The Future of Radioactive Medicine.

The discovery of X rays in the late 19th century heralded the beginning of a new age in medicine, and the advent of channeling the power of radiation to diagnose and treat human disease. Radiation has been leveraged in medicine in a multitude of ways and is a critical element of cancer care including screening, diagnosis, surveillance, and interventional treatments. Modern radiotherapy techniques include a multitude of methodologies utilizing both externally and internally delivered radiation from a variety of approaches. This review provides a comprehensive overview of contemporary radiotherapy methodologies, the field of radiopharmaceuticals and theranostics, effects of low dose radiation and highlights the phenomena of fear of exposure to radiation and its impact in modern medicine.

Advances in 4D medical imaging and 4D radiation therapy.

This paper reviews recent advances in 4D medical imaging (4DMI) and 4D radiation therapy (4DRT), which study, characterize, and minimize patient motion during the processes of imaging and radiotherapy. Patient motion is inevitably present in these processes, producing artifacts and uncertainties in target (lesion) identification, delineation, and localization. 4DMI includes time-resolved volumetric CT, MRI, PET, PET/CT, SPECT, and US imaging. To enhance the performance of these volumetric imaging techniques, parallel multi-detector array has been employed for acquiring image projections and the volumetric image reconstruction has been advanced from the 2D to the 3D tomography paradigm. The time information required for motion characterization in 4D imaging can be obtained either prospectively or retrospectively using respiratory gating or motion tracking techniques. The former acquires snapshot projections for reconstructing a motion-free image. The latter acquires image projections continuously with an associated timestamp indicating respiratory phases using external surrogates and sorts these projections into bins that represent different respiratory phases prior to reconstructing the cyclical series of 3D images. These methodologies generally work for all imaging modalities with variations in detailed implementation. In 4D CT imaging, both multi-slice CT (MSCT) and cone-beam CT (CBCT) are applicable in 4D imaging. In 4D MR imaging, parallel imaging with multi-coil-detectors has made 4D volumetric MRI possible. In 4D PET and SPECT, rigid and non-rigid motions can be corrected with aid of rigid and deformable registration, respectively, without suffering from low statistics due to signal binning. In 4D PET/CT and SPECT/CT, a single set of 4D images can be utilized for motion-free image creation, intrinsic registration, and attenuation correction. In 4D US, volumetric ultrasonography can be employed to monitor fetal heart beating with relatively high temporal resolution. 4DRT aims to track and compensate for target motion during radiation treatment, minimizing normal tissue injury, especially critical structures adjacent to the target, and/or maximizing radiation dose to the target. 4DRT requires 4DMI, 4D radiation treatment planning (4D RTP), and 4D radiation treatment delivery (4D RTD). Many concepts in 4DRT are borrowed, adapted and extended from existing image-guided radiation therapy (IGRT) and adaptive radiation therapy (ART). The advantage of 4DRT is its promise of sparing additional normal tissue by synchronizing the radiation beam with the moving target in real-time. 4DRT can be implemented differently depending upon how the time information is incorporated and utilized. In an ideal situation, the motion adaptive approach guided by 4D imaging should be applied to both RTP and RTD. However, until new automatic planning and motion feedback tools are developed for 4DRT, clinical implementation of ideal 4DRT will meet with limited success. However, simplified forms of 4DRT have been implemented with minor modifications of existing planning and delivery systems. The most common approach is the use of gating techniques in both imaging and treatment, so that the planned and treated target localizations are identical. In 4D planning, the use of a single planning CT image, which is representative of the statistical respiratory mean, seems preferable. In 4D delivery, on-site CBCT imaging or 3D US localization imaging for patient setup and internal fiducial markers for target motion tracking can significantly reduce the uncertainty in treatment delivery, providing improved normal tissue sparing. Most of the work on 4DRT can be regarded as a proof-of-principle and 4DRT is still in its early stage of development.

Optically stimulated luminescent glass optical fibre dosemeter.

