Robust treatment planning with 4D intensity modulated carbon ion therapy for multiple targets in stage IV non-small cell lung cancer.

Intensity modulated particle therapy (IMPT) with carbon ions can generate highly conformal treatment plans; however, IMPT is limited in robustness against range and positioning uncertainty. This is particularly true for moving targets, even though all motion states of a 4DCT are considered in 4D-IMPT. Here, we expand 4D-IMPT to include robust non-linear RBE-weighted optimization to explore its potential in improving plan robustness and sparing critical organs. In this study, robust 4D-optimization-based on worst-case optimization on 9 scenarios-was compared to conventional 4D-optimization with PTV margins using 4D dose calculation and robustness analysis for 21 uncertainty scenarios. Slice-by-slice rescanning was used for motion mitigation. Both 4D-optimization strategies were tested on a cohort of 8 multi-lesion lung cancer patients with the goal of prioritizing OAR sparing in a hypofractionated treatment plan. Planning objectives were to keep the OAR volume doses below corresponding limits while simultaneously achieve CTV coverage with D95% ≥ 95 %. For the conventional plans, average D95% was at 98.7% which fulfilled the target objective in 83.2% of scenarios. For the robust plans, average D95% was reduced to 97.6% which still fulfilled the target objective in 80.7% of cases, but led to significantly improved overall OAR sparing: Volume doses were below the limits in 96.2% of cases for the conventional and 99.5% for the robust plans. When considering the particularly critical smaller airways only, fulfillment rates could be increased from 76.2% to 96% for the robust plans. This study has shown that plan robustness of 4D-IMPT could be improved by using robust 4D-optimization, offering greater control over uncertainties in the actual delivered dose. In some cases, this required sacrificing target coverage for the benefit of better OAR sparing.

Optically addressed direct-view display based on bacteriorhodopsin.

First experimental results from a direct-view display made from bacteriorhodopsin (BR) are presented. A dielectric mirror in direct contact with the photoactive BR layer forms the core of the BR display. The dielectric layer both decreases the light intensity necessary for writing and protects the observer from transmitted laser light. By illuminating the BR display with a suitably filtered light source from the rear we achieve the result that the information appears to the observer with an intensity contrast of more than 70:1, accompanied by a significant color shift. The combination of both enhances the visibility of and the ability to discern the information significantly. On the BR display the information appears in yellow on a dark purple-red background.

Comparison of the recovery and half-life of a high-purity factor IX concentrate with those of a factor IX complex concentrate. Factor IX Study Group.

BACKGROUND: Recovery and half-life estimations were carried out to compare a high-purity factor IX concentrate with an established factor IX complex concentrate. STUDY DESIGN AND METHODS: Two high-purity factor IX concentrates, which are identical except for the presence or absence of heparin (Immuninehep-plus and Immuninehep-minus), were evaluated in two independent crossover studies using an intermediate-purity factor IX complex concentrate (Bebulin) as reference drug. RESULTS: In the Immuninehep-plus crossover study (n = 27), Immuninehep-plus and Bebulin had, respectively, a recovery of 0.90 +/- 0.26 and 0.84 +/- 0.23 IU per dL per IU per kg, a compartmental half-life of 17.11 +/- 6.18 and 15.94 +/- 4.69 hours, and an effective half-life of 16.51 +/- 3.48 and 16.48 +/- 4.26 hours. In the Immuninehep-minus crossover study (n = 26), Immuninehep-minus and Bebulin had, respectively, a recovery of 0.92 +/- 0.31 and 1.02 +/- 0.36 IU per dL per IU per kg, a compartmental half-life of 17.42 +/- 5.60 and 18.77 +/- 6.27 hours, and an effective half-life of 16.39 +/- 4.44 and 16.48 +/- 4.28 hours. Equivalence tests indicated that the recovery and half-life of Immunine, with or without heparin, are equivalent to those of Bebulin. CONCLUSION: The equivalence in pharmacokinetics and bioavailability indicates that the dosage schedule for Immunine should be the same as or very similar to that of Bebulin. The high specific activity of the former, however, allows administration at lower volumes.

Low risk of viral infection after administration of vapor-heated factor VII concentrate or factor IX complex in first-time recipients of blood components. International Factor Safety Study Group.

