Computerized method for estimation of the location of a lung tumor on EPID cine images without implanted markers in stereotactic body radiotherapy.

The purpose of this study was to develop a computerized method for estimation of the location of a lung tumor in cine images on an electronic portal imaging device (EPID) without implanted markers during stereotactic body radiotherapy (SBRT). Each tumor region was segmented in the first EPID cine image, i.e., reference portal image, based on a multiple-gray level thresholding technique and a region growing technique, and then the image including the tumor region was cropped as a 'tumor template' image. The tumor location was determined as the position in which the tumor template image took the maximum cross-correlation value within each consecutive portal image, which was acquired in cine mode on the EPID in treatment. EPID images with 512 x 384 pixels (pixel size: 0.56 mm) were acquired at a sampling rate of 0.5 frame s(-1) by using energies of 4, 6 or 10 MV on linear accelerators. We applied our proposed method to EPID cine images (226 frames) of 12 clinical cases (ages: 51-83, mean: 72) with a non-small cell lung cancer. As a result, the average location error between tumor points obtained by our method and the manual method was 1.47 +/- 0.60 mm. This preliminary study suggests that our method based on the tumor template matching technique might be feasible for tracking the location of a lung tumor without implanted markers in SBRT.

INVESTIGATION OF A PRACTICAL PATIENT DOSE INDEX FOR ASSESSMENT OF PATIENT ORGAN DOSE FROM CONE-BEAM COMPUTED TOMOGRAPHY IN RADIATION THERAPY USING A MONTE CARLO SIMULATION.

The purpose of this study was to investigate a practical patient dose index for assessing the patient organ dose from a cone-beam computed tomography (CBCT) scan by comparing eight dose indices, i.e. CTDI100, CTDIIEC, CTDI∞, midpoint doses f(0)PMMA for a cylindrical polymethyl methacrylate (PMMA) phantom, f(0)Ap for an anthropomorphic phantom and f(0)Pat for a prostate cancer patient, as well as the conventional size specific dose estimations (SSDEconv) and modified SSDE (SSDEmod), with organ dose for the prostate (ODprost) obtained via Monte Carlo (MC) simulation. The ODprost was the reference dose used to find the practical dose index at the center of the pelvic region of a prostate cancer patient. The smallest error rate with respect to the ODprost of 19.3 mGy (reference) among eight dose indices was 5% for f(0)Pat. The practical patient dose index was the f(0)Pat, which showed the smallest error with respect to the reference dose.

Monoclonal antibody against human gallbladder carcinoma-associated antigen.

Monoclonal antibody HI-531 of immunoglobulin G2b subclass was produced against a human gallbladder carcinoma cell line. HI-531 was investigated for reactivity with a panel comprising ten types of different origin in fluorescence-activated cell sorter analysis. The antibody reacted with the gallbladder carcinoma cell line G-415 used for immunization and with four unrelated tumors. HI-531 was further shown, with the use of the avidin-biotin complex-immunoperoxidase technique and surgically resected tissues, to be strongly reactive with carcinoma of the gallbladder, pancreas, bile duct, and gastrointestinal tract. The antibody was reacted with several types of normal epithelial cells but often more weakly expressed than on corresponding tumors. One of six fetal lung tissues was weakly stained. All other fetal organ tissues tested showed negative staining reactions. These observations suggest that HI-531 may be of value in identifying the tumor-associated antigen expressed in gallbladder carcinoma. HI-531 immunoprecipitated the Mr 43,000 molecule from extracts of Na125I- or [35S]methionine-labeled tumor cells, but not from those of [3H]glucosamine-labeled tumor cells. In addition, cytofluorometric analysis showed that cells treated with trypsin or protease greatly decreased a reactivity to the antibody. The findings suggest that the antibody recognizes a Mr 43,000 protein molecule. Sequential immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis studies and analyses by nonequilibrium pH gradient and polyacrylamide gel electrophoreses showed that the Mr 43,000 molecule defined by HI-531 was not a Mr 43,000 heavy chain of HLA-A,B,C antigens detected by monoclonal antibody W6/32.

