Farhad Daghighian

Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer.

PURPOSE A phase I/II study was designed to determine the maximum-tolerated dose (MTD) of iodine 125-labeled monoclonal antibody A33 (125I-mAb A33), its limiting organ toxicity, and the uptake and retention of radioactivity in tumor lesions. PATIENTS AND METHODS Patients (N = 21) with advanced chemotherapy-resistant colon cancer who had not received prior radiotherapy were treated with a single 125I-mAb A33 dose. 125I doses were escalated from 50 to 350 mCi/m2 in 50-mCi/m2 increments. Radioimmunoscintigrams were performed for up to 6 weeks after 125I-mAb A33 administration. RESULTS All 20 patients with radiologic evidence of disease showed localization of 125I to sites of disease. Twelve of 14 patients, who underwent imaging studies 4 to 6 weeks after antibody administration, had sufficient isotope retention in tumor lesions to make external imaging possible. No major toxicity was observed, except in one patient with prior exposure to mitomycin who developed transient grade 3 thrombocytopenia. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild or absent, and in no case did stools become guaiac-positive. The MTD was not reached at 125I doses up to 350 mCi/m2. However, cytotoxicity assays demonstrated that patients treated with the highest dose had sufficiently high serum levels of 125I-mAb A33 to lyse colon cancer cells in vitro. Among 21 patients, carcinoembryonic antigen (CEA) levels returned to normal in one patient and decreased by 35% and 23%, respectively, in two patients; one additional patient had a mixed response on computed tomography. Additional, significant responses were observed in those patients treated with chemotherapy [carmustine [BCNU], vincristine, flourouracil, and streptozocin [BOF-Strep]) after completion of the 125I-mAb A33 study. CONCLUSION Low-energy emission radioimmunotherapy with doses of up to 350 mCi/m2 of 125I-mAb A33 did not cause bowel or bone marrow toxicity. The modest antitumor activity in these heavily pretreated patients is encouraging because of lack of toxicity at the doses studied. The long radioactivity retention in tumors suggests that isotopes with a long half-life may have a therapeutic advantage, based on calculated dose delivery to tumor versus normal tissue. Due to the low bone marrow dose, further 125I trials with humanized mAb A33 are warranted, and controlled studies must be conducted to evaluate the combination of radioimmunotherapy and chemotherapy.

Evaluation of cerium doped lutetium oxyorthosilicate (LSO) scintillation crystals for PET

A new scintillation crystal, cerium-doped lutetium oxyorthosilicate (LSO), was recently discovered, with light intensity 75% of NaI(Tl), scintillation decay time of 12 ns (30%) and 42 ns (70%), effective Z of 66, and density of 7.4 g/cc. The fast decay time and scintillation light output of LSO are superior to those of bismuth germanate (BGO) for positron emission tomography (PET) and the stopping power of LSO for 511 keV photons is only slightly lower than that of BGO. The authors directly compared the detection characteristics relevant to PET applications of small crystals of LSO (2*2*10 mm) with those of BGO. The energy resolution at 511 keV was 12% FWHM for LSO and two to three times wider for BGO. The coincidence timing of two opposing crystals, using a position sensitive photomultiplier tube (PMT) (Hamamatsu R2486), were 1.4 ns FWHM for LSO and more than three times higher for BGO. Using a fast PMT (Hamamatsu R3177), coincidence timing for LSO yielded 0.46 ns FWHM. These crystals are being used to simulate a small-scale PET scanner and to investigate its imaging performance. >

Development of a method to measure kinetics of radiolabelled monoclonal antibody in human tumour with applications to microdosimetry: positron emission tomography studies of iodine-124 labelled 3F8 monoclonal antibody in glioma

We present a method to assess quantitatively the immunological characteristics of tumours using radiolabelled monoclonal antibody and positron emission tomography (PET) to improve dosimetry for radioimunotherapy. This method is illustrated with a glioma patient who was injected with 96.2 MBq of iodine-124 labelled 3F8, a murine antibody (IgG3) specific against the ganglioside GD2. Serial PET scans and plasma samples were taken over 11 days. A three-compartment model was used to estimate the plasma to tumour transfer constant (K1), the tumour to plasma transfer constant k2, the association and dissociation constants (k3, k4) of antibody binding, and the binding potential. Tumour radioactivity peaked at 18 h at 0.0045% ID/g. The kinetic parameters were estimated to be: K1 = 0.048 ml h−1 g−1, k2 = 0.16 h−1, k3 = 0.03 h−1, k4 = 0.015 h−1 and BP = 2.25. Based on these kinetic parameters, the amount of tumour-bound radiolabelled monoclonal antibody was calculated. This method permits estimates of both macrodosimetry and microdosimetry at the cellular level based on in vivo non-invasive measurement.