An optical fibre radiation dosemeter has been developed that utilises optically stimulated luminescence and scintillation to provide independent, remote, real-time dose measurements. The radiation sensitive element consists of a 1 mm long, 0.4 mm diameter piece of copper-ion-doped fused quartz that is attached to a 1 m length of commercial optical fibre. The dosemeter probe is 0.6 mm in diameter and is flexible enough to be used in standard medical catheters for internal radiation dose measurements. A four-channel dosemeter system has been built and characterised under conditions typical of a radiotherapy environment. The device exhibits a linear response over the range of doses from 0.01 Gy to 10 Gy. The dosemeter responds identically to both electrons and photons in the range from 4 to 20 MV and the calibration was retained to within +/-2% over a period of 4 weeks. The fibre dosemeter has been used successfully to verity doses received by three patients receiving radiotherapy treatments.

Ewing sarcoma and sinonasal neuroectodermal tumors as second malignant tumors after retinoblastoma and other neoplasms.

BACKGROUND: Excesses of various childhood cancers have been reported after retinoblastoma, including a trickle of Ewing sarcoma (ES) and perhaps histologically similar olfactory neuroblastoma, both of which are neural tumors. To update and advance this information, case reports were sought by an extensive review of the literature. PROCEDURE: The search was made through the use of PubMed, and the Web of Science (Citation Index Expanded), keying on primary references. Three sinonasal cancers diagnosed as ES were immunohistochemically stained for MIC-2 protein (positive in ES). RESULTS: Retinoblastoma occurred before ES in ten cases (seven bilateral). In four others, retinoblastoma (three bilateral) developed before sinonasal neural tumors (poorly differentiated). ES also occurred after 14 cancers other than retinoblastoma (five lymphomas, four leukemias, and one each of five miscellaneous cancers). The predominance of retinoblastoma prior to ES differs markedly from the low-frequency of retinoblastoma among childhood cancers in the general population. On the contrary, cancers other than retinoblastoma were proportionate to those in the general population. Previously, retinoblastoma followed by excesses of osteosarcoma and soft tissue sarcomas has been attributed to the action of the inherited RB-1 gene. The sinonasal tumors stained negative for MIC-2 protein. CONCLUSIONS: Heritable retinoblastoma may predispose to ES and perhaps to a subset of poorly differentiated neuroectodermal tumors in the sinonasal region that may be related to olfactory neuroblastoma.

Transition state complexes of the Klebsiella pneumoniae nitrogenase proteins. Spectroscopic properties of aluminium fluoride-stabilized and beryllium fluoride-stabilized MgADP complexes reveal conformational differences of the Fe protein.

Stable inactive 2 : 1 complexes of the Klebsiella pneumoniae nitrogenase components (Kp2/Kp1) were prepared with ADP or the fluorescent ADP analogue, 2'(3')-O-[N-methylanthraniloyl] ADP and AlF(4)(-) or BeF(3)(-) ions. By analogy with published crystallographic data [Schindelin et al. (1997) Nature 387, 370-376)], we suggest that the metal fluoride ions replaced phosphate at the two ATP-binding sites of the iron protein, Kp2. The beryllium (BeF(x)) and aluminium (AlF(4)(-)) containing complexes are proposed to correspond to the ATP-bound state and the hydrolytic transition states, respectively, by analogy with the equivalent complexes of myosin [Fisher et al. (1995) Biochemistry 34, 8960-8972]. (31)P NMR spectroscopy showed that during the initial stages of complex formation, MgADP bound to the complexed Kp2 in a manner similar to that reported for isolated Kp2. This process was followed by a second step that caused broadening of the (31)P NMR signals and, in the case of the AlF4- complex, slow hydrolysis of some of the excess ADP to AMP and inorganic phosphate. The purified BeFx complex contained 3.8 +/- 0.1 MgADP per mol Kp1. With the AlF(4)(-) complex, MgAMP and adenosine (from MgAMP hydrolysis) replaced part of the bound MgADP although four AlF(4)(-) ions were retained, demonstrating that full occupancy by MgADP is not required for the stability of the complex. The fluorescence emission maximum of 2'(3')-O-[N-methylanthraniloyl] ADP was blue-shifted by 6-8 nm in both metal fluoride complexes and polarization was 6-9 times that of the free analogue. The fluorescence yield of bound 2'(3')-O-[N-methylanthraniloyl] ADP was enhanced by 40% in the AlF(4)(-) complex relative to the solvent but no increase in fluorescence was observed in the BeFx complex. Resonance energy transfer from conserved tyrosine residues located in proximity to the Kp2 nucleotide-binding pocket was marked in the AlF(4)(-) complex but minimal in the BeFx fluoride complex, illustrating a clear conformational difference in the Fe protein of the two complexes. Our data indicate that complex formation during the nitrogenase catalytic cycle is a multistep process involving at least four conformational states of Kp2: similar to the free Fe protein; as initially complexed with detectable (31)P NMR; as detected in mature complexes with no detectable (31)P NMR; in the AlF(4)(-) complex in which an altered tyrosine interaction permits resonance energy transfer with 2'(3')-O-[N-methylanthraniloyl] ADP.