Concurrent use of granulocyte colony-stimulating factor with low-dose cytosine arabinoside and aclarubicin for previously treated acute myelogenous leukemia: a pilot study.

We used a new chemotherapy regimen for the treatment of 18 consecutive patients with relapsed AML (median age 44 years, range 18-74). The regimen consisted of low-dose cytosine arabinoside (10 mg/m2/12 h, usually day 1 to 14), low-dose aclarubicin (10-14 mg/m2/day, day 1 to 4), and concurrent use of G-CSF (200 micrograms/m2/day) (CAG regimen). Overall, 15/18 patients (83%) achieved complete remission (CR) after one or two courses, including eight out of ten refractory patients with early relapse, second or subsequent relapses, and/or resistant relapse. Two of three patients who relapsed, achieved CR again after reinduction with a modified CAG regimen. Fourteen of the 15 complete remitters received consolidation therapy with the CAG regimen modified, followed by oral busulfan in eight cases, and by allogeneic bone marrow transplantation in two cases. At a median follow-up of 12 months, median CR duration and survival were 6 months and 17 months, respectively. Myelosuppression in the first course of induction therapy was moderate to severe. However, severe non-hematologic toxicity (WHO grade > or = 3) was characteristically rare. Although this is a preliminary study, the CAG combination seems promising for the treatment of relapsed AML, with its low toxicity contributing to a higher quality of life for the patient.

Philadelphia-chromosome-positive, monosomy 7 biphenotypic acute mixed lineage leukemia in adults: a pluripotent stem cell disorder.

Two adult patients with acute mixed lineage leukemia (AMLL) having combined Philadelphia chromosome (Ph1) positivity and monosomy 7 are presented. The phenotypes of leukemic blasts from both cases were almost same (early B-lymphoid lineage and myeloid lineage); CD10+, CD13+, CD19+. HLA-DR+, and dual-color analysis showed simultaneous expression of CD10 (CD19) and CD13 antigens in individual blasts (biphenotypic) in both cases. On molecular analysis, the leukemic blasts showed rearrangement in the first intron of the BCR gene with breakpoint just outside of 3' end of m-BCR-2 (bcr 3) in case 1, and in the M-BCR in case 2. Immunoglobulin heavy chain gene (IgH) rearrangement was noted in both cases, but rearrangement of the T-cell receptor beta-chain gene (TCR beta) was detected only in case 1. Clinically, both cases achieved complete remission by the combination chemotherapy consisting of L-asparaginase, doxorubicin, vincristine, and prednisolone (L-AdVP). In remission, all these molecular abnormalities disappeared in both patients. These results suggest that the Ph1-positive and monosomy 7 AMLL in adults is de novo acute leukemia with both early B-lymphoid and myeloid phenotypes and may arise from malignant transformation of pluripotent stem cell, and expresses a heterogenous rearrangement pattern of the BCR gene.

Molecular cloning of cDNA coding for human preprourokinase.

A cDNA library was constructed in pBR322 from 18S to 20S mRNA that was extracted from human kidney cells, fractionated on oligo(dT)-cellulose column and sucrose-density gradient, and confirmed for urokinase production in Xenopus laevis oocytes. The Escherichia coli RR1 transformants were hybridized to synthetic oligonucleotide probe prepared according to the known amino acid sequence, Glu 73 to Glu 77 of human urinary urokinase chain B. The entire cloned cDNA covers a 2250-bp region, wherein the 1293-bp sequence codes for preprourokinase consisting of 431 amino acids, with the first 20 residues being a signal peptide. The 5'-untranslated region is at least 80 bp long and the 3'-untranslated region is longer than 850 bp.

Hereditary motor and sensory neuropathy with myelin folding and juvenile onset glaucoma.

