Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer

PURPOSE: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine. PATIENTS AND METHODS: Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi). RESULTS: At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (Cmax) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t1/2; median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was described by a one-compartment model with a t1/2 of 0.41 hours; peak levels of UFTi were 5.2% +/- 2.5% those of TPTi. CONCLUSION: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.     

Patient education for discharge after coronary bypass surgery in the 1990s: are patients adequately prepared?

Short hospitalizations for patients undergoing coronary artery bypass grafting (CABG) require continuous nursing evaluation of patients' discharge education. Six institutions collaborated in surveying 300 postoperative patients with CABG to identify learning priorities and patients' perceptions of the effectiveness of discharge education. Data analysis from the self-administered questionnaire demonstrated consistent patient priorities across institutions. Differences in teaching methods and content did not affect perceived preparedness or importance scores. Regional experience demonstrates that variable teaching efforts meet patients' priorities and provide high overall patient preparedness for discharge. Patients with the shortest hospitalizations had higher preparedness scores.     

Misleading symptoms after a minor blunt chest trauma. Thoracoscopic treatment of diaphragmatic rupture

We present a case of missed diaphragmatic rupture which was treated thoracoscopically. Rupture of the diaphragm is a serious complication of blunt trauma. The diaphragmatic injury can easily be overlooked. This report illustrates the diagnostic dilemma in a patient where the injury was missed at the time of initial presentation. The role of thoracoscopy both for diagnosis and therapy is discussed.     

Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substituent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1, respectively. The best of these compounds, 18 (EC50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.     

Current options in prosthetic vascular graft infection

Debate continues over which procedure is the best treatment for prosthetic graft infections. We retrospectively reviewed the medical records at our institution for all vascular graft infections that occurred from 1985 to 1995 to evaluate their occurrence, treatment, and outcome. Twenty-four patients had prosthetic graft infections. The average patient age was 62 years, and 67 per cent of the patients studied were men. The initial operation was for treatment of occlusive disease in 92 per cent of the patients, and aortofemoral bypasses were the most common procedures performed (15 of 24 patients, 63%). The average interval from graft implantation to presentation of infection was 29 months. In lower-extremity bypasses, the site of infection was most commonly in the groin (87%). Gram-positive organisms, including coagulase-negative Staphylococcus (32%) and Staphylococcus aureus (28%), were the most frequently isolated bacteria. Thirty procedures were performed for management of the graft infections. Extra-anatomic bypass was associated with no recurrent graft infections. Graft preservation was successful in two cases of early S. aureus infection (less than 1 year after original procedure), and in situ graft replacement was successful in all four cases of late-appearing coagulase-negative Staphylococcus infection (more than 1 year after original procedure). Both treatments failed in all five cases of Gram-negative infection (P = 0.008 by Fisher's exact test). The overall mortality and amputation rates were 17 per cent and 21 per cent, respectively, without significant differences between the treatment modalities. Extra-anatomic bypass remains the best treatment for prosthetic graft infection. In situ replacement and graft preservation treatments should be selective and based on presentation of the infection and the type of pathogenic organism.     

Kinetic analysis of the activation of transducin by photoexcited rhodopsin. Influence of the lateral diffusion of transducin and competition of guanosine diphosphate and guanosine triphosphate for the nucleotide site

The activation of transducin (T) by photoexcited rhodopsin (R*) is kinetically dissected within the framework of Michaelis-Menten enzymology, taking transducin as substrate of the enzyme R*. The light scattering "release" signal (Vuong, T.M., M. Chabre, and L. Stryer, 1984, Nature (Lond.). 311:659-661) was used to monitor the kinetics of transducin activation at 20 degrees C. In addition, the influence of nonuniform distributions of R* on these activation kinetics is also explored. Sinusoidal patterns of R* were created with interference fringes from two crossed laser beams. Two characteristic times were extracted from the Michaelis-Menten analysis: t(form), the diffusion-related time needed to form the enzyme-substrate R*-transducin is 0.25 +/- 0.1 ms, and T(cat), the time taken by R* to perform the chemistry of catalysis on transducin is 1.2 +/- 0.2 ms, in the absence of added guanosine diphosphate (GDP) and at saturating levels of guanosine triphosphate (GTP). With t(form) being but 20% of the total activation time t(form) + t(cat), transducin activation by R* is not limited by lateral diffusion. This is further borne out by the observation that uniform and sinusoidal patterns of R* elicited release signals of indistinguishable kinetics. When (GDP) = (GTP) = 500 microM, t(cat) is lengthened twofold. As the in vivo GDP and GTP levels are comparable, the exchange of nucleotides may well be the rate-limiting process.     

