The effect of Fe-coverage on the structure, morphology and magnetic properties of α-FeSi2 nanoislands.

Self-assembled α-FeSi(2) nanoislands were formed using solid-phase epitaxy of low (~1.2 ML) and high (~21 ML) Fe coverages onto vicinal Si(111) surfaces followed by thermal annealing. At a resulting low Fe-covered Si(111) surface, we observed in situ, by real-time scanning tunneling microscopy and surface electron diffraction, the entire sequence of Fe-silicide formation and transformation from the initially two-dimensional (2 × 2)-reconstructed layer at 300 °C into (2 × 2)-reconstructed nanoislands decorating the vicinal step-bunch edges in a self-ordered fashion at higher temperatures. In contrast, the silicide nanoislands at a high Fe-covered surface were noticeably larger, more three-dimensional, and randomly distributed all over the surface. Ex situ x-ray photoelectron spectroscopy and high-resolution transmission electron microscopy indicated the formation of an α-FeSi(2) island phase, in an α-FeSi(2){112} // Si{111} orientation. Superconducting quantum interference device magnetometry showed considerable superparamagnetism, with ~1.9 µ(B)/Fe atom at 4 K for the low Fe-coverage, indicating stronger ferromagnetic coupling of individual magnetic moments, as compared to high Fe-coverage, where the calculated moments were only ~0.8 µ(B)/Fe atom. Such anomalous magnetic behavior, particularly for the low Fe-coverage case, is radically different from the non-magnetic bulk α-FeSi(2) phase, and may open new pathways to high-density magnetic memory storage devices.

Shape-controlled nanopores in single crystals.

Nanometer length-scale holes (nanopores) are often formed in amorphous materials for fundamental studies of molecular mass transport. In the current study, electron beam irradiation in the transmission electron microscope was used to form nanopores in a crystalline material (Si). Analysis of the nanopores showed that they are formed by knock-on of atoms by the high energy incident electron beam, and surface diffusion is partially responsible for the hour-glass shapes that are found for some nanopores. Energetically favorable three-dimensional shapes of nanopores were simulated, and the nanopores simulated in the model crystalline material were found to be more stable than the nanopores simulated in the amorphous material. The nanopore shape was also found to depend on the nanopore diameter-to-length ratio. Based on the above, we demonstrate the advantage in using a crystalline material for nanopore formation and show that control of the three-dimensional shape of nanopores formed by electron beam irradiation is possible.

An experimental method for calibration of the plasmon mean free path.

Transmission electron microscopy specimens in the form of elongated, conical needles were made using a dual-beam focused ion beam system, allowing the specimen thickness to be geometrically determined for a range of thickness values. From the same samples electron energy loss maps were acquired and the plasmon mean free path (lambda) for inelastic scattering was determined experimentally from the measured values of specimen thickness. To test the method lambda was determined for Ni (174 +/- 17 nm), alpha-Al(2)O(3) (143 +/- 14 nm), Si (199 +/- 20 nm) and amorphous SiO(2) (238 +/- 12 nm), and compared both to experimental values of lambda taken from the literature and to calculated values. The calculated values of lambda significantly underestimate the true sample thickness for high accelerating voltages (300 kV) and large collection angles. A linear dependence of lambda on thickness was confirmed for t/lambda < 0.5-0.6, but this method also provides an approach for calibrating lambda at sample thicknesses for which multiple scattering occurs, thus expanding the thickness range over which electron energy loss spectroscopy can be used to determine the absolute sample thickness (t/lambda > 0.6). The experimental method proposed in this contribution offers a means to calibrate lambda for any type of material or phase that can be milled using a focused ion beam system.

Quantitative HRTEM analysis of FIB prepared specimens.

