Multi-source domain adaptation of social media data for disaster management.

Labeled data scarcity at the time of an ongoing disaster has encouraged the researchers to use the labeled data from some previous disaster for training and transferring the knowledge to the current disaster task using Domain Adaptation (DA). However, often labeled data from more than one previous disaster may be available. As all deep learning models are data-hungry and perform better if fed with more annotated data, it is advisable to use data from multiple sources for training a Deep Convolutional Neural Network (DCNN). One of the easiest ways is to simply combine the data from multiple sources and use it for training. However, this arrangement is not that straightforward. The models trained on the combined data from various sources do not perform well on the target, mainly due to distribution discrepancies between multiple sources. This has motivated us to explore the challenging area of multi-source domain adaptation for disaster management. The aim is to learn the domain invariant features and representations across the domains and transfer more related knowledge to solve the target task with improved accuracy than single-source or combined-source domain adaptation. This study proposes a Multi-Source Domain Adaptation framework for Disaster Management (MSDA-DM) to classify disaster images posted on social media based on unsupervised DA with adversarial training. The empirical results obtained confirm that the proposed model MSDA-DM performs better than single-source DA by up to 10.83% and combined-source DA by up to 5.06% in terms of F1-score for different sets of source and target disaster domains. We also compare our model with current state-of-the-art models. The main challenge of multi-source DA is the choice of the relevant sources taken for training since, unlike single-source DA that handles only source-target distribution drift, the multi-source DA network has to address both source-target and source-source distribution drifts.

scJVAE: A novel method for integrative analysis of multimodal single-cell data.

The study of cellular decision-making can be approached comprehensively using multimodal single-cell omics technology. Recent advances in multimodal single-cell technology have enabled simultaneous profiling of more than one modality from the same cell, providing more significant insights into cell characteristics. However, learning the joint representation of multimodal single-cell data is challenging due to batch effects. Here we present a novel method, scJVAE (single-cell Joint Variational AutoEncoder), for batch effect removal and joint representation of multimodal single-cell data. The scJVAE integrates and learns joint embedding of paired scRNA-seq and scATAC-seq data modalities. We evaluate and demonstrate the ability of scJVAE to remove batch effects using various datasets with paired gene expression and open chromatin. We also consider scJVAE for downstream analysis, such as lower dimensional representation, cell-type clustering, and time and memory requirement. We find scJVAE a robust and scalable method outperforming existing state-of-the-art batch effect removal and integration methods.

A novel reversible logic gate and its systematic approach to implement cost-efficient arithmetic logic circuits using QCA.

Quantum-dot cellular automata, is an extremely small size and a powerless nanotechnology. It is the possible alternative to current CMOS technology. Reversible QCA logic is the most important issue at present time to reduce power losses. This paper presents a novel reversible logic gate called the F-Gate. It is simplest in design and a powerful technique to implement reversible logic. A systematic approach has been used to implement a novel single layer reversible Full-Adder, Full-Subtractor and a Full Adder-Subtractor using the F-Gate. The proposed Full Adder-Subtractor has achieved significant improvements in terms of overall circuit parameters among the most previously cost-efficient designs that exploit the inevitable nano-level issues to perform arithmetic computing. The proposed designs have been authenticated and simulated using QCADesigner tool ver. 2.0.3.

Review of five consecutive studies of radiolabeled immunoglobulin therapy in Hodgkin's disease.