BACKGROUND: Vapor-heated human factor VII concentrate and human factor IX complex are both obtained from prothrombin complex, undergo similar methods of manufacture, and are subjected to an identical two-step vapor-heating process for virus inactivation. STUDY DESIGN AND METHODS: Intermediate-purity vapor-heated human factor VII concentrate and vapor-heated human factor IX complex were monitored for safety with regard to viral infection in the context of an International Factor Safety Study, a prospective study that follows the revised recommendations from the International Congress of Thrombosis and Hemostasis (ICTH). Because the rarity of the respective hereditary deficiencies would have made separate analyses unrealizable, the results were combined for the final analysis. Entry required that patients have no history of transfusion with any blood derivative. After the first infusion of the study drug, patients were monitored for 6 months for the development of non-A, non-B hepatitis (NANBH) and infection with hepatitis B virus (HBV) and for 15 months for infection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV). An event was defined as a positive result on any test for any infection. An alanine aminotransferase level more than 2.5 times the upper limit of normal on two consecutive occasions was defined as an event for NANBH. HBV infection was monitored with tests for three different HBV markers: the HBV surface antigen, antibody against the HBV surface antigen, and antibody against HBV core antigen. HCV and HIV infection were monitored with tests for HCV and HIV antibodies. RESULTS: The 25 patients who completed the study (1 has not completed the study and 1 dropped out) received a total of 434 infusions comprising 17 different production lots of the concentrates. Twenty patients were analyzable for NANBH and 25 for HCV and HIV infection. Since most patients had been given HBV vaccination, only 4 patients were analyzable for this end point. None of the patients showed evidence of having developed an event. These data satisfy ICTH criteria when the products are considered together, but vapor-heated factor VII concentrate does not qualify alone because there were only five patients in this group. CONCLUSION: Vapor-heated factor VII concentrate and vapor-heated factor IX complex are associated with a low risk of viral infection. Preliminary results are also presented, indicating that the concentrates are safe with regard to inhibitor development.

Low risk of viral infection after administration of vapor-heated factor VIII concentrate. International Investigator Group.

A multicenter prospective study was carried out to evaluate whether a vapor-heated factor VIII concentrate transmitted blood-borne viral infections over a surveillance period of 15 months. Thirty-five patients with hemophilia and von Willebrand disease who had never received any blood components were treated. Twenty-eight were analyzed and found not to have non-A, non-B hepatitis. Sera from 20 of these 28 patients were also tested for the antibody to the hepatitis C virus. None had sero-converted during the follow-up period. None of the patients analyzed developed markers of the hepatitis B virus (n = 17) or the human immunodeficiency virus (n = 31). This vapor-heated factor VIII concentrate carries a low risk of transmitting hepatitis and human immunodeficiency virus infection.

Review of studies with plasminogen concentrates and proposals for further therapeutic strategies with plasminogen concentrates.

Since the introduction of thrombolytic treatment based on the activation of plasminogen (PLG) by streptokinase (SK) and urokinase (UK) the search for new and improved methods has been continuing. The pivotal issue is how to achieve clot-specific fibrinolysis without producing systemic fibrinogenolysis. One out of various approaches to enhance lysis rates has been the use of PLG either alone or in combination with UK or SK in the light of the fact that fibrinolytic treatment, particularly using SK, is associated with a consumption of PLG, and that thrombi contain relatively small amounts of native PLG, however, are capable of incorporating added PLG in vitro. PLG-concentrates from various manufactures have been administered intravenously for treatment of deep venous thrombosis, mainly in combination with SK, and of pulmonary embolism in combination with UK. Local intracoronary and intraarterial administration in combination with UK has been reported in patients with myocardial infarction, and peripheral arterial occlusions, respectively. Lysis rates obtained in these studies were in most cases superior to results obtained with SK or UK alone, without increasing the incidence of bleeding complications. In addition, excellent results in larger group of patients with cerebral thrombosis were obtained with PLG alone. The encouraging results of these studies may be explained by the fact that all of the preparations used contained partially activated forms of PLG (commonly designated lys-PLG) to a greater or lesser extent. Lys-PLG has a higher affinity for fibrin than the native glu-PLG and is activated by UK or SK by a manyfold faster. These properties allow for a rapid formation of plasmin which--bound to fibrin--is also protected from the attack of neutralizing antiplasmin. The design and results of previous studies with lys-PLG concentrates will be reviewed and approaches to further improve fibrinolytic regimens with lys-PLG-concentrates discussed.

Reduced fibrinolytic potential in patients with arterial occlusive disease (AOD) in comparison with normal subjects.

When combining angioplasty and local lysis with urokinase (UK) in treatment of peripheral arterial occlusions we have observed marked differences in the individual patient's response irrespective of the age of the thrombus. The extensive arteriosclerotic changes revealed by angiography in some of these patients suggest a reduced fibrinolytic potential depending on the underlying disease. In the standard in vitro test system we measured the UK-dependent thrombolysis in blood samples from 10 normal controls at UK concentrations of 150, 200, and 300 IU/ml of whole blood. In comparison we determined the whole blood thrombolysis time (WBTT) of 10 patients with AOD using UK concentrations of 150, 200, and 300 IU/ml of whole blood. The mean WBTT values for normal controls obtained at UK concentrations of 150 IU/ml, 200 IU/ml, and 300 IU/ml, respectively, amounted to 9.5, 5.5, and 3.5 minutes, respectively, while in patients mean values of 20.7, 8.1, and 5.5 minutes, respectively, were found. Studies on plasma samples had shown that the lysis time could be shortened in a dose-dependent manner by addition of lys-plasminogen (LYS-PLASMINOGEN Steam Treated) and to some extent also glu-plasminogen. Since lys-plasminogen gave clearly superior results we tried to improve the lytic potential in terms of a shortening of the WBTT by adding different doses of lys-plasminogen (0.14-0.56 CU/ml whole blood) to each patient sample. Although the individual response varied, the addition of lys-plasminogen to the patient samples resulted in a clear dose-dependent improvement of pathologically prolonged lysis times.(ABSTRACT TRUNCATED AT 250 WORDS)