The preparation of good transmission electron microscopy specimens with minimum milling damage can be very complicated, especially from a specific area in a sample. Therefore, a novel approach for transmission electron microscopy specimen preparation using a focused ion beam system is proposed, based on the use of low energy (5 kV)Ga ions and a low incident ion angle (approximately 1 degree ) from a thickness of approximately 500 nm until the sample is electron transparent. Transmission electron microscopy specimens prepared by this method have significantly less irradiation damage, demonstrated by successful quantitative high-resolution transmission electron microscopy conducted on sapphire from data acquired using an aberration-corrected field emission gun transmission electron microscopy. Quantitative analysis was conducted by iterative digital image matching. The accuracy and sensitivity of the matching process is discussed.

Optical control of capacitance in a metal-insulator-semiconductor diode with embedded metal nanoparticles.

This paper describes a metal-insulator-semiconductor (MIS) capacitor with flat capacitance voltage characteristics and a small quadratic voltage capacitance coefficient. The device characteristics resemble a metal-insulator-metal diode except that here the capacitance depends on illumination and exhibits a strong frequency dispersion. The device incorporates Fe nanoparticles (NPs), mixed with SrF2, which are embedded in an insulator stack of SiO2 and HfO2. Positively charged Fe ions induce dipole type traps with an electronic polarization that is enhanced by photogenerated carriers injected from the substrate and/or by inter nanoparticle exchange of carriers. The obtained characteristics are compared with those of five other MIS structures: two based on Fe NPs, one with and the other without SrF2 sublayers. Additionally, devices contain Co NPs embedded in SrF2 sublayers, and finally, two structures have no NPs, with one based on a stack of SiO2 and HfO2 and the other which also includes SrF2. Only structures containing Fe NPs, which are incorporated into SrF2, yield a voltage independent capacitance, the level of which can be changed by illumination. These properties are essential in radio frequency/analog mixed signal applications.

Protection against daunorubicin cytotoxicity by expression of a cloned human carbonyl reductase cDNA in K562 leukemia cells.

Carbonyl reductase (CBR) catalyzes the reduction of daunorubicin (DN) to its corresponding alcohol, daunorubicinol (DNOL), and changes the pharmacological properties of this cancer chemotherapeutic drug. The DN reductase associated with CBR reduces the C13 methyl ketone group and does not metabolize the quinone ring of DN. Reports comparing DN and DNOL toxicity have resulted in various conclusions depending on the cells tested. Differences in toxicity could be due to variations in several enzymes involved in DN metabolism. In this report, the effects of CBR expression on DN metabolism and cell toxicity were determined by cloning and expressing a human CBR cDNA in DN reductase-deficient myeloid erythroleukemia K562 cells. CBR activity increased 83-fold in the K562-transfected cells and was associated with a 2-3-fold reduction in DN toxicity. Maximum protection occurred at 30 nM DN where 94% of the intracellular DN was converted to DNOL within 2 h. The reduced toxicity was specific for DN. Other CBR substrates such as menadione, phenanthrenequinone, and doxorubicin were equally toxic to both the CBR expresser cells and the control cells under the conditions tested. Our results suggest that high levels of CBR in tumor cells could contribute to drug resistance. The results also suggest that reduction of DN to DNOL protects against DN toxicity by altering interaction of the drug at one or more of the many target sites.

Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen.

A preliminary serotherapeutic trial was undertaken with a monoclonal antibody designated antibody 89 (Ab 89) directed against a lymphoma-associated antigen. In vitro studies demonstrated that Ab 89 could mediate complement-dependent lysis and macrophage adherence but not antibody-dependent cell-mediated cytotoxicity. To evaluate toxicity and therapeutic efficacy, two courses of Ab 89 were administered to a patient with an Ab 89-reactive tumor. Transient decreases in the number of circulating tumor cells and the appearance of circulating dead cells were noted with the infusion of Ab 89. Following administration of 150 mg or more of Ab 89, small amounts of antibody could be demonstrated on circulating tumor cells at a time when no free antibody was found in the serum. The inability to deliver a significant amount of Ab 89 to tumor cells in vivo is thought to be secondary to a circulating tumor antigen. Following each infusion, the amount of this blocking antigen decreased but could not be entirely cleared from the serum. This study provides preliminary evidence for the lack of clinical toxicity of a monoclonal antibody and identifies circulating blocking antigens as a significant obstacle to serotherapy.