Recurrent Hodgkin's Disease (HD) provides unique opportunities to improve radiolabeled immunoglobulin therapy (RIT). Normal tissue toxicity after RIT is limited to bone marrow damage and is well documented and quantified in HD patients. Anti-antibody formation is rare in patients with HD, allowing for multiple RIT cycles. Overall, 134 patients with recurrent HD were treated on five different studies with i.v. antiferritin, labeled with 131I or with 111In for diagnostic purposes and 90Y for therapeutic purposes. Patients with recurrent, end-stage HD obtain a 60% response rate following 90Y-labeled antiferritin. One-half of the therapy responses are complete. Responses are more common in patients with longer disease histories (> 3 years) and smaller tumor volumes (< 30 cm3) and in patients receiving at least 0.4 mCi 90Y-labeled antiferritin/kg body weight. Complete responders survive significantly longer than partial responders (2 years versus 1 year). Partial responders survive longer than patients with progressive disease (1 year versus 4 months). HD in one-third of the patients recurs in new areas. A low protein dose (2-5 mg) and a moderate specific activity (10 mCi/mg) are recommended. Results obtained with 90Y-labeled antiferritin are significantly better than results with 131I-labeled antiferritin. Further translational research in vitro in the radio pharmacy and in vivo with experimental animals is ongoing to improve the therapeutic results of RIT in HD. Obviously, many permutations of RIT cannot be explored in HD patients for ethical, financial, or logistic reasons, and predictive preclinical research is required to achieve further progress. Currently, RIT is a low-toxicity, low-cost outpatient procedure for recurrent HD with a high response rate in a patient population with an unfavorable prognosis.

Preclinical analysis of intraperitoneal administration of 111In-labeled human tumor reactive monoclonal IgM AC6C3-2B12.

An IgM lambda human tumor cell-reactive monoclonal antibody was developed that reacts with cells of ovarian cancer, colorectal cancer, breast cancer, and certain other malignancies. The monoclonal antibody AC6C3-2B12, which was obtained from a recent recloning, was purified from tissue culture supernatants and analyzed by high-performance liquid chromatography and sodium dodecyl sulfate-PAGE. An animal model was developed in which human tumors grew either as solid peritoneal metastases or as s.c. nodules utilizing the human colorectal carcinoma cell line SW620. The biodistribution of 111In-labeled IgM conjugate was studied after i.v. or i.p. administration in nude mice bearing an s.c. xenograft or peritoneal tumor lumps of a human colorectal carcinoma (SW620). IgM administered i.v. cleared rapidly from blood and was deposited mainly in the liver [50% injected dose/g (ID)/g)], pancreas (20% ID/g), and kidney (10% ID/g) at 24 h. Tumor deposition was low (< or = 1.0% ID/g) in the s.c. tumor xenograft. In contrast, high tumor targeting (29% ID/g) was found in peritoneal tumor lumps after i.p. administration of 111In-labeled IgM. The biological half-life of IgM in the tumor was 100 h. Long peritoneal residence time (t 1/2 = 67 h) and low liver uptake (7% ID/g) were observed after i.p. administration. Blood activity was < 1% of the injected activity. Tumor:normal organ ratios were high (range, 2-290) from 2 to 144 h after i.p. administration. Whole body autoradiograms at 24 h after i.p. 111In-labeled IgM administration confirmed the biodistribution results. In normal beagle dogs, 75% of the i.p.-administered 111In-IgM decayed in the peritoneal cavity. The majority of the remaining radioactivity was taken up by mediastinal lymph nodes. Biological half-life in both locations was approximately 137 h. The i.p. administration of intact, specific radiolabeled IgM provides prolonged retention of radioactivity in tumor, low normal tissue uptake, a long peritoneal residence time, and very limited spillover of IgM into the circulation. This approach offers a promising new method for the diagnosis and treatment of certain patients with peritoneal carcinomatosis.

Survival of patients with resistant Hodgkin's disease after polyclonal yttrium 90-labeled antiferritin treatment.

