Phase I/II clinical radioimmunotherapy with an iodine-131-labeled anti-carcinoembryonic antigen murine monoclonal antibody IgG

The aim of this study was to determine, in a Phase I/II clinical trial, the pharmacokinetics, dosimetry and toxicity, as well as antitumor activity, of the 131I-labeled murine anti-carcinoembryonic antigen (CEA) monoclonal antibody, NP-4 (IgG1 subtype). METHODS: A total of 57 patients with CEA-expressing tumors (29 colorectal, 9 lung, 7 pancreas, 6 breast and 4 medullary thyroid cancer patients), mostly in very advanced stages, were treated. The patients underwent a diagnostic study (1-3 mg of IgG and 8-30 mCi of 131I) to assess tumor targeting and to estimate dosimetry, followed by the therapeutic dose (4-23 mg and 44-268 mCi), based on the radiation dose to the red marrow. Imaging was performed from 4-240 hr postinjection (planar and SPECT). Blood and whole-body clearance were determined; radiation doses were calculated by the Medical Internal Radiation Dose scheme. RESULTS: Red marrow doses ranged from 45 to 706 cGy, and whole-body doses ranged from 31 to 344 cGy. Differences in pharmacokinetics were found between different types of CEA-producing tumors: blood T 1/2 was significantly lower in colorectal cancer when compared to all other tumor types (21.4 +/- 11.1 hr versus 35.8 +/- 13.2 hr, p < 0.01), as was also whole-body t 1/2. Myelotoxicity was dose-limiting, and its severity was related to the types of prior therapy and extent of bone marrow involvement. In patients without prior radiation or chemotherapy, marrow doses as high as 600 cGy were tolerated without evidence of dose-limiting toxicity. No major toxicity to other organs was observed. Tumor doses were inversely related to the tumor mass and ranged between 2 and 218 cGy/mCi. Modest antitumor effects were seen in 12 of 35 assessable patients (1 partial remission, 4 minor/mixed responses and 7 with stabilization of previously rapidly progressing disease). CONCLUSION: These results suggest that prior chemotherapy or external beam radiation is an important risk factor for the development of hematological toxicity in radioimmunotherapy and that higher radiation doses may be delivered to tumors of patients without prior therapy compromising the bone marrow reserve. The different and, in the individual cases, unpredictable clearance rates suggest the necessity of dosimetry-based treatment planning rather than mCi/m2 dosing. Small tumors seem to be more suitable for radioimmunotherapy because of their favorable dosimetry, but to achieve better therapeutic results in patients with bulky disease, the application of higher, potentially myeloablative doses is indicated.     

Bladder sensory power factor (BSPF): a novel diagnostic tool

45 patients who had received total laryngectomy for laryngeal neoplasia were reviewed with CT, using a study protocol for systematic evaluation as well as the identification of the principal sites of probable recurrence. The advantages of this technique, and some of the considerations which have to be taken into account to avoid error in diagnosis, are commented upon.     

Evaluation of reproductive toxicity in male rats treated with novel synthesized ruthenium(II) and gold(I)-NHC complexes

In this study, we aimed to determine the reproductive toxicity in rat induced by ruthenium(II)-NHC (Ru(II)) and gold(I)-NHC (Au(I)) complexes that have anticarcinogenic effects. For this purpose, 35 Sprague-Dawley rats were randomly divided into 5 equal groups. In control group, rats treated with saline, Ru(II), and Au(I) complexes were intraperitoneally given high (10?mg/kg) and low (5?mg/kg) doses to rats via a one-time administration. The animals were sacrificed, and testis tissues were taken on Day 10 of the drug administration for the determination of the biochemical, histopathological, spermatological, and hormonal parameters. It was determined that treatment group that was subjected to treatment using both Ru(II) and Au(I) complexes significantly caused oxidative, histopathological, spermatological, and hormonal damage compared to control group. However, the sexual and accessory organ weight did not significantly change when compared to control. In addition, it was shown that Au(I) treatment generally caused more adverse effects than Ru(II) treatment in a dose-dependent manner. In conclusion, when these synthesized compounds are used for the treatment of cancer, they could cause toxic effects on male reproductive system and lead to infertility. However, Ru(II) complex is a more preferable option in cancer treatment, particularly in terms of user safety.     