Pulmonary uptake of technetium 99m macroaggregated albumin: a predictor of gastrointestinal toxicity during hepatic artery perfusion.

Hepatic artery infusion of 5-fluoro-2-deoxyuridine (5-FUdR) provides high hepatic drug levels but little systemic toxicity, since, by this route of administration, the drug is detoxified by the hepatocytes. Slow infusion of technetium 99m- (99mTc) labeled macroaggregated albumin (MAA) through the hepatic artery is an aid in catheter placement, in predicting response of liver metastases to therapy, and in identifying extra-hepatic flow in the gastroduodenal or splenic arteries as an indicator of systemic toxicity. Marked pulmonary uptake of this tracer after slow radionuclide hepatic angiography was noted in four patients who showed major gastrointestinal (GI) toxicity. A retrospective examination of pulmonary accumulation of 99mTcMAA as a predictor of GI toxicity is the subject of this paper. Two groups of patients were evaluated. The first group consisted of 14 consecutive patients in whom continuous infusion of drug was administered by an external pump by way of a percutaneous catheter. Patients received baseline and follow-up (seven to 27 days) slow-infusion tracer studies (2 to 4 mCi 99mTcMAA at 10 to 21 mL/h). The second group included 14 consecutive patients who were receiving intraarterial chemotherapy by a totally implantable pump system. All received baseline slow-infusion studies (2 to 4 mCi 99mTcMAA at approximately 0.5 to 1.0 mL/min). The percentage of the injected dose in the lung was determined. Patients with greater than 20% of tracer in the lung after radionuclide hepatic angiography had significantly greater severe GI toxicity than patients with baseline values of less than 20%. Our findings support the existence of hepatic arteriovenous (A-V) communications in some patients and suggest that they are present pretherapy. Presence of these A-V communications, which can result in a vascular bypass of normal hepatic parenchyma and the subsequent decrease in hepatic detoxification of chemotherapeutic agents, is the likely cause of GI toxicity. Pulmonary uptake of tracer injected in the hepatic artery may be useful in quantifying the degree of shunting and facilitate the monitoring of potential systemic toxicity.

Gallium-67 imaging: a predictor of residual tumor viability and clinical outcome in patients with diffuse large-cell lymphoma.

Durable complete remissions (CRs) can be achieved in patients with diffuse large-cell lymphoma (DLCL) with multidrug chemotherapy. The length of time to reach CR may be predictive of treatment outcome. However, defining CR by chest radiograph or computed tomography (CT) is often difficult since residual abnormalities do not always indicate residual disease. We have prospectively evaluated the ability of gallium-67 citrate (Ga-67) imaging to define residual disease and predict outcome in 37 consecutive patients with DLCL. Patients received 296 to 370 megabecquerels (MBq) Ga-67 and were imaged prior to, following cycles 4 to 6, and at completion of intensive chemotherapy. Ga-67 scan results were correlated with radiographic studies. Seventeen of 37 patients (46%) showed persistent, abnormal Ga-67 uptake halfway through chemotherapy. Of these, four were in CR, 11 were in partial remission (PR), and two showed no change in tumor size. At follow-up, 10 (59%) have died (three who were scored as CR and seven who were in PR halfway through therapy), two are alive with active tumor, one relapsed and survives following bone marrow transplant, and four (three in PR and one in CR at the therapeutic halfway point) are without disease at a median of 28 months from presentation. Of the 20 patients who were Ga-67-negative halfway through therapy, 11 were in CR and nine were in PR. Five of 20 patients (25%) have died. Three, in radiographic CR died at 11, 26, and 28 months, and two in radiographic PR died at 15 and 17 months. One patient is alive with active tumor, and 14 patients (70%) are alive without disease at a median of 34 months from presentation. Ga-67 imaging proved to be an excellent indicator of residual viable tumor; a positive scan halfway through therapy predicted for a poor outcome and may well justify a change in treatment.

