Michael L. Goris

Efficacy and Safety of Tositumomab and Iodine-131 Tositumomab (Bexxar) in B-Cell Lymphoma, Progressive After Rituximab

PURPOSE To determine overall response (OR) and complete response (CR) rates, response duration, progression-free (PFS) and overall survival and safety with the tositumomab and iodine-131 tositumomab ((131)I tositumomab) therapeutic regimen in patients with indolent, follicular large-cell, or transformed B-cell lymphoma, progressive after rituximab. PATIENTS AND METHODS From July 1998 to November 1999, 40 patients (24 rituximab nonresponders: 11 with response < 6 months, and five with response > or = 6 months) received a therapeutic dose (0.65 to 0.75 Gy per platelet count) of (131)I tositumomab based on total-body dosimetry in this prospective phase II study. The median number of prior treatments was four; 59% of patients were chemotherapy-resistant. RESULTS Confirmed OR (65%) and CR (38%) rates were not significantly associated with prior rituximab response. With a median follow-up of 3.3 years, the median PFS was 10.4 months, 24.5 months for responders, and not reached for CR patients. Among follicular grade 1 or 2 patients with tumors < or = 7 cm (n = 21), the OR and CR rates were 86% and 57%. Estimated 3-year PFS in this subgroup was 48%, compared with 11% for all others (P = .002). Transient grade 3 to 4 marrow toxicity was seen in 50% of patients. Two patients, one of whom received two subsequent chemotherapy regimens, developed secondary myelodysplasia. CONCLUSION (131)I tositumomab is effective in CD20-positive lymphoma progressive after rituximab, with a 65% OR rate and median PFS of 24.5 months for responders. Patients with follicular grade 1 or 2 histology and tumors < or = 7 cm achieved very high OR and CR rates, with 48% PFS at 3 years.

Therapeutic lymphangiogenesis with human recombinant VEGF-C

Chronic regional impairments of the lymphatic circulation often lead to striking architectural abnormalities in the lymphedematous tissues. Lymphedema is a common, disabling disease that currently lacks a cure. Vascular endothelial growth factors C and D mediate lymphangiogenesis through the VEGFR‐3 receptor on lymphatic endothelia. The purpose of this study was to investigate the therapeutic potential for lymphangiogenesis with VEGF‐C. We developed a rabbit ear model to simulate human chronic postsurgical lymphatic insufficiency. Successful, sustained surgical ablation of the ear lymphatics was confirmed by water displacement volumetry. After complete healing, the experimental animals (n=8) received a single, s.c. 100 μg dose of VEGF‐C in the operated ear; controls (n=8) received normal saline. Radionuclide lymphoscintigraphy was performed to quantitate lymphatic function. Immunohistochemistry (IHC) was performed 7–8 days following treatment. After VEGF‐C, there was a quantifiable amelioration of lymphatic function. IHC confirmed a significant increase in lymphatic vascularity, along with reversal of the intense tissue hypercellularity of untreated lymphedema. This study confirms the capacity of a single dose of VEGF‐C to induce therapeutic lymphangiogenesis in acquired lymphedema. In addition to improving lymphatic function and vascularity, VEGF‐C can apparently reverse the abnormalities in tissue architecture that accompany chronic lymphatic insufficiency.

Myocardial Perfusion Imaging With 99mTc Tetrofosmin Comparison to 201Tl Imaging and Coronary Angiography in a Phase III Multicenter Trial