OBJECTIVE: We describe three patients from a family with motor and sensory neuropathy accompanied by open-angle glaucoma. BACKGROUND: Autosomal recessive demyelinating hereditary motor and sensory neuropathies (HMSN) include different disorders. To our knowledge, autosomal recessive HMSN has not been associated with juvenile onset glaucoma. METHODS: Sural nerve pathology of the three patients were examined, and genetic analysis of the family was performed. RESULT: - The most prominent pathologic finding was a highly unusual myelin abnormality consisting of irregular redundant loops and folding of the myelin sheath. The family survey supports autosomal recessive inheritance. The molecular analysis failed to demonstrate either linkage of the disease to MPZ gene, PMP22 gene, Cx32 gene, orEGR2 gene. Analysis did not establish linkage of the disease to the locus of CMT4A, 4B, and 4C genes. CONCLUSION: The present cases may represent a new type of HMSN accompanied by juvenile onset glaucoma.

Development of an integrated radiotherapy network system.

PURPOSE: To introduce the process of developing an integrated radiotherapy network. METHODS AND MATERIALS: We developed a new radiotherapy treatment-planning system in 1987 that we named the Computer Tomography (CT) simulator. CT images were immediately transported to multiimage monitors and to a planning computer, and treatment planning could be performed with the patient lying on the CT couch. The results of planning were used to guide a laser projector, and radiation fields were projected onto the skin of the patient. Since 1991, an integrated radiotherapy network system has been developed, which consists of a picture archiving and communicating system (PACS), a radiotherapy information database, a CT simulator, and a linear accelerator with a multileaf collimator. RESULTS: Clinical experience has been accumulated in more than 1,000 patients. Based on our 7 years of experience, we have modified several components of our original CT simulator and have developed a second generation CT simulator. A standard protocol has been developed for communication between the CT scanner, treatment planning computer, and radiotherapy apparatus using the Ethernet network. As a result, treatment planning data can be transported to the linear accelerator within 1 min after completion of treatment planning. CONCLUSION: This system enables us to make optimal use of CT information and to devise accurate three-dimensional (3D) treatment-planning programs. Our network also allows for the performance of fully computer-controlled dynamic arc conformal therapy.

Rescue of photoreceptors from the damaging effects of constant light by midkine, a retinoic acid-responsive gene product.

PURPOSE: To evaluate the protective effects of midkine (MK), the product of a retinoic acid-responsive gene, on constant light-induced retinal degeneration in albino Sprague-Dawley rats. METHODS: Midkine, basic fibroblast growth factor (bFGF), MK plus heparin, or buffer controls were injected intravitreally 2 days before constant light exposure. After 7 days of continuous light exposure, the eyes were perfused with fixative, bisected along the vertical meridian, embedded in paraffin, and sectioned. The degree of retinal light damage was assessed for paraffin-embedded sections by cytologic analysis, by measuring the thickness of the outer nuclear layer (ONL), and by counting the number of macrophages. RESULTS: After 1 week of constant light exposure, uninjected controls and those injected with phosphate-buffered saline (PBS) lost most of the photoreceptor inner and outer segments, and the thickness of the ONL was decreased. Eyes that were injected with MK or bFGF demonstrated a significant rescue in the photoreceptor layer with a two- to threefold increase in the ONL thickness. The number of macrophages in eyes injected with MK was significantly suppressed compared with controls. Those injected with bFGF had a 1.5-fold increase in number compared with controls. CONCLUSIONS: Midkine has shown strong survival-promoting activity in constant light-induced retinal degeneration, and thus has a high degree of neurotrophic activity in vivo.

Action of enflurane on cholinergic transmission in identified Aplysia neurones.