Large-cell and immunoblastic lymphoma of the mediastinum: prognostic features and treatment outcome in 57 patients.

PURPOSE: A retrospective study was performed to define clinical characteristics and therapeutic outcome for patients with large-cell and immunoblastic lymphoma of the mediastinum. PATIENTS AND METHODS: Fifty-seven patients who presented with primary, mediastinal large-cell and immunoblastic lymphoma were retrospectively studied to determine initial sites of disease, radiologic characteristics, treatment, outcome, and factors that have prognostic significance for progression-free and overall survival. RESULTS: Fifty-six of the 57 patients had disease that was confined to sites above the diaphragm. Bulky disease and extensive intrathoracic infiltration were common in these patients. All patients were treated with intensive chemotherapy regimens, and 44% of patients received chest irradiation. The overall 5-year survival by Kaplan-Meier estimation was 50% with a freedom-from-relapse rate of 45%. Predictors of disease relapse after chemotherapy included the presence of a pleural effusion (P = .015), a number of involved extranodal sites (P < .01), and a lactic dehydrogenase (LDH) ratio > 3.0 (LDH value/upper limit of assay; P = .04) as well as an incomplete treatment response as evidenced by residual mass on chest radiograph (P = .02) or persistent gallium 67 avidity (P = .01) after chemotherapy. Predictors of decreased survival included the presence of pleural effusion (P = .001), the number of involved extranodal sites (P = .022), and a positive posttreatment 67Ga scan (P = .027). CONCLUSION: Patients with primary mediastinal large-cell and immunoblastic lymphoma have an approximate 50% chance of surviving disease-free after initial therapy. The presence of pleural effusion at presentation was associated with an extremely poor outcome. Bulk disease per se was a negative predictive factor only in patients without pleural effusions when compared with patients who did not have bulk disease. In addition, all patients with involvement of two or more extranodal sites relapsed when treated with standard chemotherapy.

Long-term hepatic arterial infusion of 5-fluorodeoxyuridine for liver metastases using an implantable infusion pump.

Twenty-one patients with liver metastases of various histologies (predominantly colorectal carcinoma) underwent Infusaid pump implantation for long-term hepatic arterial 5-fluorodeoxyuridine (5-FUdR) infusion. Patients received 5-FUdR infusion on a 2-wk cycle alternating with a 2-wk saline--heparin infusion. A dosage of 0.2-0.3 mg/kg/day (average 0.23 mg/kg/day) was infused for a cumulative 5-FUdR administration of 1940 days. Six patients (29%) responded to therapy (five colorectal, one carcinoid); median response duration was 6 mo. Median survival for the treated group was 17 mo from diagnosis of liver metastases and 13 mo from pump implantation. Median survival among the six responding patients was 15 mo from diagnosis of liver metastases and 11 mo from pump implantation. Comparison of survival from the diagnosis of liver metastases of the treated group to ten patients found ineligible for the study by virtue of extrahepatic metastases revealed no significant difference in median (18 mo for ineligible group) or overall survival. However, median survival for the treated group after pump implantation (13 mo) was significantly better than the median survival of the ineligible group after evaluation for this study (4 mo). Toxicities of therapy included fatigue, anorexia, nausea, vomiting, toxic hepatitis, epigastric pain, and diarrhea. No patients died of toxicity, but six patients required hospitalization for management of pain or vomiting. No serious technical complications developed in any patient except separation of the infusion catheter at its junction with the pump in one patient, necessitating pump replacement for continuation of therapy. These survival data suggest identification of new anticancer agents for hepatic arterial infusion.

Genetic manipulation of an abnormal jump response in Drosophila.