Ciliated epithelia in the urethra: case report and literature review.

The presence of ciliated epithelial cells in the urethra has not been well recognized. Only two reports in the literature, both of which used scanning microscopy studies, have described this phenomenon. In this report, we illustrate the presence of scattered, ciliated epithelial cells in penile urethral biopsy specimens from a 38-year-old man with a history of bladder calculi and hematuria, by both light and transmission electron microscopy studies. The cilia in the urethra showed typical light microscopic and ultrastructural features of those seen in other organs. These ciliated cells are present in association with urothelial papilloma, condyloma acuminatum and acute inflammation of the urethra. These findings suggest that ciliated cells in the penile 0 urethra might be a consequence of metaplastic change of the urothelium, secondary to local stimulation or irritation.

Atypical osteosarcomas in Werner Syndrome (adult progeria).

Werner syndrome (WS), adult progeria, is more common in Japan than elsewhere. It predisposes to osteosarcoma (OS) and five other rare tumors. To determine if and how OS is atypical in this genetic disorder, we studied the characteristics of ten Japanese cases with respect to clinical features, pathology, and radiographs, and compared them with a hospital series of 36 skeletal OS with the same atypical age-range, 35 - 57 years. The anatomic sites were also atypical: seven ankle / foot, two radius and one patella compared with only one at the ankle in the hospital series. The osteoblastic cell-type was about equally frequent in both series, but, among others than the three major subtypes, there was only one in WS as compared with 14 (39%) in the hospital series. The types of mutations were sought in five WS cases with OS. One showed no mutation at any of the ten known loci for Japanese, two were of type 4 / 4 and two of type 6 / 6. The mutations 4 and 6 have been found in 66% of alleles of WS cases in Japan. The increased frequency and unusual age and site distributions of OS in WS may be due to increased susceptibility, related to later-life leg ulcers, and weight-bearing on spindly ankles weakened by severe loss of lower limb subcutaneous tissue.

Development of the one-on-one quality assessment assay for entomopathogenic nematodes.

The one-on-one bioassay was developed using Steinernema carpocapsae (All) nematodes against the wax moth larva, Galleria mellonella. The assay was used to develop and compare virulence profiles of both in vitro- and in vivo-produced nematodes and to provide a quality assessment 'standard' for in vitro-produced nematodes. The bioassay was subsequently used to develop virulence profiles for Steinernema carpocapsae (UK), S. feltiae (UK), S. feltiae (R1.5), S. feltiae (SN), S. glaseri (NJ-43), and S. riobrave (RGV). These profiles are unique for each species and isolate and are used as a standard of virulence in routine quality assessment of nematodes produced in liquid fermentation.

Discussion: severe mental retardation and cancer among atomic bomb survivors exposed in utero.

When I was in medical school, Douglas Power Murphy, Professor of Obstetrics and Gynecology, told us of his inexpensive, simple study of "microcephaly" and mental retardation in newborn infants whose mothers had received therapeutic radiation early in pregnancy. His review of the literature and mail inquiry of other obstetrics centers in the United States revealed 14 published cases (Murphy, '28) and 16 unpublished (Goldstein and Murphy, '29). Here am I, 52 years later, still updating his findings.