A novel method to localize antibody-targeted cancer deposits intraoperatively using handheld PET beta and gamma probes.

BackgroundAssessing cancer margins, lymph nodes, and small cancer deposits intraoperatively can be challenging. A new device has become available that allows the detection of positron emission tomography (PET) radiotracers through both high-energy gamma and short-range beta emissions. These PET probes are handheld, allowing for real-time evaluation of cancer using a tool that provides surgeons with better intraoperative assessment of tumor sites.MethodsWithin the context of two institutional review board (IRB)-approved protocols investigating new applications of antibody-labeled PET scanning, 124I-labeled humanized monoclonal antibodies specific for colorectal cancer (huA33) and renal tumors (cG250) were constructed. Patients underwent preoperative PET scans, approximately seven days post-tracer infusion, when tumor-to-nontumor ratios were high. Suspected tumor deposits were evaluated intraoperatively with handheld beta and gamma PET probes.ResultsHandheld PET probes detected emissions from all tumors. Count rates from the gamma probe on tumor ranged from 48 to 306 cps, and for the beta probe ranged from 18 to 190 cps. Gamma and beta emissions exhibited a strong positive correlation. The ratio of gamma and beta counts was at least twice that of the background counts for all tumors evaluated.ConclusionsThis study is the first to demonstrate the utility of beta probes for the intraoperative detection of radiolabeled antibodies targeting cancer. Importantly, the recorded beta count rates from the beta probe correlate with the count rates from the high-energy gamma probe. Furthermore, the beta probe may offer superior specificity for real-time localization of small tumor deposits, compared to gamma probes. The intraoperative portable PET probe may prove a valuable bridge to combining tumor biology and PET technology to guide surgical therapy.

Clinical comparison of radiolocalization of two monoclonal antibodies (mAbs) against the TAG-72 antigen

Ten patients with colorectal cancer metastases received 125I-B72.3 and 131I-CC49 prior to laparotomy (five patients received 1 mg, and five 20 mg of each mAb). Tumor:serum ratios of 131I-CC49 were better than those of 125I-B72.3 (P < 0.01 at 1 mg; P = 0.05 at 20 mg; P < 0.01 at both doses). All known lesions > or = 1 cm in diameter were visualized at the 20 mg dose. There was no difference in absolute tumor uptake of 125I-B72.3 or 131I-CC49. We conclude that mAb CC49 has better relative uptake in colorectal cancers than mAb B72.3.

Quantitative studies of monoclonal antibody targeting to disialoganglioside GD2 in human brain tumors

Iodine-131 3F8, a murine IgG3 monoclonal antibody that targets to GD2-bearing tumors, was administered intravenously to 12 patients with brain tumors. Six patients received 2 mCi (0.74 Bq) of131I-3F8, five patients 10 mCi (3.7 Bq)/1.73 m2 of131I-3F8, and one patient 2.6 mCi (0.96 Bq) of124I-3F8, with no side-effects. Nine of 11 malignant gliomas and the single metastatic melanoma showed antibody localization, with the best tumor delineation on single-photon emission tomography (SPET) following 10 mCi (3.7 Bq)/1.73 m2 dose. No nonspecific uptake in the normal craniospinal axis was detected. There was no difference in the pharmacokinetics of low-dose versus the higher-dose antibody groups; plasma and total-body half-lives were 18 h and 49 h, respectively. Surgical sampling and time-activity curves based on quantitative imaging showed peak uptake in high-grade glioma at 39 h, with a half-life of 62 h. Tumor uptake at time of surgery averaged 3.5×10−3 %ID/g and peak activity by the conjugate view method averaged 9.2×10−3 %ID/g (3.5–17.8). Mean radiation absorption dose was 3.9 rad per mCi injected (range 0.7–9.6) or 10.5 cGy/Bq (range 1.9–26). There was agreement on positive sites when immunoscintigraphy was compared with technetium-99m glucoheptonate/diethylene triamine penta-acetic acid planar imaging, thallium-201 SPET, and fluorine-18 fluorodeoxyglucose positron emission tomography. Taken together, these data suggest that quantitative estimates of antibody targeting to intracranial tumors can be made using the modified conjugate view method.

