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In this paper, we present an approach to optimizing the yield of embedded static random access memories (SRAM) on mobile SoC chips. This methodology is based on new and ongoing developments in design approach, test methods, diagnosis, and data analysis which has been improved over several process nodes and fully integrated for our 7nm SoC and modem chips. In preparation for future nodes, we are developing methodologies to improve resolution of our fast diagnosis methodologies so that we can collect failing bit information during Wafer Sort and Final Test. We are also researching methods to isolate fault in logic periphery circuits to eliminate or minimize the need for electrical failure analysis such as Photoemission Electron Microscopy and Dynamic Laser Stimulation which are time and resource intensive. This paper concludes by sharing the status and promise of these ongoing developments.

In a twelve-year period (1980-1992) 23 patients (9 men, 14 women; mean age 65 [25-82] years) with malignant non-Hodgkin lymphoma of the stomach, in localized stage I or II (Ann Arbor classification), were given chemo- and radiotherapy without preceding operation. The results were compared with those of a group of 34 patients (19 men, 15 women; mean age 55 [17-77] years) who had been admitted during the same period, having first been treated by surgical resection and most of them additionally by chemo- and/or radiotherapy. Three not previously operated patients with inadequate response to chemotherapy subsequently underwent laparotomy and remained in remission after further treatment. There was in each group one fatal recurrence. Five-year total probability of survival in the operated and non-operated groups was 90% and 92%, respectively; five-year total recurrence-free probability was 88% and 86%, respectively. There were no cases of severe bleeding or perforation. These results demonstrate that conservative management of localized gastric lymphoma by combined chemo- and radiotherapy does not bring about a rise in recurrence rate and does not seem to be inferior to surgical treatment.

In der Chirurgie ist die Bedeutung des Ernah−rungsstatus fur die postoperative Morbiditatund Letalitat bei verschiedenen Krankheitsbil−dern retrospektiv [1±6] und auch prospektiv[7±22] gezeigt worden.Haufig ist das Bestehen einer MangelernahrungAusdruck der Grunderkrankung z.B. eines Tu−morleidens oder einer chronischen Organinsuffi−zienz [22±31] (s. auch entsprechende Kapitel).So ist die Mangelernahrung besonders relevantfur die Prognose nach Organtransplantation[32±41]. Der Ernahrungsstatus beeinflusst auchwesentlich die Morbiditat in der Chirurgie alterMenschen [42].Rasche Rekonvaleszenz nach chirurgischen Ein−griffen (¹Enhanced Recovery after Surgery =ERAS“) ist die Voraussetzung fur die auch okono−misch gebotene Senkung der Krankenhausver−weildauer. Insbesondere nach Koloneingriffen istder sog. ¹Fast Track“ zum Masstab des postope−rativen Managements geworden. Grundlage istim multimodalen Vorgehen die perioperativsparsame Volumenzufuhr, adaquate Schmerz−therapie vor allem mittels epiduraler Anasthesieunter Minimierung der Gabe von Opioiden, Gabevon Antiemetika und Peristaltika. Ziel ist der fru−hestmogliche orale Kostaufbau mit Vollmobili−sierung.Die Indikationen fur eine kunstliche Ernahrungsind auch in der Chirurgie die Prophylaxe und Be−handlung von Katabolie und Mangelernahrung.Dies betrifft vor allem perioperativ ¹substitutiv“den Erhalt des Ernahrungszustandes zur Verhin−derung einer Mangelernahrung. Kriterien des Er−folgs fur die ¹therapeutische“ Indikation einer PEsind unter Berucksichtigung okonomischer Im−plikationen, die sogenannten OutcomeparameterMorbiditat, Krankenhausverweildauer und Leta−litat. Bei ¹palliativer“ Indikation und poststatio−nar steht neben der Verbesserung des Ernah−rungsstatus die Lebensqualitat im Vordergrund[43±55].

It has been demonstrated that achieving therapeutic levels of cyclosporine (CsA) exposure in the first days posttransplant is critical for effective prevention of rejection. In patients receiving oral CsA, it has been shown that C(2)-monitoring is superior to trough (trough level [C(0)]) measurement. Intravenous administration may overcome the problem of CsA absorption dysfunction seen in some patients. Currently, little evidence is available concerning CsA exposure after intravenous application. Twenty de novo liver transplant recipients were given twice-daily 4-hour infusions of intravenous CsA, with full pharmacokinetic profiles undertaken during the first postoperative week. The greatest CsA exposure occurred during the period 2 to 4 hours after the start of infusion. The correlation between C(0) and area under the curve (AUC(0-12)) was r(2) = 0.18; the correlation between C(2) and AUC(0-12) was r(2) = 0.82. The best 2-point predictive model included both C(2) and C(4) (r(2) = 0.90). There was a poor correlation between CsA dose per kilogram of body weight and AUC(0-12) (r(2) = 0.19); total CsA dose also showed a weak relationship to exposure (r(2) = 0.37). When patients were divided according to initial or delayed graft function, there was good correlation between total CsA dose and AUC(0-12) (initial function, r(2) = 0.71; delayed function, r(2) = 0.86). In conclusion, previous discouraging results with intravenous CsA in liver transplant patients may have been due to a limited understanding of CsA pharmacokinetics. Our results show that C(2)-monitoring during 4 hour infusion provides a reliable indication of CsA exposure. Calculation of starting dose based on initial graft function is more precise than use of body weight. Using C(2)-monitoring to individualize dosing and function-based calculations of starting dose could be expected to improve clinical outcomes in patients receiving intravenous CsA.

