S. James Adelstein

Primer on certain elements of medical decision making.

The value of a diagnostic test lies in its ability to detect patients with disease (its sensitivity) and to exclude patients without disease (its specificity). For tests with binary outcomes, these measures are fixed. For tests with a continuous scale of values, various cutoff points can be selected to adjust the sensitivity and specificity of the test to conform with the physicians goals. Principles of statistical decision theory and information theory suggest technics for objectively determining these cutoff points, depending upon whether the physician is concerned with health costs, with financial costs, or with the information content of the test.

The Physician's Responsibility toward Hopelessly Ill Patients

Abstract Physicians have a specific responsibility toward patients who are hopelessly ill, dying, or in the end stages of an incurable disease. In a summary of current practices affecting the care of dying patients, we give particular emphasis to changes that have become commonplace since the early 1980s. Implementation of accepted policies has been deficient in certain areas, including the initiation of timely discussions with patients about dying, the solicitation and execution in advance of their directives for terminal care, the education of medical students and residents, and the formulation of institutional guidelines. The appropriate and, if necessary, aggressive use of pain-relieving substances is recommended, even when such use may result in shortened life. We emphasize the value of a sensitive approach to care — one that is adjusted continually to suit the changing needs of the patient as death approaches. Possible settings for death are reviewed, including the home, the hospital, the intensive ...

Bystander effect produced by radiolabeled tumor cells in vivo

The bystander effect, originating from cells irradiated in vitro, describes the biologic response(s) of surrounding cells not directly targeted by a radiation insult. To overcome the limitations of in vitro tissue culture models and determine whether a bystander effect that is initiated by the in vivo decay of a radionuclide can be demonstrated in an animal, the ability of 5-[125I]iodo-2′-deoxyuridine (125IUdR)-labeled tumor cells to exert a damaging effect on neighboring unlabeled tumor cells growing s.c. in nude mice has been investigated. When mice are injected with a mixture of human colon LS174T adenocarcinoma cells and LS174T cells prelabeled with lethal doses of DNA-incorporated 125I, a distinct inhibitory effect on the growth of s.c. tumor (derived from unlabeled cells) is observed. Because (i) the 125I present within the cells is DNA-bound, (ii) ≈99% of the electrons emitted by the decaying 125I atoms have a subcellular range (<0.5 μm), and (iii) the overall radiation dose deposited by radiolabeled cells in the unlabeled cells within the growing tumor is <10 cGy, we conclude that the results obtained are a consequence of a bystander effect that is generated in vivo by factor(s) present within and/or released from the 125IUdR-labeled cells. These in vivo findings significantly impact the current dogma for assessing the therapeutic potential of internally administered radionuclides. They also call for reevaluation of the approaches currently used for estimating the risks to individuals and populations inadvertently exposed internally to radioactivity as well as to patients undergoing routine diagnostic nuclear medical procedures.

Measures of clinical efficacy. The value of case finding in hypertensive renovascular disease.

An attempt was made to discover the difference in outcomes between treating all patients with essential and renovascular hypertension by drug therapy independent and ignorant of etiologic classification and identifying the patients with renovascular disease and operating on them. Outcomes were categorized as well without complications of hypertension, alive but suffering from a related morbid illness such as coronary or cerebral arterial disease, and dead from the complications of diagnosis, surgery or high blood pressure. The identification and surgical treatment of hypertensive renovascular disease resulted in an incremental benefit in morbidity over blind antihypertensive medical therapy only when the compliance with medical treatment was about 50 per cent or less (the rate suggested for most patient populations). The study underscores the extent to which the quantitative efficacy of diagnositc and therapeutic procedures depends not only on the inherent risks and benefits but also on related social and medical factors.