Childhood and adult cancer after intrauterine exposure to ionizing radiation.

Since the reports in 1956 and 1958 that in utero radiation was associated with an increased risk of leukemia and solid cancers during childhood, this issue has been debated. Many epidemiological studies have been performed. Evidence for a causal association derives almost entirely from case-control studies, whereas practically all cohort studies find no association, most notably the series of atomic bomb survivors exposed in utero. Although it is likely that in utero radiation presents a leukemogenic risk to the fetus, the magnitude of the risk remains uncertain. The causal nature of the risk of cancers other than leukemia is less convincing, and the similar relative risks (RR = 1.5) for virtually all forms of childhood cancer suggests an underlying bias. Few studies have addressed the potential risk of adult cancer after intrauterine exposure. Radiotherapy given to newborns, however, has been linked to cancers of the thyroid and breast later in life.

Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS; also known as poikiloderma congenitale) is a rare, autosomal recessive genetic disorder characterized by abnormalities in skin and skeleton, juvenile cataracts, premature ageing and a predisposition to neoplasia. Cytogenetic studies indicate that cells from affected patients show genomic instability often associated with chromosomal rearrangements causing an acquired somatic mosaicism. The gene(s) responsible for RTS remains unknown. The genes responsible for Werner and Bloom syndromes (WRN and BLM, respectively) have been identified as homologues of Escherichia coli RecQ, which encodes a DNA helicase that unwinds double-stranded DNA into single-stranded DNAs. Other eukaryotic homologues thus far identified are human RECQL, Saccharomyces cerevisiae SGS1 and Schizosaccharomyces pombe rqh1. We recently cloned two new human helicase genes, RECQL4 at 8q24.3 and RECQL5 at 17q25, which encode members of the RecQ helicase family. Here, we report that three RTS patients carried two types of compound heterozygous mutations in RECQL4. The fact that the mutated alleles were inherited from the parents in one affected family and were not found in ethnically matched controls suggests that mutation of RECQL4 at human chromosome 8q24.3 is responsible for at least some cases of RTS.

Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race.

BACKGROUND: Werner syndrome (WS), an autosomal recessive disease characterized by premature aging, has a high frequency of association with six rare neoplasms in Japanese patients, and only four of these neoplasms also occur excessively in whites. Several differ from what is usual in their epidemiology and/or histology. Described in this article are peculiarities in the occurrences of follicular and papillary thyroid carcinomas among Japanese patients and the possible genotype-phenotype relations pertaining to cell types and the absence of excess thyroid carcinoma occurrence in whites with WS. METHODS: Epidemiologic features of 23 histologically diagnosed thyroid carcinomas from a series of 150 cancers in 845 Japanese patients with WS were compared with those of 19,446 tumors in a Japanese national registry of thyroid carcinomas from 1977-1991. Germline mutations had been determined by molecular studies of peripheral blood. RESULTS: The average age of patients with thyroid carcinoma was 39 years for those with WS and 49 years for the registry patients. The female-to-male ratios were 2.3:1 and 6.6:1, respectively. The rates of occurrence of papillary, follicular, and anaplastic carcinomas were 35%, 48%, and 13% for Japanese patients with WS and 78%, 14%, and 2% in the general Japanese population. All four cases of follicular carcinoma had germline mutations of the WS gene in the C-terminal region, and the germline mutation for the only papillary carcinoma was in the N-terminal region. CONCLUSIONS: This study suggests two possible WS genotype-phenotype relations. One concerns thyroid carcinoma histology; the other concerns frequent mutations that occur in the C-terminal region in Japanese patients, but not in white patients, with WS. These may account for the excess thyroid carcinoma occurrence among Japanese.

Merkel cell carcinoma and melanoma: etiological similarities and differences.