Background Our objective was to compare the sensitivity and specificity of tetrofosmin, a new 99m Tc-labeled myocardial perfusion imaging agent for the detection of myocardial perfusion abnormalities, with those of 201 Tl and coronary angiography. Our hypothesis was that same-day stress/rest tetrofosmin imaging could provide data comparable to those of 201 Tl imaging. Myocardial perfusion imaging plays an important role for the evaluation of coronary artery disease. Newer 99m Tc-labeled agents offer several advantages over 201 Tl, the conventional myocardial perfusion imaging agent. Tetrofosmin is a new 99m Tc-labeled agent with promising results in preliminary studies. Methods and Results Two hundred fifty-two patients with suspected coronary artery disease were enrolled in 10 centers in the United States and Europe. All patients underwent exercise and rest myocardial perfusion imaging with 99m Tc-tetrofosmin using two separate injections of the radiotracer 4 hours apart on the same day. Planar images were obtained in three standard views 15 to 60 minutes after radiotracer injection. Patients also underwent standard exercise and redistribution planar 201 Tl imaging within 2 weeks of tetrofosmin imaging. In addition, 58 healthy subjects with low likelihood of coronary artery disease underwent exercise and rest tetrofosmin imaging. Coronary angiograms were available in 181 patients with suspected coronary artery disease. All radionuclide images were processed in the central core laboratory and interpreted blindly by a panel of four experienced readers. 201 Tl images and tetrofosmin images were read separately. Discrepancies were resolved by consensus. The workload, peak heart rate, and double products were comparable during exercise for both imaging agents. Technically acceptable paired 201 Tl and tetrofosmin images were available in 224 of 252 patients. Tetrofosmin images were generally of good quality, with low extracardiac activity, and easy to interpret. Patients were categorized as showing normal, ischemia, infarction, or mixture with each imaging modality. Precise concordance for each of these categories was 59.4% (κ=0.44; 95% CI, 0.35 to 0.53). When patients were categorized as normal or abnormal, the concordance was 80.4% (κ=0.55; 95% CI, 0.43 to 0.67). When each of five anatomic territories (septal, anterior, inferior, lateral, and apical) was categorized as normal versus abnormal, the concordance varied from 81% to 90%. When similar comparison was made for the specific category of abnormality, the concordance was 64% to 84%. When coronary angiography was used as the criterion, the sensitivity and positive and negative predictive accuracy of tetrofosmin and 201 Tl were comparable. The normalcy rate of tetrofosmin images in the healthy subjects with low likelihood of coronary artery disease was 97%. Conclusions 99m Tc tetrofosmin is a new myocardial imaging agent with favorable imaging characteristics with results comparable to those of 201 Tl.Background Our objective was to compare the sensitivity and specificity of tetrofosmin, a new 99m Tc-labeled myocardial perfusion imaging agent for the detection of myocardial perfusion abnormalities, with those of 201 Tl and coronary angiography. Our hypothesis was that same-day stress/rest tetrofosmin imaging could provide data comparable to those of 201 Tl imaging. Myocardial perfusion imaging plays an important role for the evaluation of coronary artery disease. Newer 99m Tc-labeled agents offer several advantages over 201 Tl, the conventional myocardial perfusion imaging agent. Tetrofosmin is a new 99m Tc-labeled agent with promising results in preliminary studies. Methods and Results Two hundred fifty-two patients with suspected coronary artery disease were enrolled in 10 centers in the United States and Europe. All patients underwent exercise and rest myocardial perfusion imaging with 99m Tc-tetrofosmin using two separate injections of the radiotracer 4 hours apart on the same day. Planar images were obtained in three standard views 15 to 60 minutes after radiotracer injection. Patients also underwent standard exercise and redistribution planar 201 Tl imaging within 2 weeks of tetrofosmin imaging. In addition, 58 healthy subjects with low likelihood of coronary artery disease underwent exercise and rest tetrofosmin imaging. Coronary angiograms were available in 181 patients with suspected coronary artery disease. All radionuclide images were processed in the central core laboratory and interpreted blindly by a panel of four experienced readers. 201 Tl images and tetrofosmin images were read separately. Discrepancies were resolved by consensus. The workload, peak heart rate, and double products were comparable during exercise for both imaging agents. Technically acceptable paired 201 Tl and tetrofosmin images were available in 224 of 252 patients. Tetrofosmin images were generally of good quality, with low extracardiac activity, and easy to interpret. Patients were categorized as showing normal, ischemia, infarction, or mixture with each imaging modality. Precise concordance for each of these categories was 59.4% (κ=0.44; 95% CI, 0.35 to 0.53). When patients were categorized as normal or abnormal, the concordance was 80.4% (κ=0.55; 95% CI, 0.43 to 0.67). When each of five anatomic territories (septal, anterior, inferior, lateral, and apical) was categorized as normal versus abnormal, the concordance varied from 81% to 90%. When similar comparison was made for the specific category of abnormality, the concordance was 64% to 84%. When coronary angiography was used as the criterion, the sensitivity and positive and negative predictive accuracy of tetrofosmin and 201 Tl were comparable. The normalcy rate of tetrofosmin images in the healthy subjects with low likelihood of coronary artery disease was 97%. Conclusions 99m Tc tetrofosmin is a new myocardial imaging agent with favorable imaging characteristics with results comparable to those of 201 Tl.