PURPOSE: A follow-up study was initiated of patients with Hodgkin's disease who were treated with yttrium 90-labeled antiferritin. Prescription method, pharmacokinetics, acute and late side effects, and survival were evaluated. METHODS: Patients had measurable disease and failed > or = two multiagent chemotherapy regimens previously (N = 44). All patients received 5-mCi indium 111-labeled antiferritin 2 mg intravenously and were scanned repeatedly by gamma camera. In five patients, polyclonal antiferritin (rabbit, pig, or baboon) failed to target the tumor. Thirty-nine patients were injected intravenously with 10-, 20-, 30-, 40-, or 50-mCi yttrium 90-labeled antiferritin 2 to 5 mg. Patients received between one and five cycles. Some patients were supported with 5 x 10(7) autologous bone marrow cells per kilogram. RESULTS: Yttrium 90-labeled polyclonal antiferritin does not produce immunologic, pharmacologic, or microbiologic complications in vivo. Bone marrow toxicity is the only side effect observed. Overall response rate is 20 of 39, or 51%. Two patients had stable disease. A significant positive correlation is found between blood radioactivity level 1 hour after radioimmunoconjugate administration and subsequent response of Hodgkin's disease. A dosage in millicuries per kilogram provides a higher positive correlation with blood radioactivity levels 1 hour after administration than a dosage in millicuries per square meter of body-surface area or in total millicuries. Fifty percent of patients survive for > or = 6 months. CONCLUSION: The low-dose protein used (2 to 5 mg) indicates that the high response rate is due to radiation and not to immunologic effects of the antibody. High-activity administrations followed by bone marrow transplantation are not required for tumor response. The therapeutic ratio of radiolabeled antiferritin is higher than the therapeutic ratio observed in most phase I studies of chemotherapeutic agents. This analysis does not identify a superior mode of treatment for patients with end-stage Hodgkin's disease. However, in a heavily pretreated patient population, prolonged survival is observed after relatively inexpensive treatment. Preclinical research with yttrium 90-labeled antiferritin indicates that significant increases in tumor dose can be obtained in the future without an increase in normal tissue toxicity.

Yttrium 90-labeled antiferritin followed by high-dose chemotherapy and autologous bone marrow transplantation for poor-prognosis Hodgkin's disease.

PURPOSE: This study was undertaken to examine the feasibility of combining radiolabeled antibody therapy with high-dose chemotherapy followed by autologous bone marrow transplantation in patients with poor-prognosis Hodgkin's disease. PATIENTS AND METHODS: Patients were entered onto this protocol if they had chemotherapy-resistant disease, bulky disease, or extensive prior therapy. Patients received yttrium-labeled antiferritin on day -13, -12, or -11, followed by high-dose cyclophosphamide, carmustine, and etoposide (CBV) on days -6 to -3, and then bone marrow infusion on day 0. RESULTS: Twelve patients received both radiolabeled antibody and high-dose chemotherapy followed by autologous transplantation. Two additional patients started the study, but were unable to complete all therapy. Four of 12 patients experienced early transplant-related mortality. Four patients are alive more than 2 years following transplantation and three are free from disease progression at 24+, 25+, and 28+ months following transplantation. The progression-free survival rate at 1 year is estimated to be 21%. Considering the poor prognostic characteristics of these patients, toxicity on this protocol was not necessarily greater than that observed with high-dose chemotherapy alone. CONCLUSION: This report demonstrates the feasibility of combining radiolabeled antibody therapy with high-dose chemotherapy and autologous bone marrow transplantation.

Pharmacokinetics of radiolabeled polyclonal antiferritin in patients with Hodgkin's disease.