Merkel cell carcinoma (MCC) of the skin and cutaneous malignant melanoma can now be compared epidemiologically through the use of population-based data not previously available for MCC. The results may provide new clues to etiology. In this study, United States data covered by the Surveillance, Epidemiology, and End Results (SEER) Program were from nine areas of the United States (approximately 10% of the population). In 1986-1994, 425 cases of MCC were registered. The annual age-adjusted incidence per 100,000 of MCC was 0.23 for whites and 0.01 for blacks; among whites, the ratio of melanoma to MCC was approximately 65 to 1. Only 5% of MCC occurred before age 50, unlike the lifelong risk of nodular and superficial spreading melanoma. Regional incidence rates of both cancers increased similarly with increasing sun exposure as measured by the UVB solar index. The most sun-exposed anatomical site, the face, was the location of 36% of MCC but only 14% of melanoma. Both cancers increased in frequency and aggressiveness after immunosuppression and organ transplantation (36 cases from the Cincinnati Transplant Tumor registry and 12 from published case reports) and after B-cell neoplasia (5 cases in this study; 13 from case series in the literature). The SEER data contained reports of six patients with both types of cancer; 5 melanomas before the diagnosis of MCC and 1 after diagnosis. MCC and melanoma are similarly related to sun exposure and immunosuppression, but they differ markedly from one another in their distributions by age, race, and anatomical site, especially the face.

CD40 signaling of monocyte inflammatory cytokine synthesis through an ERK1/2-dependent pathway. A target of interleukin (il)-4 and il-10 anti-inflammatory action.

Ligation of CD40 on monocytes through its interaction with CD40 ligand (CD154) present on activated T helper cells, results in activation of monocyte inflammatory cytokine synthesis and rescue of monocytes from apoptosis induced through serum deprivation. Both of these consequences of CD40 stimulation have been shown to be dependent on the induction of protein tyrosine kinase activity. CD40-mediated activation of protein tyrosine kinase activity and subsequent inflammatory cytokine production are abrogated by treatment of monocytes with the T helper type 2 cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10). In the current study we demonstrate that stimulation of monocytes through CD40 resulted in the phosphorylation and activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinases, whereas phosphorylation of mitogen-activated protein kinases family members p38 and c-Jun N-terminal kinase was not observed in response to this stimuli over the time course examined. PD98059, an inhibitor of the upstream activator of ERK1/2, the MAP/ERK kinase MEK1/2, suppressed IL-1beta and tumor necrosis factor-alpha production in a dose-dependent fashion. Pretreatment of monocytes with IL-4 and IL-10 inhibited CD40-mediated activation of ERK1/2 kinase activity when used individually, and are enhanced in effectiveness when used in combination. Together, the data demonstrate that CD40-mediated induction of IL-1beta and tumor necrosis factor-alpha synthesis is dependent on a MEK/ERK pathway which is obstructed by signals generated through the action of IL-4 and IL-10.

A practice pathway for the initial diagnostic evaluation of isolated sixth cranial nerve palsies.

PURPOSE: To define a practice pathway for the evaluation of sixth-nerve palsies (SNPs) and to determine its cost-effectiveness and validity in a retrospective chart review. METHODS: A Medline search of the English-language literature from 1966 to 1995 was performed to define the available clinical evidence and develop the practice pathway. The authors retrospectively reviewed 407 charts with the diagnosis of SNP seen at three centers. Information obtained included: etiologic diagnosis if known; development of new neurologic or ophthalmologic findings; and results and costs of neuroimaging studies, if performed. RESULTS: Of the 407 patients, 98 underwent computed tomography scans and 212 underwent magnetic resonance imaging of the head. Eighty cases were non-isolated, 317 were isolated SNP, and ten could not be classified from chart information. Of the 317 cases of isolated SNP, 49 were classified as traumatic; 5, congenital; 158, vasculopathic; 63, nonvasculopathic; and 42, progressive or unresolved. Following the recommendations of the practice pathway, the 158 patients classified as having vasculopathic SNP would not have undergone neuroimaging studies, realizing a savings of $100,000 in this study population of 407 patients. CONCLUSION: The recommendations of the practice pathway are supported by review of the literature and the retrospective review of these cases. However, a prospective study with a matched control group is needed to demonstrate regional and specialty-specific variations in care and to strengthen the clinical certainty of the pathway recommendations.