Cardiac damage produced by direct current countershock applied to the heart.

This study examined the pathophysiology of the myocaridal damage produced by direct current shock over a dose range of 10 to 90 watt-seconds, applied directly to the heart in 26 dosgs. The extent of injury produced was assessed with creatine kinase depletion and light and electron microscopy, and was correlated with in vivo imaging and tissue distributions of the isotopes technetium-99m pyrophosphate and thallium-201. Changes in intramyocardial temperature and regional myocardial blood flow were also measured. Uptake of technetium-99m pyrophosphate occurred exponentially with graded increases in shocks, and this agent was more sensitive than thallium-201 in detecting injury both on imaging and at tissue level. The threshold for significant injury was approximately 30 watt-seconds, and on electron microscopy a characteristic feature was marked dehiscence of the intercalated disks between the damaged myocytes. The use of different-size paddles did not appear to affect the total number of cells damaged. However, with large paddles the injury was more superficial and spread over a wider area. With short time intervals between successive shocks, a greater amount of injury occurred, in part because of a compounding of the thermal component of the damage. Hypothermia can reduce the degree of injury.

The radioisotope contributes significantly to the activity of radioimmunotherapy

Purpose: A multicenter, randomized study was undertaken to estimate the single agent activity of Tositumomab and to determine the contribution of radioisotope-labeling with 131I to activity and toxicity by comparing treatment outcomes for Tositumomab and Iodine I 131 Tositumomab (BEXXAR) to an equivalent total dose of unlabeled Tositumomab. Experimental Design: Seventy-eight patients with refractory/relapsed non-Hodgkin’s lymphoma were randomized to either unlabeled Tositumomab or Iodine I 131 Tositumomab. Patients progressing after unlabeled Tositumomab could cross over to receive Iodine I 131 Tositumomab. The median follow-up at analysis was 42.6 months (range 1.9 to 71.5 months). Results: Responses in the Iodine I 131 Tositumomab versus unlabeled Tositumomab groups: overall response 55% versus 19% (P = 0.002); complete response 33% versus 8% (P = 0.012); median duration of overall response not reached versus 28.1 months (95% confidence interval: 7.6, not reached); median duration of complete response not reached in either arm; and median TTP 6.3 versus 5.5 months (P = 0.031), respectively. Of the patients who had a complete response after initial Iodine I 131 Tositumomab therapy, 71% (10 of 14) continued in complete response at 29.8 to 71.1 months. Two patients who achieved a complete response after unlabeled Tositumomab had ongoing responses at 48.1 to 56.9 months. Nineteen patients received Iodine I 131 Tositumomab crossover therapy. Responses after crossover versus prior response to unlabeled Tositumomab were as follows: complete response rates of 42% versus 0% (P = 0.008); overall response 68% versus 16% (P = 0.002); median durations of overall response 12.6 versus 7.6 months (P = 0.001); and median TTP 12.4 versus 5.5 months (P = 0.01), respectively. Hematologic toxicity was more severe and nonhematologic adverse events were more frequent after Iodine I 131 Tositumomab than after Tositumomab alone. Elevated thyrotropin occurred in 5% of patients. Seroconversion to human antimurine antibody after Iodine I 131 Tositumomab, unlabeled Tositumomab, and Iodine I 131 Tositumomab-crossover was 27%, 19%, and 0%, respectively. Conclusions: Unlabeled Tositumomab showed single agent activity, but in this direct comparison, all of the therapeutic outcome measures were significantly enhanced by the conjugation of 131I to Tositumomab.