The intelligence, measurement, knowledge, models, and desktop “best practice” tools discussed in this article are the types of “products” being developed by the 21st-century business researchers who are determined to add quantifiable value to the business enterprise—and the fact-based support being used by the brand and agency teams that are determined to win in the marketplace, quarter-to-quarter and year-to-year. By accounting for, improving, and achieving a return on advertising investments consistent with quarterly business objectives, what is traditionally viewed as a “cost of doing business” can be transformed to “wise investments in the business.”

Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.

The optimum treatment conditions of interferon (IFN) alpha therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CML-study I and it had been planned in advance to add the HU patients of study I (n=194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n=21), major in 14% (n=24), and at least minimal in 35% (n=59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (P

We evaluated toxicity, engraftment, chimerism, graft-versus-host disease (GVHD), and response to a dose-reduced allograft after cytoreductive autografting in 17 patients with advanced stage II/III multiple myeloma (MM). After autografting with melphalan (200 mg/m2) the patients received after a median interval of 119 days (range 60-210) a dose-reduced regimen consisting of fludarabine (180 mg/m2), melphalan (100 mg/m2), and antithymocyte globulin (3 × 10 mg/kg) followed by allografting from related (n = 7), mismatched related (n = 2), or unrelated (n = 8) donors to induce a graft-versus-myeloma effect. After dose-reduced allografting all patients became neutropenic ( 1 × 109/L) and platelet (> 20 × 109/L) counts of 16 (range, 11-24) and 23 days (range, 12-43), respectively. Complete donor chimerism was detected after a median of 30 days (range, 19-38). Acute GVHD stage II occurred in 4 patients (25%) and grade III GVHD in 2 patients (13%). Chronic GVHD developed in 40% of the patients, but only 1 patient experienced extensive chronic GVHD requiring further immunosuppressive therapy. Two patients died of alveolar hemorrhage and pneumonia, resulting in a day 100 mortality rate of 11%. The rate of complete remission with negative immunofixation increased from 18% after autografting to 73% after allografting. After a median follow-up of 17 months after autologous and 13 months after allogeneic transplantation 13 patients are alive and 12 of them free of relapse or progression. The tandem auto-allotransplant protocol is highly active and provides rapid engraftment with complete donor chimerism and tolerable toxicity.

It has been demonstrated that total parenteral nutrition (TPN) modulates the function of the hepatic reticuloendothelial system (RES). The objective of this study was to evaluate the impact of two different TPN lipid emulsions on the recovery of allograft RES function after orthotopic liver transplantation (OLTx). In a prospective, double-blind study, OLTx patients were randomly assigned to two treatment groups. Group I ( n=13) received a TPN regimen that included long-chain triglycerides (LCT). Group II ( n=9) received a TPN regimen that included a fat emulsion consisting of both medium-chain triglycerides (MCT) and LCT. At baseline, i.e., on days 2 or 3 after OLTx ( t1), before lipids for TPN were started, hepatic RES function was determined using the human serum albumin millimicrosphere technique (K-value, 1/min). A second measurement ( t2) was obtained after 7 days of TPN, including one of the study's two fat emulsions. The mean (+/- SD) K-value (1/min) was 0.48+/-0.16 in the LCT group and 0.55+/-0.28 in the MCT/LCT group at t1, and it improved to 0.62+/-0.21 in the LCT group and to 0.86+/-0.32 in the MCT/LCT group at t2. RES function recovery was significantly better in the MCT/LCT group ( Por = 0.05). MCT/LCT emulsion appears to be the TPN fat emulsion of choice after OLTx as it seems to have less impact on hepatic RES recovery.

A major thrust of transplantation research is to find more effective and less broadly toxic immunosuppressive agents. One potential way is the use of monoclonal antibodies directed to IL-2Rα. Immunoprophylaxis with daclizumab, a humanized anti-IL-2Rα monoclonal antibody, has been shown to be effective in the prevention of acute rejection in kidney transplant patients. These results encouraged us to initiate a pilot study in 28 liver transplant patients in 1997. Daclizumab was administered intravenously approximately 6 h after reperfusion (1 mg/kg) and on day 4 post-transplant (0.5 mg/kg). Additional immunosuppression consisted of cyclosporine A as well as of corticosteroids. Administration of daclizumab was not associated with any side-effects. We only experienced one acute rejection in a patient on day 17 post-transplant. It resolved immediately under therapy with prednisolone. The rate of opportunistic infections did not differ from results with conventional immunosuppressive regimens. At 4 years post-transplant no lymphoproliferative disease was observed. Patient survival at 12, 24, 36 and 48 months post-transplant was 88.5, 84.6, 80.8 and 73.1%, respectively. Immunoprophylaxis with a two-dose daclizumab regimen is safe, effective and well tolerated, and does not lead to increased opportunistic infections.