Portable PET probes are a novel tool for intraoperative localization of tumor deposits

BackgroundPositron emission tomography (PET) identifies cancer deposits by detecting sites of gamma emissions that are released from radioactively labeled molecules targeting tumor to formulate a PET image. Correlating preoperative PET scans with intraoperative findings remains a challenge. We investigated whether high-energy gamma emissions detected by a novel hand-held PET probe would detect tumors and offer a real-time method to localize tumor intraoperatively. Furthermore, we investigated the novel beta probe, which detects emissions at a shorter range than gamma emissions, making them undetectable by PET scanners, but potentially valuable for close range intraoperative detection of tumor deposits.MethodsSix-to-eight-week-old athymic mice were injected with one of four possible tumor cell lines: gastric, pancreas, squamous cell and breast cancer. After tumors reached at least 1 cm in size, they were euthanized and imaged with a micro-PET imager. Hand-held gamma and beta probes were then used in vivo and ex vivo to measure high-energy gamma and beta emissions.ResultsThe portable PET probes detected high-energy gamma and beta emissions from all tumors evaluated. These emissions were reproducible and we established that beta emissions correlate with high-energy gamma emissions and conventional PET scans. There was a strong positive correlation (R = 0.8) between gamma and beta counts. Beta emission showed a stronger correlation than gamma emission with overall tissue radioactivity.ConclusionThis study is the first to demonstrate that gamma emission detected by conventional PET imaging correlates with beta emissions. This study shows that compared to detection of gamma emissions, beta counts may offer superior real-time localization of tumor deposits. Intraoperative portable PET probe may become a useful way to exploit tumor biology and PET technology to guide real-time tissue characterization during surgery.

An Analysis of the Utility of Handheld PET Probes for the Intraoperative Localization of Malignant Tissue

IntroductionThe intraoperative localization of suspicious lesions detected by positron emission tomography (PET) scan remains a challenge. To solve this, two novel probes have been created to accurately detect the 18F-FDG radiotracer intraoperatively.MethodsNude rats were inoculated with mesothelioma. When PET scans detected 10-mm tumors, animals were dissected and the PET probes analyzed the intraoperative radiotracer uptake of these lesions as tumor to background ratio (TBR).ResultsThe 17 suspicious lesions seen on PET scan were localized intraoperatively (by their high TBR) using the PET probes and found malignant on pathology. Interestingly, smaller tumors not visualized on PET scan were detected intraoperatively by their high TBR and found malignant on pathology. Furthermore, using a TBR threshold as low as 2.0, both gamma (sensitivity, 100%; specificity, 80%; positive predictive value (PPV), 96%; and negative predictive value (NPV), 100%) and beta (sensitivity, 100%; specificity, 60%; PPV, 93%; and NPV, 100%) probes reliably detected suspicious lesions on PET scan imaging. They also showed an excellent area under the curve of 0.9 and 0.97 (95% CI of 0.81–0.99 and 0.93–1.0) for gamma and beta probes, respectively, in the receiver operating characteristic analysis for detecting malignancy.ConclusionThis novel tool could be used synergistically with a PET scan imaging to maximize tissue selection intraoperatively.

Design considerations of an animal PET scanner utilizing ESO scintillators and position sensitive PMTs

Various parameters relevant to the design of a small scale PET scanner were studied both experimentally and by computer simulation. LSO (cerium-doped lutetium oxyorthosilicate) was compared with EGO, using a position sensitive PMT (PSPMT). (Compared to EGO, LSO has 8 times faster decay time, 4 times the scintillation light output, but 14% lower attenuation coefficient for 511 keV photons). The experiments with EGO and LSO involved: the crystal identification on the face of a PSPMT, measurement of the coincidence line-spread functions, and measurement of the sensitivity above the electronic noise. The resulting coincidence images clearly resolved each LSO crystal. EGS4 Monte Carlo simulations were used to estimate the efficiency, singles rate and mispositioning due to the depth of interaction for PET scanners with various sizes of LSO and EGO.<<ETX>>

Evaluation of arrays of silicon photomultipliers for beta imaging

Silicon photomultipliers (SiPMs) have shown great promise as photodetectors in detecting scintillation light from gamma and beta rays, and are currently being investigated for use in imaging. Most studies have been done with single sensors for gamma detection. We have built linear and two dimensional arrays of SiPMs and evaluated them for suitability in beta imaging. Both arrays employ 1 mm × 1 mm Multi Pixel Photon Counters (MPPCs). The first array is a 1 × 4 array with 2.5 mm pixel pitch. The second is a 5 × 5 array with 3 mm pitch. For both arrays we acquired energy spectra for annihilation photons with LYSO scintillators, and for positrons from F-18 and Tl-204 with blue plastic scintillator. We imaged collimated F-18 beta sources, and measured the spatial resolution and sensitivity. For the linear array, the spatial resolution is 2.6 mm at the center of the array, and the sensitivity is 0.27 cps/Bq. For the 5 × 5 array, the spatial resolution is 2.1 mm at the center of the array, and the sensitivity is 0.36 cps/Bq.