Neurochemistry of the mammalian cone 'synaptic complex'

The cone 'synaptic complex' is a unique structure in which a single presynaptic axon secretes glutamate onto processes of bipolar cells (both ON and OFF) and horizontal cells. In turn, the horizontal cell processes antagonize cone and bipolar responses to glutamate (probably by GABA). What still remains largely unknown is the molecular identity of the postsynaptic receptors and their exact locations. We identified several subunits of the glutamate receptor and the GABAA receptor expressed at the cone synaptic complex and localized them ultrastructurally. Glutamate receptors: (i) Invaginating (probably ON) bipolar dendrites in the monkey and rat express the metabotropic glutamate receptor, mGluR6. The stain is intense on the dendritic membrane where it first enters the invagination, and weak at the tip nearest to the ribbon. The cone membrane is electron-dense where it apposes the intense stain for mGluR6. Surprisingly, invaginating bipolar dendrites in the cat also express the AMPA receptor subunits, GluR2/3 and GluR4. (ii) Dendrites forming basal contacts in the cat (probably OFF) express the AMPA subunits GluR2/3, GluR4, and also the kainate subunit, GluR6/7. The stain is especially intense at the dendritic tips in apposition to electron-dense regions of cone membrane. (iii) Horizontal cells in the cat express the AMPA subunits GluR2/3, GluR4 and the kainate subunit, GluR6/7. The stain is strongest in the cytosol of somas and primary dendrites, but is also present in the invaginating terminals where it localizes to the membrane subjacent to the ribbon. GABAA receptors: (i) ON and OFF bipolar dendrites in the monkey express the alpha 1 and beta 2/3 subunits. The stain is localized to the bipolar cell membrane in apposition to horizontal cell processes. (ii) Cones did not express the GABAA subunits tested by immunocytochemistry, but beta 3 mRNA was amplified by RT-PCR from rat photoreceptors. Conclusions: (i) mGluR6 receptors concentrate on dendrites at the base of the invagination rather than at the apex. This implies that receptors at both 'invaginating' and 'basal' contacts lie roughly equidistant from the release sites and should therefore receive similar spatiotemporal concentrations of glutamate. (ii) The 'cone' membrane is electron-dense opposite to the receptor sites on both ON and OFF bipolar cells. This suggests a special role for this region in synaptic transmission. Possibly, these densities signify a transporter that would regulate glutamate concentration at sites remote (> 200 nm) from the locus of vesicle release.     

The prevalence of cutaneous manifestations in IDDM patients and their association with diabetes risk factors and microvascular complications

A questionnaire was administered to a random sample of family practitioners, internists, cardiologists, and geriatricians to examine the current management of heart failure patients with preserved versus reduced left ventricular systolic function. In patients with preserved systolic function, electrocardiogram at rest, chest x-ray, echocardiography, digitalis, angiotensin-converting enzyme inhibitors, and restriction of dietary sodium and physical activity are used less often, whereas calcium channel blockers and beta blockers are given more often than to patients with reduced systolic function.     

Evaluating Semi-Exhaustive Verification Techniques for Bug Hunting

We propose a methodology to evaluate a rich set of BDD subsetting heuristics with respect to bug hunting and apply it to a set of real-life Intel designs. Our results illustrate that the evaluation metrics used to rate these heuristics in previous work were not tuned for bug-finding efficiency, which we believe is the major criterion that the heuristics need to meet.     

Orthodox Jews have a lower incidence of malignant melanoma. A note on the potentially protective role of traditional clothing

The incidence of malignant melanoma (MM) in orthodox and non-orthodox Jews in Israel during the years 1970-1982 was compared through an assessment of incidence rates in the orthodox and non-orthodox neighborhoods in the city of Jerusalem and by a comparison of the rates in 2 cities on the outskirts of Tel Aviv, one of which has a strongly orthodox population. Within the city of Jerusalem the incidence of MM for the European-American born in the orthodox neighborhoods was significantly lower than in the rest of the city in males, and of borderline significance in females. A similar pattern was seen upon comparison of the orthodox city of Bnei Brak to its neighbor city, Givatayim. The findings are consistent with the role of sun exposure in the etiology of malignant melanoma.     

Infinitary logics and 0–1 laws

We investigate the infinitary logic L_∞ω^ω, in which sentences may have arbitrary disjunctions and conjunctions, but they involve only finite numbers of distinct variables. We show that various fixpoint logics can be viewed as fragments of L_∞ω^ω, and we describe a game-theoretic characterization of the expressive power of the logic. Finally, we study asymptotic probabilities of properties expressible in L_∞ω^ω on finite structures. We show that the 0–1 law holds for L_∞ω^ω, i.e., the asymptotic probability of every sentence in this logic exists and is equal to either 0 or 1. This result subsumes earlier work on asymptotic probabilities for various fixpoint logics and reveals the boundary of 0–1 laws for infinitary logics.     

A New Heuristic for Bad Cycle Detection Using BDDs

We describe a new heuristic for detecting bad cycles (reachable cycles that are not confined within one or another designated sets of model states), a fundamental operation for model-checking algorithms. It is a variation on a standard implementation of the Emerson-Lei algorithm, which our experimental data suggests can result in a significant speed-up for verification runs that pass. We conclude that this heuristic can be used to advantage on mature designs for which the anticipated result of the verification is pass.