Target Score—A Proteomics Data Selection Tool Applied to Esophageal Cancer Identifies GLUT1-Sialyl Tn Glycoforms as Biomarkers of Cancer Aggressiveness

Esophageal cancer (EC) is a life-threatening disease, demanding the discovery of new biomarkers and molecular targets for precision oncology. Aberrantly glycosylated proteins hold tremendous potential towards this objective. In the current study, a series of esophageal squamous cell carcinomas (ESCC) and EC-derived circulating tumor cells (CTCs) were screened by immunoassays for the sialyl-Tn (STn) antigen, a glycan rarely expressed in healthy tissues and widely observed in aggressive gastrointestinal cancers. An ESCC cell model was glycoengineered to express STn and characterized in relation to cell proliferation and invasion in vitro. STn was found to be widely present in ESCC (70% of tumors) and in CTCs in 20% of patients, being associated with general recurrence and reduced survival. Furthermore, STn expression in ESCC cells increased invasion in vitro, while reducing cancer cells proliferation. In parallel, an ESCC mass spectrometry-based proteomics dataset, obtained from the PRIDE database, was comprehensively interrogated for abnormally glycosylated proteins. Data integration with the Target Score, an algorithm developed in-house, pinpointed the glucose transporter type 1 (GLUT1) as a biomarker of poor prognosis. GLUT1-STn glycoproteoforms were latter identified in tumor tissues in patients facing worst prognosis. Furthermore, healthy human tissues analysis suggested that STn glycosylation provided cancer specificity to GLUT1. In conclusion, STn is a biomarker of worst prognosis in EC and GLUT1-STn glycoforms may be used to increase its specificity on the stratification and targeting of aggressive ESCC forms.     

Development of a high‐resolution RGBW flexible display using a white organic light‐emitting diode with microcavity structure and that of a side‐roll touch panel

In this study, white organic electroluminescent devices with microcavity structures were developed. A flexible high‐resolution active‐matrix organic light‐emitting diode display with low power consumption using red, green, blue, and white sub‐pixels formed by a color‐filter method was fabricated. In addition, a side‐roll touch display was developed in combination with a capacitive flexible touch screen.     

Repeatedly foldable AMOLED display

In this study, a 5.9‐inch foldable active‐matrix organic light emitting diode (AMOLED) display was developed. A folding test was performed repeatedly. The display survived the folding test (100,000 folds) with a curvature radius of 2 mm. To protect an organic light emitting diode (OLED) against moisture, inorganic passivation layers are provided on the upper and lower sides of the flexible display. Using our transfer technology, high density passivation layers can be obtained. The measured water vapor transmission rate of the layer is 7 × 10^?6 g/m²?day or less, which improves OLED reliability. With these techniques, we have developed a book‐type display, which is repeatedly foldable like a book, and a tri‐fold display including a display area, which is foldable in three.     

Three-year outcome after balloon aortic valvuloplasty. Insights into prognosis of valvular aortic stenosis

BACKGROUND: To identify predictors of long-term outcome after balloon aortic valvuloplasty, we analyzed data on 674 adults (mean age, 78 +/- 9 years; 56% were women) undergoing this procedure at 24 clinical centers who had a mean initial increase in aortic valve area of 0.3 cm2. METHODS AND RESULTS: Baseline data included clinical, echocardiographic, and catheterization variables. Follow-up data included mortality, cause of death, rehospitalization, 6-month echocardiography, and functional status. Kaplan-Meier curves and log-rank tests were used to evaluate survival in subgroups. Multivariate Cox regression models were used to identify independent predictors of survival. Overall survival was 55% at 1 year, 35% at 2 years, and 23% at 3 years, with the majority of deaths (70%) classified as cardiac by an independent review committee. Rehospitalization was common (64%), although 61% of survivors at 2 years reported improved symptoms. Echocardiography at 6 months (n = 115) showed restenosis from the postprocedural valve area of 0.78 +/- 0.31 cm2 to 0.65 +/- 0.25 cm2 (P < .0001). With stepwise multivariate analysis, sequentially adding clinical, echocardiographic, and catheterization variables, the overall model identified independent predictors of survival as baseline functional status, baseline cardiac output, renal function, cachexia, female gender, left ventricular systolic function, and mitral regurgitation. Baseline and postprocedural variables were examined to identify which subgroup of patients has the best outcome after aortic valvuloplasty. A "lower-risk" subgroup (28% of the study population), defined by normal left ventricular systolic function and mild clinical functional limitation, had a 3-year survival of 36% compared with 17% in the remainder of the study group. CONCLUSIONS: Long-term survival after balloon aortic valvuloplasty is poor with 1- and 3-year survival rates of 55% and 23%, respectively. Although survivors report fewer symptoms, early restenosis and recurrent hospitalization are common.