A combined approach to data mining of textual and structured data to identify cancer-related targets

BackgroundWe present an effective, rapid, systematic data mining approach for identifying genes or proteins related to a particular interest. A selected combination of programs exploring PubMed abstracts, universal gene/protein databases (UniProt, InterPro, NCBI Entrez), and state-of-the-art pathway knowledge bases (LSGraph and Ingenuity Pathway Analysis) was assembled to distinguish enzymes with hydrolytic activities that are expressed in the extracellular space of cancer cells. Proteins were identified with respect to six types of cancer occurring in the prostate, breast, lung, colon, ovary, and pancreas.ResultsThe data mining method identified previously undetected targets. Our combined strategy applied to each cancer type identified a minimum of 375 proteins expressed within the extracellular space and/or attached to the plasma membrane. The method led to the recognition of human cancer-related hydrolases (on average, ~35 per cancer type), among which were prostatic acid phosphatase, prostate-specific antigen, and sulfatase 1.ConclusionThe combined data mining of several databases overcame many of the limitations of querying a single database and enabled the facile identification of gene products. In the case of cancer-related targets, it produced a list of putative extracellular, hydrolytic enzymes that merit additional study as candidates for cancer radioimaging and radiotherapy. The proposed data mining strategy is of a general nature and can be applied to other biological databases for understanding biological functions and diseases.

Inhibitory and Stimulatory Bystander Effects are Differentially Induced by Iodine-125 and Iodine-123

Abstract Kishikawa, H., Wang, K., Adelstein, S. J. and Kassis, A. I. Inhibitory and Stimulatory Bystander Effects are Differentially Induced by Iodine-125 and Iodine-123. Radiat. Res. 165, 688–694 (2006). The bystander effect, originating from cells irradiated in vitro, describes responses of surrounding cells not targeted by the radiation. Previously we demonstrated that the subcutaneous injection into nude mice of human adenocarcinoma LS174T cells lethally irradiated by Auger electrons from the decay of DNA-incorporated 125I inhibits growth of co-injected LS174T cells (inhibitory bystander effect; Proc. Natl. Acad. Sci. USA 99, 13765–13770, 2002). We have repeated these studies using cells exposed to lethal doses of 123I, an Auger electron emitter whose emission spectrum is identical to that of 125I, and report herein that the decay of 123I within tumor cell DNA stimulates the proliferation of neighboring unlabeled tumor cells growing subcutaneously in nude mice (stimulatory bystander effect). Similar inhibitory bystander effects (125I) and stimulatory bystander effects (123I) are obtained in vitro. Moreover, supernatants from cultures with 125I-labeled cells are positive for tissue inhibitors of metalloproteinases (TIMP1 and TIMP2), and those from cultures with 123I-labeled cells are positive for angiogenin. These findings call for the re-evaluation of current dosimetric approaches for the estimation of dose–response relationships in individuals after radiopharmaceutical administration or radiocontamination and demonstrate a need to adjust all “calculated” dose estimates by a dose modification factor (DMF), a radionuclide-specific constant that factors in hitherto not-so-well recognized biophysical processes.

Radiobiologic implications of the microscopic distribution of energy from radionuclides

A significant increase in our understanding of the dosimetry and therapeutic potential of various types of radioactive decay has augmented the possibility of utilizing specific radiolabeled carriers in tumor therapy. At least three types of radioactive decay lend themselves to this approach. Most fastidious in their distribution requirements are the Auger electron emitters whose radiotoxicity can only be realized with their intranuclear localization. Alpha emitters irradiate regions of several cell diameters. Beta emitters are less stringent as far as proximity to the total tumor mass, but doses to normal tissues can be high. The advantages and the limitations of each type of decay are presented.

Iododestannylation. Position-specific synthesis of iodotamoxifen

Abstract A procedure has been developed for the synthesis of iodotamoxifen 3 from tamoxifen ( 1 ), an anti-estrogenic agent currently employed in the treatment of breast cancer. Ortho-directed metalation of tamoxifen with sec -butyllithium at −78°C followed by addition of tri- n -butyltin chloride gave the stannyl derivative 2 in 98% isolated yield. Iododestannylation of 2 at 0°C with iodine afforded the desired iodotamoxifen 3 in quantitative yield. The dimethylaminoethoxy group appears to be more strongly activating for ortho metalation than methoxy.