The objective was to identify pharmacokinetic parameters predictive for tumor response and normal tissue side effects after i.v. administered radiolabeled rabbit antihuman ferritin IgG. Twenty-eight patients with recurrent Hodgkin's disease received 2 mg of rabbit antihuman ferritin i.v., labeled with 4-7 mCi of In-111 followed by two doses of 0.25, one dose of 0.3, or one dose of 0.4 mCi of Y-90-labeled antiferritin per kg of body weight 1 week later. Radioactivity and HPLC measurements of blood and urine samples and liver and tumor volumes identified on sequential whole-body scans provided the data for a pharmacokinetic analysis covering the first 6 days after the administration of the radioimmunoconjugate. Side effects and tumor response were recorded. Temporary hematological toxicity was noted in all patients. Sixteen patients showed a tumor response. The Y-90 blood level at 1 h after administration correlated with the severity of subsequent hematological toxicity. The rapid blood elimination half-life of radioactivity was 4.4 h. Less than 5% of the administered radioactivity was eliminated in the first 24 h urine. The slow blood elimination half-life was 44 and 37 h for In-111 and Y-90, respectively. One of 12 retreated patients produced anti-rabbit IgG antibodies. The volume of distribution was larger for Y-90 than for In-111-labeled antiferritin (160 versus 110% of estimated blood volume). Accidentally extravasated rabbit IgG was rapidly catabolized in perivascular tissues with an effective half-life of less than 35 h. Slower catabolism was noted for rabbit IgG in blood (t(1/2) = 40 h), liver (t(1/2) = 62 h) or tumor (t(1/2) = 40-80 h). Twelve of 13 patients with an effective tumor half-life > 57 h showed a tumor response. I.v. administered polyclonal rabbit antihuman ferritin, labeled with In-111 or Y-90 is stable in vivo and targets Hodgkin's disease. Intravascular Y-90 causes a vascular leak and a larger volume of distribution for antiferritin. Elevated Y-90 blood levels at 1 h and a tumor half-life of >57 h predict for hematological toxicity and tumor response, respectively.

Fractionated radiolabeled antiferritin therapy for patients with recurrent Hodgkin's disease.

The objective of this study was to determine the therapeutic ratio of fractionated radiolabeled immunoglobulin therapy (RIT) for patients with recurrent Hodgkin's disease. Ninety patients with recurrent Hodgkin's disease received 2 mg of yttrium-90-labeled polyclonal rabbit antihuman ferritin IgG i.v. Fifty-seven patients received a single (unfractionated) administration per treatment cycle; 11 of them were treated with 0.3 mCi/kg body weight, 39 were treated with 0.4 mCi/kg body weight, and 7 received 0.5 mCi/kg body weight per treatment cycle. Thirty-three patients had their radiolabeled immunoglobulin administration separated (fractionated) in 2 x 0.25 mCi/kg body weight (total activity, 0.5 mCi/kg). The interval between fractions was 1 week. Radioimmunoconjugates did not cause serious acute side effects. In vivo radioimmunoconjugates were stable. Human antirabbit IgG antibodies were found in 2 of 50 retreated patients (<5%). Hematological toxicity was the only side effect noted in all patients, and it was usually temporary. Response rates (RRs) were 20%, 61%, and 86% after 0.3, 0.4, or 0.5 mCi/kg unfractionated yttrium-90-labeled antiferritin. The RR for patients treated with fractionated RIT was 42%. In the fractionated RIT group, complete responses were decreased, and progressive disease increased (P < 0.05). Complete responses had a medium duration of 6 months. Median survival times were 390 days for 1 x 0.4 mCi/kg and 300 days for the 2 x 0.25 mCi/kg patient group. Fractionation did not provide the expected decrease in hematological toxicity or the expected increase in tumor RRs.

Hematologic side effects of radiolabeled immunoglobulin therapy.

Radiolabeled immunoglobulin therapy (RIT) is a new cancer treatment that is more selective than its predecessors. Its dose-limiting normal tissue side effect is bone marrow toxicity, and hematopoietic stem cell damage appears to be its most significant mechanism. Platelet consumption in irradiated normal liver tissues and apoptosis of circulating peripheral blood lymphocytes are other, less important, hematologic side effects. 131I and 90Y are the radioisotopes most commonly used for RIT; in addition, animal toxicology and initial clinical studies of chelate immunoglobulins radiolabeled with 111In (for diagnosis) or 90Y (for therapy) are reviewed. The bone-seeking properties of free 90Y are not considered to be a major component of the hematologic damage caused by yttrium-labeled immunoglobulins. The microenvironment of the bone marrow system is not significantly damaged by current RIT protocols. Moreover, granulocyte colony-stimulating factor (G-CSF) can open the blood-marrow barrier. Bone marrow toxicity after RIT can be corrected by bone marrow transplantation, growth factors, blood products, or fractionation of RIT. Selection of the appropriate corrective regimen depends on the severity of the bone marrow damage and will further enhance the therapeutic ratio of RIT.