Sensitivity and specificity of radionuclide ejection fractions in doxorubicin cardiotoxicity

We examined radionuclide-determined left ventricular ejection fractions (LVEF) at rest and during graded exercise in 37 patients receiving doxorubicin (Adriamycin) therapy in whom the risk of developing congestive heart failure (CHF) was precisely defined by endomyocardial biopsy and right heart catheterization. Echocardiographic (Echo %FS) and phonocardiographic (PEP/LVET) measurements of LV function were also determined. An abnormal LVEF at rest (less than or equal to 45%) had a sensitivity of 53% and a specificity of 75% for detecting patients at moderate or high risk of developing CHF. The addition of exercise LVEF increased the sensitivity of detection of moderate or high-risk patients to 89% but lowered the specificity to 41%. Exercise LVEF improved the sensitivity of detection of high-risk patients from 58% to 100%. Echo %FS and PEP/LVET yielded lower sensitivities than rest or exercise LVEF. As a single test, exercise LVEF possesses the sensitivity for use as a screening method for anthracycline cardiotoxicity, but the lack of specificity prevents the use of single values as a definitive test. Single rest LVEF determinations, although more specific than exercise LVEF, do not possess the sensitivity for use as screening or definitive tests.

Reproducibility of thallium-201 myocardial imaging.

Seventy-six thallium-201 myocardial perfusion studies were performed on twenty-five patients to assess their reproducibility and the effect of varying the level of exercise on the results of imaging. Each patient had a thallium-201 study at rest. Fourteen patients had studies on two occasions at maximum exercise, and twelve patients had studies both at light and at maximum exercise. Of 70 segments in the 14 patients assessed on each of two maximum exercise tests, 64 (91%) were reproducible. Only 53% (16/30) of the ischemic defects present at maximum exercise were seen in the light exercise study in the 12 patients assessed at two levels of exercise. Correlation of perfusion defects with arteriographically proven significant coronary stenosis was good for the left anterior descending and right coronary arteries, but not as good for circumflex artery disease. Thallium-201 myocardial imaging at maximum exercise is reproducible within acceptable limits, but careful attention to exercise technique is essential for valid comparative studies.

Automatic registration and alignment on a template of cardiac stress and rest reoriented SPECT images

Single photon emission computed tomography (SPECT) imaging with /sup 201/Tl or /sup 99m/Tc agent is used to assess the location or the extent of myocardial infarction or ischemia. A method is proposed to decrease the effect of operator variability in the visual or quantitative interpretation of scintigraphic myocardial perfusion studies. To effect this, the patients myocardial images (target cases) are registered automatically over a template image, utilizing a nonrigid transformation. The intermediate steps are: 1) Extraction of feature points in both stress and rest three-dimensional (3-D) images. The images are resampled in a polar geometry to detect edge points, which in turn are filtered by the use of a priori constraints. The remaining feature points are assumed to be points on the edges of the left ventricular myocardium. 2) Registration of stress and rest images with a global affine transformation. The matching method is an adaptation of the iterative closest point algorithm. 3) Registration and morphological matching of both stress and rest images on a template using a nonrigid local spline transformation following a global affine transformation. 4) Resampling of both stress and rest images in the geometry of the template. Optimization of the method was performed on a database of 40 pairs of stress and rest images selected to obtain a wide variation of images and abnormalities. Further testing was performed on 250 cases selected from the same database on the basis of the availability of angiographic results and patient stratification.

The Na/I - Symporter Mediates Iodide Uptake in Breast Cancer Metastases and Can Be Selectively Down-Regulated in the Thyroid