In silico design, synthesis, and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase–mediated cancer diagnosis and therapy

As part of the development of enzyme-mediated cancer imaging and therapy, a novel technology to entrap water-insoluble radioactive molecules within solid tumors, we show that a water-soluble, radioactive quinazolinone prodrug, ammonium 2-(2′-phosphoryloxyphenyl)-6-[125I]iodo-4-(3H)-quinazolinone (125IQ2-P), is hydrolyzed by alkaline phosphatase to a water-insoluble, radiolabeled drug, 2-(2′-hydroxyphenyl)-6-[125I]iodo-4-(3H)-quinazolinone (125IQ2-OH). Biodistribution data suggest the existence of two isoforms of the prodrug (IQ2-P(I) and IQ2-P), and this has been confirmed by their synthesis and characterization. Structural differences of the two isoforms have been examined using in silico molecular modeling techniques and docking methods to describe the interaction/binding between the isoforms and human placental alkaline phosphatase (PLAP), a tumor cell, membrane-associated, hydrolytic enzyme whose structure is known by X-ray crystallographic determination. Docking data show that IQ2-P, but not IQ2-P(I), fits the active binding site of PLAP favorably and interacts with the catalytic amino acid Ser92, which plays an important role in the hydrolytic process. The binding free energies (ΔGbinding) of the isoforms to PLAP predict that IQ2-P will be the better substrate for PLAP. The in vitro incubation of the isoforms with PLAP leads to the rapid hydrolysis of IQ2-P only and confirms the in silico expectations. Fluorescence microscopy shows that in vitro incubation of IQ2-P with mouse and human tumor cells causes the extracellular, alkaline phosphatase–mediated hydrolysis of the molecule and precipitation of fluorescent crystals of IQ2-OH. No hydrolysis is seen in the presence of normal mouse and human cells. Furthermore, the intratumoral injection of 125IQ2-P into alkaline phosphatase–expressing solid human tumors grown s.c. in nude rats results in efficient hydrolysis of the compound and retention of ∼70% of the injected radioactivity, whereas similar injection into normal tissues (e.g., muscle) does not produce any measurable hydrolysis (∼1%) or retention of radioactivity at the injected site. These studies support the enzyme-mediated cancer imaging and therapy technology and show the potential of such quinazolinone derivatives in the in vivo radiodetection (123I/124I) and therapy (131I) of solid tumors. [Mol Cancer Ther 2006;5(12):3001–13]

Se75-selenomethionine incorporation into human plasma proteins and erythrocytes☆

Abstract The disappearance of Se75-selenomethionine from blood following its i.v. injection and its reappearance in total plasma proteins, albumin, fibrinogen, and hemoglobin has been studied over 25 days in 2 groups of subjects: (1) a group of 8 normal volunteers, (2) a group of patients on whom parathyroid scanning with Se75-selenomethionine was performed. These patients were premedicated with triiodothyronine for 4 days before the isotope administration. The free selenomethionine disappears rapidly from blood. By the tenth hour, virtually very little cold TCA soluble radioactivity could be detected. (1) There is gradual build-up of plasma protein bound radioactivity, reaching a maximum in 8 hours in the first group, and in 6 hours in the second group. It could be shown that a small fraction of the TCA insoluble fraction is bound to protein through a reducible seleno-sulfur bond. This reducible fraction practically disappears after the twelfth hour. The plasma protein activity at its maximum total value accounts for 14 to 22 per cent of the injected isotope in normal subjects, and 21 to 32 per cent in T3-treated patients. (2) The fall of the total plasma protein specific activity over the first 25 days followed a multiexponential pattern. The albumin specific activity build-up and decay curves could be defined. As with I131 labeled albumin, a multiexponential disappearance curve could be demonstrated. The terminal slope was, however, less steep with the Se75-selenomethionine label than has been shown by using an I131 label. The mean T 1 2 was 21.8 days. The fibrinogen specific activity build-up and decay curves were defined. The disappearance curve could be fitted to a single exponential with a mean T 1 2 of 7.0 days. Triiodothyronine pretreatment markedly increased the uptake of radioactivity into this component. (3) The incorporation of Se75-selenomethionine into hemoglobin was demonstrated to follow a pattern which strongly suggests that the label was incorporated into red cells during their early development. Ninty-five per cent of the red cell activity could be accounted for by Hb; 0.5 per cent of the red cell activity was associated with the red cell membrane. In 1 normal subject, the Hb specific activity dropped between the 100th and the 140th day to low levels. It is felt, therefore, that this represents the life span distribution range of normal erythrocytes.