Association of Periodontal Health with Orthodontic Appliances among Indian Patients.

BACKGROUND: To assess the association of periodontal status of the patients with and without orthodontic treatment. MATERIALS AND METHODS: This cross-sectional study was conducted among 520 patients (220 undergoing orthodontic procedure and 300 non-orthodontic patients). Periodontal health status was assessed using community periodontal index and loss of attachment. Data were analyzed using SPSS version 16 and level of significance used was 5% level. RESULT: Overall mean number of segments for bleeding component (Score 1) was 0.86 ± 0.708, that of calculus (Score 2) 0.30 ± 0.460, for shallow pockets (4-5 mm) (Score 3) 0.33 ± 0.744 and for deep pockets (6 mm or more) (Score 4) 0.38 ± 0.476. Patients with orthodontic appliances had poor periodontal status than the non-orthodontic patients (P < 0.05). CONCLUSION: Patients undergoing orthodontic treatment have increased the level of periodontal status as it leads to more retention of food debris. Hence, these patients should be motivated to maintain good oral hygiene.

Selection of reagents for human radioimmunotherapy.

Promising response rates are noted in patients with refractory Hodgkin's disease after radioimmunoglobulin therapy (RIT) with Yttrium-90 labeled polyclonal antiferritin. To explore the most efficacious selection of RIT reagents for use in humans, experimental animal data are reviewed for radiolabeled antiferritin and B72.3. Nude mice with subcutaneously implanted human malignancies provide an excellent primary screen for radiolabeled antibodies under consideration for use in humans. They provide information on the potential of a new reagent to target a human malignancy in vivo. The other determinant of the therapeutic ratio of RIT reagents--normal tissue toxicity--is best analyzed in large animals, such as dogs. Hematologic toxicity is dose limiting in all species and best predicted by a prescription of radiolabeled antibodies in mCi per kilogram body weight and the presence or absence of bone marrow targeting. Per cGy, RIT is more effective in causing BM damage in dogs than in rats. In dogs, bone marrow transplantation with autologous cryopreserved bone marrow cells or G-CSF treatment can accelerate hemopoietic recovery and granulopoiesis, respectively, after RIT. When dose escalation beyond bone marrow toxicity is performed, the liver (dog) or the intestinal tract (rat) become the next dose limiting tissue in dose escalation studies. Significant improvement in RIT results will be achieved when the normal liver uptake of chelated monoclonal antibody in dogs and in human patients can be prevented. The described animal models and continued investigations of RIT in patients with endstage Hodgkin's disease will allow for further improvement in the therapeutic ratio of RIT and the applicability of RIT in humans.

Evaluation of indium-111- and yttrium-90-labeled linker-immunoconjugates in nude mice and dogs.

Rapid uptake and slow transit of radioactivity from normal organs are detrimental to any clinical utilized radioimmunoconjugate because they lower the target-to-nontarget ratio and deliver undesirable radiation to normal organs. To mitigate this problem, two labile chemical linkages (EGS and DST) were introduced between a monoclonal antiferritin antibody (QCI) and a chelating agent (DTPA). The biodistribution of labile-linker immunoconjugates (EGS and DST) and stable linker immunoconjugates (DSS and ITCB) were compared. In a nude mouse model, all of the four immunoconjugates labeled with 111In targeted subcutaneously-implanted human tumor cells. Tumor-to-normal organ ratios were enhanced for the EGS linkage in comparison to the two stable linkages. Serial whole-body immunoscintigraphy confirmed the biodistribution study. The EGS and ITCB 90Y-labeled immunoconjugates had biodistributions similar to their respective 111In-labeled immunoconjugates. As the mouse model is not representative of the high uptake of monoclonal antibodies in the human liver, beagle dogs were used to further explore the retention of radiolabel in normal liver. The EGS-linked immunoconjugate significantly reduced the dog liver activity when compared to the ITCB immunoconjugate. The combination of the animal models (mouse and dog) appears to allow for a more compete and optimal preclinical analysis of chelated radiolabeled monoclonal antibodies for diagnosis or treatment and illustrates the potential clinical improvements possible with labile chemical linkages in radioimmunoconjugates.