Purpose: The Na+/I− symporter (NIS) is a key plasma membrane protein that mediates active iodide (I−) transport in the thyroid, lactating breast, and other tissues. Functional NIS expression in thyroid cancer accounts for the longstanding success of radioactive iodide (131I) ablation of metastases after thyroidectomy. Breast cancer is the only other cancer demonstrating endogenous functional NIS expression. Until now, NIS activity in breast cancer metastases (BCM) was unproven. Experimental Design: Twenty-seven women were scanned with 99mTcO4− or 123I− to assess NIS activity in their metastases. An 131I dosimetry study was offered to patients with I−-accumulating tumors. Selective down-regulation of thyroid NIS was tested in 13 patients with T3 and in one case with T3 + methimazole (MMI; blocks I− organification). NIS expression was evaluated in index and/or metastatic tumor samples by immunohistochemistry. Results: I− uptake was noted in 25% of NIS-expressing tumors (two of eight). The remaining cases did not show NIS expression or activity. Thyroid I− uptakes were decreased to ≤2.8% at 24 h in T3-treated patients and 1/100 normal with T3/MMI. Uptake (2.9%) was calculated in a peribronchial metastasis on 131I dosimetry scans at 4 h with disappearance of the signal by 24 h. We estimated a therapeutic dose of 3000 cGy could be achieved in this metastasis with 100 mCi of 131I if the tumor exhibited the same dynamics as the T3/MMI-suppressed thyroid. Conclusions: This is the first article of in vivo, scintigraphically detected, NIS-mediated I− accumulation in human BCM. T3/MMI down-regulation of thyroid NIS makes 131I-radioablation of BCM possible with negligible thyroid uptake and radiation damage.

Pilot Pharmacokinetic and Dosimetric Studies of 18F-FPPRGD2: A PET Radiopharmaceutical Agent for Imaging αvβ3 Integrin Levels

PURPOSE To assess the safety, biodistribution, and dosimetric properties of the positron emission tomography (PET) radiopharmaceutical agent fluorine 18 ((18)F) FPPRGD2 (2-fluoropropionyl labeled PEGylated dimeric RGD peptide [PEG3-E{c(RGDyk)}2]), which is based on the dimeric arginine-glycine-aspartic acid (RGD) peptide sequence and targets α(v)β(3) integrin, in the first volunteers imaged with this tracer. MATERIALS AND METHODS The protocol was approved by the institutional review board, and written informed consent was obtained from all participants. Five healthy volunteers underwent whole-body combined PET-computed tomography 0.5, 1.0, 2.0, and 3.0 hours after tracer injection (mean dose, 9.5 mCi ± 3.4 [standard deviation] [351.5 MBq ± 125.8]; mean specific radioactivity, 1200 mCi/mmol ± 714 [44.4 GBq/mmol ± 26.4]). During this time, standard vital signs, electrocardiographic (ECG) readings, and blood sample values (for chemistry, hematologic, and liver function tests) were checked at regular intervals and 1 and 7 days after the injection. These data were used to evaluate tracer biodistribution and dosimetric properties, time-activity curves, and the stability of laboratory values. Significant changes in vital signs and laboratory values were evaluated by using a combination of population-averaged generalized estimating equation regression and exact paired Wilcoxon tests. RESULTS The administration of (18)F-FPPRGD2 was well tolerated, with no marked effects on vital signs, ECG readings, or laboratory values. The tracer showed the same pattern of biodistribution in all volunteers: primary clearance through the kidneys (0.360 rem/mCi ± 0.185 [0.098 mSv/MBq ± 0.050]) and bladder (0.862 rem/mCi ± 0.436 [0.233 mSv/MBq ± 0.118], voiding model) and uptake in the spleen (0.250 rem/mCi ± 0.168 [0.068 mSv/MBq ± 0.046]) and large intestine (0.529 rem/mCi ± 0.236 [0.143 mSv/MBq ± 0.064]). The mean effective dose of (18)F-FPPRGD2 was 0.1462 rem/mCi ± 0.0669 (0.0396 mSv/MBq ± 0.0181). With an injected dose of 10 mCi (370 MBq) and a 1-hour voiding interval, a patient would be exposed to an effective radiation dose of 1.5 rem (15 mSv). Above the diaphragm, there was minimal uptake in the brain ventricles, salivary glands, and thyroid gland. Time-activity curves showed rapid clearance from the vasculature, with a mean 26% ± 17 of the tracer remaining in the circulation at 30 minutes and most of the activity occurring in the plasma relative to cells (mean whole blood-plasma ratio, 0.799 ± 0.096). CONCLUSION (18)F-FPPRGD2 has desirable pharmacokinetic and biodistribution properties. The primary application is likely to be PET evaluation of oncologic patients-especially those with brain, breast, or lung cancer. Specific indications may include tumor staging, identifying patients who would benefit from antiangiogenesis therapy, and separating treatment responders from nonresponders early.