of 8 tumors with RIT + HT + 5-FU and 3 out of 10 with RIT + HT. No tumor showed complete response with RIT + 5-FU or RIT alone. 5-FU slightly increased myelotoxicity of RIT, but HT did not affect it. Body weight loss was not enhanced by the combination. These results indicate that the combination of three modalities is a feasible approach to enhance the antitumor efficacy of RIT without serious increase of toxicity.

Staging efficacy of breast cancer with sentinel lymphadenectomy.

Seventy-two patients underwent dye-guided or dye- and gamma probe-guided sentinel lymphadenectomy (SLND) followed by complete axillary lymph node dissection (ALND). The results of imprint cytology, frozen sections, and permanent sections of the sentinel lymph node (SLN) were compared to each other and to the histologic findings in the nonsentinel nodes. The SLN was identified in 62 (88%) of 72 patients. Evaluation of the SLN on the permanent sections yielded a diagnostic accuracy of 95%, a sensitivity of 89%, and a specificity of 100%, although the reliability of SLN diagnosis using frozen sections or imprint cytology is limited. Therefore, it may be concluded that SLND with multiple sectioning and histopathologic examination of the SLNs can predict the presence or absence of axillary-node metastases in patients with breast cancer. However, further studies will be needed to investigate the value of SLND in respect to the long-term regional control and any possible detriment or benefit to survival, before it can replace routine ALND as the preferred staging operation for operable breast cancer.

Preoperative assessment of residual hepatic functional reserve using 99mTc-DTPA-galactosyl-human serum albumin dynamic SPECT.

UNLABELLED: Preoperative assessment of residual hepatic functional reserve offers important strategic information for hepatic resection. To predict the postoperative residual liver function, we assessed the value of hepatic 99mTc-diethylenetriamine pentaacetic acid-galactosyl-human serum albumin (99mTc-GSA) clearance estimated by dynamic SPECT analysis. METHODS: We investigated 114 consecutive patients with liver disease, including 55 hepatectomy cases. One minute after injection of 185 MBq 99mTc-GSA, 15 serial dynamic SPECT images were obtained every minute. The initial five sets of SPECT images were analyzed by Patlak plot to estimate the sequential initial hepatic 99mTc-GSA clearance (mL/min) as an index of hepatic function. The sum of hepatic 99mTc-GSA clearance of the segments immune from resection was categorized as predicted residual 99mTC-GSA clearance. In the hepatectomy cases, scintigraphy was performed before and 37 +/- 10 d after the operation. RESULTS: Good correlation was observed between the total hepatic 99mTc-GSA clearance and conventional hepatic function tests: plasma retention rate of iodocyanine green (ICG) at 15 min (ICG R15), r = -0.600, P < 0.0001, n = 94; plasma disappearance rate of ICG (K ICG), r = 0.670, P < 0.0001, n = 83; cholinesterase, r = 0.539, P < 0.0001, n = 121; serum albumin, r = 0.421, P = 0.0001, n = 123; and hepaplastin test, r = 0.456, P < 0.0001, n = 120. There was good correlation between the predicted residual 99mTc-GSA clearance and the postoperative total hepatic 99mTc-GSA clearance in patients who underwent segmentectomy or lobectomy (r = 0.84, P < 0.0001, n = 28) and between the pre- and postoperative total hepatic 99mTc-GSA clearance in patients who underwent subsegmentectomy (r = 0.91, P < 0.0001, n = 25). Five patients who had postoperative complications due to hepatic insufficiency (2 patients died of postoperative hepatic failure within 2 mo after operation) showed significantly lower predicted residual 99mTc-GSA clearance compared with the patients without complications (90.3 +/- 37.2 versus 320.9 +/- 158.8 mL/min; P < 0.005). CONCLUSION: The total hepatic 99mTC-GSA clearance reflected hepatic function. In addition, preoperative predicted residual hepatic 99mTc-GSA clearance was a good indicator of postoperative hepatic function and early prognosis. 99mTc-GSA dynamic SPECT is assumed to be a useful method for determining the surgical strategy in patients with hepatic tumor and especially in patients with hepatic dysfunction.