Assessment of radiolabeled stabilized F(ab')2 fragments of monoclonal antiferritin in nude mouse model.

The biodistribution of 111In-labeled stabilized fragments of monoclonal antiferritin was studied in nude mice bearing a human hepatoma tumor xenograft. Pharmacokinetics and tumor targeting of fragment Fab'-linker-Fab' fragment molecules (stabilized F(ab')2) were compared to unmodified F(ab')2 fragment molecules and immunoglobulin G (IgG). Significant differences were observed in tumor and normal organ uptake at 12, 24, 48 and 72 hr. Tumor retention of stabilized F(ab')2 fragments was approximately 2.5-fold higher than of unmodified F(ab')2 at 48 hr. Blood clearance for stabilized F(ab')2 was relatively faster than intact IgG, while unmodified F(ab')2 cleared more rapidly from the circulation. Kidney radioactivity of unmodified F(ab')2 was at least two times higher than kidney radioactivity of stabilized F(ab')2 at all time points. Stabilized F(ab')2 demonstrated 40% less liver uptake than intact IgG. In these studies with nude mice, substantial retention of stabilized F(ab')2 in tumor and significant reduction in liver and kidney uptake of these fragments indicated that they could also have a higher therapeutic ratio than IgG or unmodified F(ab')2 in human patients.

Intraperitoneal indium-111- and yttrium-90-labeled human IgM (AC6C3-2B12) in nude mice bearing peritoneal carcinomatosis.

UNLABELLED: Radiolabeled monoclonal antibodies are utilized increasingly for the diagnosis and treatment of human cancer. Tumor targeting of radiolabeled human monoclonal IgM improves with compartmental administration and might be useful for the diagnosis or treatment of peritoneal carcinomatosis. METHODS: A human monoclonal antibody IgM lambda (AC6C3-B12) reactive with human adenocarcinomas was conjugated to isothiocyanato-2-benzyl-3-methyl-diethylenetriamine-penta-a cetic acid and labeled with either 111In or 90Y. Nude mice bearing intra-abdominal lumps of a human colorectal carcinoma cell line (SW620) were used as a model for peritoneal carcinomatosis. A human monoclonal antibody IgM lambda (CR4E8) reactive with human squamous-cell carcinoma was used as a control. RESULTS: Indium-111-IgM and 90Y-IgM immunoconjugates were compared in nude mice at 2, 24, 72, 120 and 144 hr after intraperitoneal administration. Both showed high specific tumor uptake. The tumor-effective half-lives of the immunoconjugates were 39 hr for indium and 46 hr for yttrium. Tumor-to-normal organ ratios were high and similar for both reagents. Only the femur uptake at later time points was relatively higher for the 90Y-IgM than for 111In-IgM. The tumor uptake of specific AC6C3-2B12 was about fourfold higher than the uptake of aspecific CR4E8 at 24 and 120 hr. CONCLUSION: The combination of 111In- and 90Y-labeled AC6C3-2B12 offers a new opportunity to develop safer and more effective methods for diagnosing and treating human patients with peritoneal carcinomatosis.

Indium-111- and yttrium-90-labeled human monoclonal immunoglobulin M targeting of human ovarian cancer in mice.