Effects of enflurane on the cholinergic transmission in Aplysia neurones were studied by current and voltage clamp methods. Acetylcholine (ACh) evoked three types of postsynaptic responses on different identified neurones: (1) a depolarizing response due to an increase in Na and K conductances (D-response), (2) a fast hyperpolarizing response due to an increase in C1 conductance (C1-response), and (3) a slow hyperpolarizing response due to an increase in K conductance (K-response). Enflurane altered neither the action potential nor the membrane resistance of the neurones but depressed the three ACh-induced responses, non-competitively, in a dose-dependent manner. The K-response was less suppressed than the other two. Blockade of the closed state of ion channel was suggested by a reduction in the first ACh response evoked 1 min after administration of enflurane. The anaesthetic facilitated the decay of the neurally evoked e.p.s.c. and i.p.s.c. in suggesting a reduction in the mean open time of the postsynaptic ion channel. It is concluded that enflurane depresses excitatory and inhibitory cholinergic transmission by reducing the postsynaptic currents.

Thrombolytic effect of single-chain pro-urokinase in a rabbit jugular vein thrombosis model.

The thrombolytic effect of single-chain pro-urokinase (SCPU) was examined in the rabbit using a jugular vein thrombosis model. Infusion of a low dose (120,000 IU/kg) of either urokinase (UK) or SCPU did not produce any significant thrombolysis. However, UK administration at such a low dose caused 20% degradation of circulating fibrinogen. A high dose (480,000 IU/kg) caused significant thrombolysis. The degree of fibrinogenolysis was about 20% in SCPU, but about 80% in UK. The thrombolytic efficiency of SCPU was thus about 3 times larger than that of UK. Analysis of fibrinolytic parameters such as plasminogen, alpha 2-plasmin inhibitor, etc. suggested that UK caused systemic activation of the fibrinolytic system, but SCPU, locally limited activation on the fibrin surface (fibrinolysis). These results indicate that SCPU represents a highly efficient thrombolytic agent without producing fibrinogenolysis.

Immunological abnormality in patients with lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is a rare hereditary disorder manifesting hyperammonemia induced by low levels of basic amino acids, these low levels being due to the impaired transport of these acids in the intestinal mucosa and the renal tubules. Low serum arginine levels and probably the consequently low in vivo levels of nitric oxide (NO), which against acts as a physiological and immunological mediator/modulator, are thought to influence the immunological status in patients with LPI. Accordingly, this study was conducted to. We found that patients with LPI had leukocytopenia, high serum IgG levels, a high ratio of CD44B4-positive lymphocytes (helper inducer) to CD42H4-positive lymphocytes (suppressor inducer), low levels of leukocyte phagocytic, cytotoxic, and natural killer cell activity, and increased spontaneous proliferation of lymphocytes. These results were probably the consequence of persistent low NO levels in vivo.

Relation between radiographic mottle for double and single emulsions.

The radiographic density fluctuations produced by using dual screen-film systems are designated as the radiographic mottle. The density fluctuation of the radiographic mottle for the double emulsions at a density of the double emulsions consists of those for the front and back emulsions on a radiograph. However, the relation between the Wiener spectra of the radiographic mottle for the double and single emulsions had not been studied. Hence we compared the Wiener spectra of the radiographic mottle for the double emulsions with the sum of those for the front and back emulsions on the same radiographs and with the sum of those for the emulsions at the same densities. At all densities of more than 0.62 for lower spatial frequencies (< or = 1 mm-1), the Wiener spectral values of the radiographic mottle for the double emulsions were greater than the sum of those for the front and back emulsions for both comparisons on the same radiographs and at the same densities. In order to investigate the reason of the above phenomena, we separated the Wiener spectral values of the radiographic mottle for various densities into those of the three factors, i.e., quantum mottle, structure mottle, and film granularity, and performed the same comparisons as the radiographic mottle. Also, to explain the results for the three factors, we obtained the Wiener spectral values of the spatial fluctuations of the light exposure or the fluorescence intensity and the gradients of the characteristic curves of the film for the double and single emulsions of the x-ray film. As a result of the investigation, we found that the phenomena on the radiographic mottle were caused by that (1) on the same radiographs the squares of the gradients of the characteristic curves for the double emulsions were about 5.3 times as great as those for the single emulsion at densities of more than 0.62 of the double emulsions, and (2) at the same density of more than 0.62 those were more than about 2.2 times as great as those for the single emulsion.