The hyperkinetic mutants, Hk(1) and Hk(2), jump and fall over when an object moves near them. This behavior, the kinetogenic response, has been measured by the experimenter moving his hand above a vial containing a single fly and scoring the number of positive responses in fifty trials. The response is higher in Hk(1) than in Hk(2) and has remained so over a period of several years and in different genetic backgrounds. The Hk(1)/Hk(2) heterozygote also responds to movements, establishing the allelism of the two mutants.-When Sh(5), a shaker mutant at another locus on the X chromosome, is introduced into the same chromosome as Hk(1) or Hk(2), the response is reduced in proportion to the number of Sh(5) mutant genes added.-When Hk(1) or Hk(2) is heterozygous with a deficiency for the hyperkinetic region of the X chromosome, the expression is more abnormal than the respective Hk(1) or Hk(2) homozygote. This shows that the mutant genes are producing an altered gene product, or less of the normal, since one mutant gene by itself has a more abnormal expression than two. A tentative explanation has been offered for the observed mutant behaviors.

Breast carcinoma metastatic to a meningioma. Case report and review of the literature.

We describe a patient who developed an intracranial mass that consisted of a meningioma and metastatic breast cancer. A literature review revealed 12 similar cases. In epidemiologic studies, the incidence of meningioma in patients with breast cancer is higher than expected. Both tumors are more common in women, have been reported to flare during pregnancy, and express hormone receptors. In a patient with breast cancer, an intracranial mass with radiographic features suggestive, but atypical, of a meningioma should be evaluated surgically. The lesion may represent a metastasis, a meningioma, or both.

Cloning and expression of the cDNA encoding rabbit liver carbonyl reductase.

Two cDNA sequences encoding rabbit carbonyl reductase (CBR) were cloned from a lambda gt10 rabbit liver cDNA library. The rabbit cDNAs coded for a protein with 84% identity to human CBR. Transient expression of the two rabbit cDNA sequences in COS7 cells increased both quinone reductase and aldo-keto reductase activities. These data demonstrate that CBR cDNAs from rabbit and human tissues code for similar proteins.

Increased iofetamine I 123 brain uptake in metastatic melanoma.

Four of five patients with brain metastases from melanoma had increased lofetamine I 123 uptake in the region of the tumor deposits. A comparison group of five patients with melanoma with no clinical or radiologic evidence of brain involvement and 46 of 47 patients without malignant melanoma but with known brain tumors of other histologic types had normal or decreased iofetamine I 123 brain uptake in the region of the tumor. An exception was one patient whose metastatic small cell lung cancer to the brain showed focally increased uptake. These findings suggest that certain brain tumors such as melanoma are capable of selectively binding iofetamine I 123 because of specific chemical properties of the radiopharmaceutical. Increased uptake of iofetamine I 123 in brain lesions in a patient at risk for metastatic melanoma may be a useful aid to differential diagnosis.

High-dose gallium imaging in lymphoma.

The role of gallium-67 imaging in the management of patients with lymphoma, traditionally assessed using low tracer doses and the rectilinear scanner, was assessed when using larger doses (7 to 10 mCi) and a triple-peak Anger camera. Gallium scan results in 51 patients with non-Hodgkin's lymphoma and 21 patients with Hodgkin's disease were compared with simultaneous radiologic, clinical, and histopathologic reports. Subsequent disease course was also evaluated in light of radionuclide findings. Sensitivity and specificity of the scans were 0.90 or greater for both non-Hodgkin's lymphoma and Hodgkin's disease, and overall accuracy by site was 96 percent. Although there are insufficient numbers of pretreatment scans to allow any conclusions, our data suggest that newer approaches to gallium scanning in treated patients are (1) highly specific in all lymphomas and most sensitive in high-grade non-Hodgkin's lymphoma and Hodgkin's disease; (2) valuable in assessing the mediastinum in both non-Hodgkin's lymphoma and Hodgkin's disease; and (3) helpful adjuncts to computed tomographic scanning and ultrasonography in assessing abdominal node disease.

Three-dimensional internal mammary lymphoscintigraphy: implications for radiation therapy treatment planning for breast carcinoma.