UNLABELLED: Most patients with ovarian cancer have disease in the peritoneal cavity. Treatment of this region is inadequate because recurrences are frequent. Increased radiation doses to tumor and, hence, greater tumor control may be possible with intraperitoneal (i.p.) administration of radiolabeled human monoclonal immunoglobulin M (IgM), which is reactive with tumor-associated antigens. METHODS: Biodistribution studies were performed in nude mice bearing i.p. nodules of human ovarian cancer after administration of human monoclonal IgMlambda (AC6C3-2B12), labeled with 111In or 90Y. Irrelevant 111In-labeled human IgMlambda (CH-1B9) and 90Y-aggregate served as specificity controls. RESULTS: Intravenous administration of 111In-labeled AC6C3-2B12 produced low tumor and high liver and spleen uptake. Intraperitoneal administration of AC6C3-2B12 labeled with 111In or 90Y resulted in rapid, high tumor uptake (>45% of injected dose per gram of tumor at 3 hr) that was at least three-fold higher than any normal organ. Biodistribution results were similar for 111In- and 90Y-labeled IgM. Tumor uptake of 111In-labeled AC6C3-2B12 was two-fold greater than that of 111In-labeled CH-1B9. Normal organ uptakes were similar for tumor-reactive and irrelevant IgM. Radioimmunoconjugates were retained in the peritoneal cavity for a prolonged period of time. Yttrium-90 aggregate demonstrated high tumor and bone uptake. CONCLUSION: Higher tumor uptake was observed after i.p. administration of tumor-reactive IgM than after irrelevant IgM. The in vivo behavior of tumor-reactive IgM was similar when it was radiolabeled with either 111In or 90Y. Therefore, 111In-based imaging studies can be used to predict the biodistribution of subsequently administered 90Y-labeled IgM. Further development of radiolabeled AC6C3-2B12 as a diagnostic and therapeutic agent for patients with advanced ovarian carcinoma is warranted.

Quantitative SPECT for indium-111-labeled antibodies in the livers of beagle dogs.

Results are presented for SPECT computations of liver volumes and 111In-labeled antibody activities in the livers of eight normal beagle dogs. Administered activities ranged from 1 to 2 mCi. SPECT studies were acquired 1 day postinjection using a rotating gamma camera system with elliptical orbits in a 360-degree rotation (128 views, 15 sec/view, 64 x 64 matrices). Uniformity-corrected images were reconstructed by use of the circular harmonic transform algorithm with computer software developed in-house. Liver volumes and activities were computed from transverse slices, 1 pixel (6.25 mm) in thickness. Comparison of SPECT and autopsy data demonstrated that absolute values of percent differences between measured and computed liver volumes ranged from 1.0% to 7.2%. Absolute values of percent differences between autopsy data and computed 111In activities in the liver ranged from 2.3% to 7.5%. These results suggest that quantitative SPECT has the potential of becoming an important tool in clinical trials for determining activities and localization volumes of radiolabeled antibodies directly from radionuclide images.

Reduction of background activities by introduction of a diester linkage between antibody and a chelate in radioimmunodetection of tumor.

A diester linkage was added between monoclonal anti-melanoma antibody 96.5 and a diethylenetriaminepentaacetic acid derivative to test if a tumor-to-blood and -to-organ ratio of the injected antibody in nude mice with human melanoma FEM XII xenografts could be increased by the addition of the readily cleavable linkage. Compared to the 111In-labeled antibody DTPA with a peptide linkage, the diester conjugate cleared much faster from the blood and was retained much less in muscle and normal organs such as liver, spleen and kidney over a 48-hr period. On the other hand, the activity retained in the tumor was larger than or similar to that of the peptide conjugate for this time period. This resulted in a 2.5, 2.1, and 2.6 fold increase in a tumor to blood, to liver and to kidney ratio at 48 hr for the diester conjugate as compared to the peptide conjugate. The whole-body biologic half life of the antibody was 36 hr, three times shorter than the peptide conjugate. The external imaging demonstrated a clearly visible tumor at 4 hr and a lower pool activity at 72 hr for the diester conjugate. The peptide conjugate, however, showed a persistant blood-pool activity at 72 hr. The addition of the diester linkage, therefore may be beneficial for imaging tumors in patients at early time intervals after injection.