Nucleotide binding by the nitrogenase Fe protein: a 31P NMR study of ADP and ATP interactions with the Fe protein of Klebsiella pneumoniae.

Investigation of the interaction of MgADP- and MgATP2- with the Fe protein of Klebsiella pneumoniae nitrogenase by 31P NMR showed that the adenine nucleotides are reversibly bound in slow exchange with free nucleotides. Dissociation of the MgADP--Fe protein complex was slow enough to enable its isolation by gel filtration, thus permitting the assignment of resonances to bound nucleotides. Spectra of ADP bound to Kp2 were similar to spectra of ADP bound to the myosin motor domain. Oxidative inactivation of a Kp2-MgADP- complex with excess ferricyanide ion eliminated exchange between bound and free ADP, indicating that the intact iron sulphur cluster, located 20 A from the binding sites, is required for the reversible binding of MgADP-. A change in conformation on controlled oxidation of Kp2 with indigocarmine increased the chemical shift of the beta phosphate resonance of bound MgADP-. Both oxidized and reduced conformers were observed transiently in the absence of dithionite. The 31P resonances of both the beta and gamma phosphates of bound MgATP2- indicated major changes in environment and labilization of both groups on binding to the Fe protein. Highly purified Kp2 slowly hydrolysed ATP, resulting in mixtures of bound nucleotides. Partial occupation of Kp2 MgATP2--binding sites (N=1.9+/-0.2, Kd=145 microM) in concentrated protein solutions was demonstrated by flow dialysis. Scatchard plots of data for bound and free ligand obtained after equilibration with Kp2 were linear and no co-operative interactions were detected. We conclude that MgADP- stabilizes the oxidized Fe protein conformer and this conformation in turn triggers the dissociation of the Fe protein from the MoFe protein in the rate-limiting step of the overall process of dinitrogen reduction.

Head and neck compensation for total body irradiation using opposed laterals.

Using shaped brass compensators that follow the coronal profile of a patient's head and neck, we confirm that adequate compensation can be made to prevent overdosing in these regions when delivering total body irradiation using opposed lateral fields. Initially, these compensators were custom made for each patient, but we have shown that the variation from patient to patient is sufficiently small that individual compensators can be used for a number of different patients without compromising the dose distribution. In a subgroup of 35 patients on whom diode measurements were made, 20 used compensators from the library of approximately 40 compensators made for previous patients and 15 required new compensators to be fabricated. No significant difference (3.4% on average) was observed in the dose distribution. By examining the profiles accumulated from 81 patients, we have shown that the primary difference between patients is not in the shape of the head and neck, but in the distance from the top of the head to the suprasternal notch and in the slope of the shoulders; thus, shaped compensators are not necessary and the same quality of dose homogeneity can be achieved using simple flat brass plates. Further, if the arms are supported so that the slope of the shoulders is constant, a relatively small number (15) of square-ended plates of thickness ranging from 4.0 to 11.0 mm would be sufficient to treat all 81 patients in our sample.

Qualitative and quantitative analysis of DNA fragmentation using digital imaging.

Apoptosis is an important and common pathway of cellular death. Differentiation from cellular necrosis and quantitation of apoptosis within the milieu of necrosis are analytical challenges. We describe the use of the RIT120 digital imaging software package for quantitative and qualitative analysis of apoptotic DNA ladders induced by a variety of agents, such as serum, tumor necrosis factor-alpha, transforming growth factor-beta1, and nitric oxide. Autoradiographs of DNA ladders are densitometrically scanned to yield a set of curves with peaks corresponding to specific DNA fragments, thereby allowing quantitative subtraction of concurrent DNA degradation from necrotic death. Integration of the areas specifically under the peaks yields a quantitative measure of apoptosis. We provide a useful, rapid, and objective means to quantitate apoptosis, using relatively inexpensive hardware and software.