Conservative surgery combined with radiation therapy for the treatment of early breast carcinoma has been shown to achieve both a high rate of local tumor control and good cosmetic results with a minimum of complications. Whether the internal mammary lymph nodes (IMNs) should be included in the treatment volume is a topic of considerable controversy. Radionuclide internal mammary node lymphoscintigraphy (IMN-LS) can locate these nodes in three dimensions. We have analyzed the results of IMN-LS in 167 patients imaged at the Dana-Farber Cancer Institute and treated at the Joint Center for Radiation Therapy between 1977 and 1980. The location of the IMNs was found variable from patient to patient. At least one IMN was not included within tangential fields arbitrarily arranged to have a medial entrance point 3.0 cm across the midline in 17% of evaluable patients. However, 48% and 66% of patients had IMNs that could be adequately treated with fields positioned only 1.0 cm or 2.0 cm across midline, respectively. We conclude that when treatment of the IMNs is warranted, IMN-LS not only assures their complete coverage in the majority of patients but also may help reduce the amount of heart and lung irradiated.

Utilization of parasternal lymphoscintigraphy in radiation therapy of breast carcinoma.

In radiation therapy of patients with breast carcinoma, the ipsilateral internal mammary lymph nodes are either irradiated by a separate anterior field or included by isocentric opposing tangential fields, which also treat the breast and chest wall. To determine the acceptability of a particular treatment setup, the positions of the nodes must be determined with respect to the treatment fields. For the anterior field technique the problem is two-dimensional and is solved by simply superimposing the treatment field onto an anterior lymphoscintigram. For treatment by opposing tangential fields the problem is three-dimensional and more complex. The solution described in this note is to project the three-dimensional lymph node positions, obtained by a stereo-lymphoscintigraphic procedure, onto the tangential field radiographs. A mathematical expression is given to perform the required projection of the node positions onto the radiographs.

Alpha particle radio-immunotherapy: animal models and clinical prospects.

Short-lived isotopes that emit alpha particles have a number of physical characteristics which make them attractive candidates for radioimmunotherapy. Among these characteristics are high linear energy transfer and correspondingly high cytotoxicity; particle range limited to several cell diameters from the parent atom; low potential for repair of alpha-induced DNA damage; and low dependence on dose rate and oxygen enhancement effects. This report reviews the synthesis, testing and use in animal models of an alpha particle emitting radioimmunoconjugate constructed via the noncovalent chelation of Bismuth-212 to a monoclonal IgM antibody specific for the murine T cells/neuroectodermal surface antigen, Thy 1.2. These 212Bi-anti-Thy 1.2 immunoconjugates are capable of extraordinary cytotoxicity in vitro, requiring approximately three 212Bi-labeled conjugates per target cell to suppress 3H-thymidine incorporation to background levels. The antigen specificity afforded by the monoclonal antibody contributes a factor of approximately 40 to the radiotoxicity of the immunoconjugate. Animals inoculated with a Thy 1.2+ malignant ascites were cured of their tumor in an antigen-specific fashion by intraperitoneal doses of approximately 200 microCi per mouse. Alpha particle emitting radioimmunoconjugates show great potential for regional and intracavitary molecular radiotherapy.

Biodistribution studies of anti-Thy 1.2 IgM immunoconjugates: implications for radioimmunotherapy.

We have prepared 111In radioimmunoconjugates (RICs) of the IgM isotype with specificity for the murine T cell/neuroectodermal surface antigen, Thy 1.2. Using gamma camera immunoscintigraphy, we have analyzed the biodistribution patterns of the RICs after intravenous and intraperitoneal injection into normal Thy 1.2+ and Thy 1.2- mice. Both routes of administration show antigen-specific uptake by the splenic T lymphocyte population. A high degree of nonspecific uptake by the reticuloendothelial system is also observed. Analysis of the specific activity of various segments of spleens from RIC-injected animals shows inhomogeneous uptake of the RIC not readily apparent by immunoscintigraphy. Animals injected with the RIC and then given high dose total body irradiation showed rapid shifts in radionuclide distribution away from the target cell population and into the general reticuloendothelial system, suggesting that death of the target cell can alter RIC biodistribution. Analyses of RIC biodistribution patterns will contribute to optimization of treatment by radioimmunotherapy.