Intralesional radiolabeled human monoclonal IgM in human tumor xenografts.

BACKGROUND AND PURPOSE: Intralesional (i.l.) administration of radiolabeled human monoclonal IgM could provide a new method for increasing the radiation dose delivered to a tumor without exceeding normal tissue tolerance. MATERIALS AND METHODS: Nude mice with subcutaneous human head and neck squamous cell carcinoma nodules were injected either intralesionally or intravenously with a tumor-reactive human monoclonal IgM (CR4E8) labeled with indium-111 (111In) or yttrium-90 (90Y). Groups of mice were sacrificed at different time points and their tumors and major organs were excised and counted for radioactivity. Additional mice that were treated with i.l. 90Y-labeled CR4E8 were sacrificed at the same time points for tumor autoradiography. Serial whole-body gamma camera images were obtained from additional mice treated with i.l. 111In-labeled CR4E8. Intralesionally administered 111In-labeled irrelevant IgM (CH-1B9) and 90Y-aggregate served as specificity controls. RESULTS: Intralesional administration of radiolabeled IgM resulted in prolonged high tumor radioactivity with little normal tissue uptake, with kidney and liver having the highest values. The biodistribution of i.l. CR4E8 was similar whether labeled with 111In or 90Y. Tumor uptake of i.l. irrelevant IgM appeared to be lower and tumor retention appeared to be shorter. Intravenous administration of tumor-reactive IgM resulted in very low tumor radioactivity with high liver and moderate spleen uptake. The i.l. administration of 90Y-aggregate produced prolonged high tumor radioactivity with little normal tissue uptake, with bone having the highest value. Tumor autoradiographs demonstrated that the radiolabeled IgM diffused through the tumor over time while the 90Y-aggregate remained localized at the injection site. Gamma camera scintigraphy corroborated the results of the biodistribution studies. CONCLUSIONS: Intralesional but not intravenous administration of 111In- or 90Y-labeled human IgM results in high tumor radioactivity with low normal tissue exposure. Myelotoxicity is not anticipated to be the dose-limiting normal tissue toxicity of this treatment. Further development of human IgM for the i.l. treatment of human malignancies appears to be warranted.

Proposal for translational analysis and development of clinical radiolabeled immunoglobulin therapy.

BACKGROUND AND PURPOSE: Radiolabeled immunoglobulin therapy (RIT) can be a selective, effective, low-toxicity outpatient cancer therapy. A consensus on the best approach for the preclinical and clinical development of RIT reagents needs to be developed. We report the M.D. Anderson Cancer Center prior experience in translating RIT from laboratory to clinic for the treatment of Hodgkin's disease and propose a flow diagram for the development of RIT for other malignancies. MATERIAL AND METHODS: Three different animal models are described: nude mice bearing human tumor xenografts, normal beagle dogs, and normal rhesus monkeys. We produced and purified antibodies and prepared chelate-immunoconjugates reactive with six different human tumor-associated antigens. The Igs used were derived from rabbits, mice, and humans (human-derived RIT reagents being less immunogenic in human patients). Eighty patients with refractory Hodgkin's disease were treated with radiolabeled antiferritin. RESULTS: We recommend a two-injection scheme using, (1) an indium-111-labeled radioimmunoconjugate for diagnosis, pharmacokinetic studies, and dosimetry, and (2) a yttrium-90-labeled radioimmunoconjugate for therapy. The animal models provide useful data on tumor targeting, radiotoxicology, and undesirable biodistributions. A 70% response rate is obtained in patients with advanced recurrent Hodgkin's disease. More extensive preclinical testing allows for safer and more effective clinical RIT studies. CONCLUSIONS: We recommend, (1) preclinical optimization of chelation chemistry, Ig size, Ig origin, route of administration, and fractionation, (2) new clinical Phase I-III studies more appropriate for RIT development than the classical Phase I-III studies used for the development of chemotherapeutic agents, and (3) more extensive preclinical testing of RIT reagents.