Purification and characterization of human fibroblast derived differentiation inducing factor for human monoblastic leukemia cells identical to interleukin-6.

A differentiation inducing factor for human monocytic leukemia cells was purified to homogeneity from conditioned medium of WI-26VA4, a human fibroblast cell line. The purification scheme consisted of micro bead silica gel chromatography, hydroxyapatite chromatography, gel filtration chromatography, chromatofocusing and reverse phase high performance liquid chromatography. The purified protein was almost homogeneous when determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and N-terminal sequence analysis. The protein has a molecular weight of approximately 27,000 and an isoelectric point of 5.4. The sequence of the first 13 N-terminal amino acid residues was consistent with that of B-cell stimulatory factor 2 (interleukin-6) except for the absence of the N-terminal proline. The purified factor induced differentiation of human monocytic leukemia U-937 cells into a monocyte/macrophage pathway.

Proportionality between Wiener spectra of quantum mottle and the squares of modulation transfer functions.

Rossmann proposed that the Wiener spectra of the quantum mottle of radiographs made using screen-film systems were proportional to the squares of the modulation transfer functions (MTFs) of the screen-film systems. On the other hand, Lubberts theoretically pointed out that the shape of the Wiener spectrum of the quantum mottle depended on the sum of the squares of the MTFs for different depths in the screen phosphor layer, rather than the square of the sum of the MTFs for the different depths, i.e. the square of the MTF of the screen-film systems. The purpose of this study is to experimentally investigate the proportionality between the Wiener spectra of the quantum mottle and the squares of the MTFs of screen-film systems using two screen-film systems having different screen thicknesses. For this purpose, we determined correction factors for the square of the MTF of the screen-film system in the Wiener spectrum of the quantum mottle at each spatial frequency when the Wiener spectral values of the screen mottle were separated into those of the quantum mottle and structure mottle. The correction factor is the ratio of the normalized Wiener spectrum of the quantum mottle to the square of the MTF of the screen-film system. As a result, for a thin screen, the correction factors were unity for all spatial frequencies; on the contrary, for a thick screen, the factor increased with spatial frequency. By calculating the theoretical correction factors using the models for the MTF and Wiener spectrum of the quantum mottle of Nishikawa and Yaffe based on Lubberts' theory, we verified that our experimental results agreed with Lubberts' theory. Furthermore, by obtaining the screen thickness dependence of the theoretical correction factors for the two screens, we showed that, for screens thinner than 0.02 mm, Rossmann's theory can be applied to the relationship between the Wiener spectrum of the quantum mottle and the MTF of the screen-film system, whereas for screens thicker than 0.02 mm, Lubberts' theory should be applied.

Micronucleus test with cyclophosphamide using mouse peripheral blood reticulocytes.

The usefulness of the micronucleus test using supravital staining of peripheral blood reticulocytes with acridine orange was evaluated in two laboratories after administering cyclophosphamide (CYP) as a model chemical by intraperitoneal injection (i.p.) to CD-1 mice. The frequencies of micronucleated peripheral reticulocytes (MNRETs) increased dose-dependently at each sampling time. There were no significant differences in the results obtained with this new method by the two laboratories. Although the induction of MNRETs was delayed by about 24 h compared to that of micronucleated polychromatic erythrocytes (MNPCEs) in the bone marrow, the frequencies of MNRETs and MNPCEs were almost identical at each optical sampling time, 24 h for MNPCEs and 48 h for MNRETs. Therefore, it is concluded that this method is a suitable alternative to that using femoral marrow cells.

Reduction in the myocardial sodium current by halothane and thiamylal.

Effects of two general anesthetics, halothane and thiamylal, on the fast sodium inward current (INa) of enzymatically isolated single rat ventricular cells were studied under current clamp and voltage clamp conditions. A suction pipette technique was used for potential measurement, current injection and internal perfusion of isolated cells. In current clamp experiments, sodium action potential was elicited in a Ca-free Co Krebs solution and the action potential was reduced by 0.5% halothane and 5 X 10(-5) M thiamylal. In voltage clamp experiments, the calcium current was suppressed by replacing Ca with Co and the potassium current was eliminated by replacing K with Cs and adding 4-aminopyridine and tetraethylammonium. Both anesthetics decreased INa, in a dose dependent manner, without changing the shape of the current-voltage curve. Halothane (1%) shifted the steady state inactivation curve in a negative direction along the potential axis by 8.5 +/- 2 mV (mean +/- S.D., n = 4). Thiamylal, 5 X 10(-5) and 10(-4) M, shifted the curve in a negative direction by 4.4 +/- 0.8 mV (n = 5) and 8.6 +/- 3.2 mV (n = 5), respectively. Both agents slightly reduced the maximum sodium conductance (gNa). Halothane (1%) increased half recovery time from inactivation measured at -80 mV from 30 +/- 15 to 80 +/- 25 ms (n = 4). Thiamylal (10(-4) M) prolonged it at - 75 mV from 50 +/- 20 to 110 +/- 15 ms (n = 5). With a test pulse duration of 50 ms, neither drug produced a use-dependent inhibition of INa. Halothane and thiamylal depress the INa of cardiac muscles mainly by shifting the steady state inactivation curve in a negative direction along the potential axis. Relatively small prolongation of half recovery time from inactivation and no sign of use-dependent inhibition suggest a molecular mechanism which differs in some respects from the local anesthetics.

A hemophiliac with human immunodeficiency virus (HIV)-1-associated dementia complex.

We report a 29-year-old male hemophiliac with human immunodeficiency virus (HIV)-1-associated dementia complex, who died 2.5 months after the onset of dementia. The patient's cognitive abnormalities including forgetfulness, loss of concentration and slowing of thought appeared about 7 years after HIV infection. His neurological symptoms were characterized as progressive dementia, episodic consciousness loss, transverse myelopathy and peripheral neuropathy. He had generalized slow waves in electroencephalogram (EEG), progressive cerebral atrophy and a diffuse high intensity lesion in the white matter as shown by T2-weighted brain magnetic resonance imaging (MRI). We emphasize the significance of neurological complications, especially acute progressive dementia, in Japanese patients with acquired immunodeficiency syndrome (AIDS).

Angiosarcoma of the heart presenting as fatal pulmonary hemorrhage.

A 47-year-old man died from fatal pulmonary hemorrhage. Cardiac angiosarcoma with lung metastases was found at postmortem examination. His chest radiograph showed bilateral, diffuse nodular infiltrates without cardiomegaly. No cardiac signs and symptoms were observed. The clinical outcome was rapidly fatal. Angiosarcoma of the heart should be suspected in patients with hemoptysis and nodular chest radiograph abnormalities, even in the absence of cardiac signs and symptoms.

HTLV-I associated uveitis and hyperthyroidism.

The records of 76 consecutive patients with etiology-undefined uveitis examined during the 3-year period between 1990 and 1992 were reviewed and 6 patients were found who had concomitant hyperthyroidism. These 6 patients had presented with uveitis symptoms and signs when hyperthyroidism was relieved with thiamazole therapy. The uveal disease was characterized by acute, granulomatous or nongranulomatous anterior uveal involvement and granular or membranous vitreous opacities with or without retinal vascular change. These manifestations resolved in a few weeks in response to topical and/or systemic corticosteroids. Three patients had recurrence of uveitis after remission for months to years. All of the patients had serum antibodies to HTLV-I. The uveal disease resembled HTLV-I associated uveitis that may develop in patients with HTLV-I associated myelopathy or HTLV-I carriers; 2 cases had chronic myelopathy or arthropathy that was considered associated with the retrovirus. The present observations suggest that the association between uveitis and hyperthyroidism is not accidental but shares a common underlying etiologic factor, HTLV-I, although the pathomechanism remains to be defined.