Rituximab (IDEC-C2B8) is a chimeric antibody that binds to the B-cell surface antigen CD20. Rituximab has significant activity in follicular non-Hodgkin lymphomas. Much less is known about the effects in chronic lymphocytic leukemia (CLL). We have initiated a phase II trial to evaluate the efficacy and safety of rituximab in patients with CD20+ pretreated CLL. To avoid the rituximab-associated toxicity, we restricted the tumor cell load, as measured by the number of circulating lymphocytes and the spleen size, in the first 2 cohorts of patients included in the study. Patients received 4 intravenous infusions of 375 mg/m2 once a week over a period of 1 month. Of the 28 patients evaluable for response, 7 patients showed a partial remission (National Cancer Institute criteria) lasting for a median of 20 weeks, with 1 patient still in remission after 71 weeks. Based on lymphocyte counts only, we found at least a 50% reduction of lymphocyte counts lasting for at least 4 weeks in 13 (45%) of 29 patients. Fifteen patients from 3 institutions were monitored for the immunophenotype profile of lymphocyte subsets. The number of CD5+CD20+ cells decreased significantly and remained low until day 28 after therapy. T-cell counts were not affected. With the exception of one rituximab-related death, adverse events in the remaining patients were mild. The results suggest that rituximab has clinical activity in pretreated patients with B-CLL. Toxicity is tolerable. Response duration after withdrawal of rituximab is rather short. Therefore, other modes of application and the combination with other agents need to be tested.

BACKGROUND: Experimental studies have revealed that gelatin and HES produce increased neutrophil respiratory burst activity. It was investigated whether 3-percent gelatin (MW 35,000) and three types of 6-percent HES (MW 70,000; degree of substitution, 0.5; 200,000/0.5; 450,000/0.7) preparations can influence superoxide anion production during respiratory burst under clinical conditions. STUDY DESIGN AND METHODS: Blood samples were obtained from 40 patients before and 1 hour after the infusion, before anesthesia and surgical treatment. After stimulation with bacteria (Escherichia coli), the respiratory burst was measured by oxidation of nonfluorescent dihydrorhodamine 123 to the fluorescent rhodamine 123 by the use of flow cytometry. RESULTS: Respiratory burst activity decreased significantly (p = 0.004) from the baseline (60.0 ± 6.5%) to 1 hour after the administration of the low-molecular-weight HES preparation (55.0 ± 6.8%). No significant differences in respiratory burst activity could be found after the administration of gelatin or medium-molecular-weight or high- molecular-weight HES solution. CONCLUSION: The investigated administration of gelatin and medium- and high-molecular-weight HES preparations did not influence respiratory burst activity under clinical conditions. However, the neutrophil respiratory burst was impaired after the administration of low-molecular-weight HES. Neutrophil respiratory burst activity may vary according to the type of colloidal plasma substitutes administered.

The efficacy and toxicity of a combination of fludarabine and cyclophosphamide (FC) was evaluated in patients with B-cell chronic lymphocytic leukaemia (CLL). Between April 1997 and July 1998, 36 patients with CLL (median age 59 years) received a regimen that consisted of fludarabine 30 mg/m(2) in a 30-min IV infusion, d 1-3, and cyclophosphamide 250 mg/m(2) in a 30-min IV infusion on d 1-3. Cycles were repeated every 28 d. Twenty-one patients had received between one and three different treatment regimens prior to the study, while 15 patients had received no prior therapy. The median Eastern Cooperative Oncology Group performance score was 1. One patient was at Binet stage A, 18 were stage B and 17 patients were stage C. Objective responses, assessed according to the revised guidelines of the National Cancer Institute-sponsored Working Group, were recorded in 29 out of 32 assessable patients (90.6%). Twenty-four partial remissions and five complete remissions were observed. Two patients showed no change and one patient showed disease progression. At February 2000, three of the responders had relapsed. Severe neutropenia, anaemia and thrombocytopenia (Common Toxicity Criteria grade 3 and 4) were observed in 25, six and six patients (69.4%, 16.7% and 16.7%) respectively. Other side-effects were uncommon. No treatment-related deaths and no grade 3 or 4 infections occurred. We conclude that the combination of fludarabine and cyclophosphamide showed significant activity in patients with CLL. Myelosuppression was the major side-effect. These results warrant further study on the FC combination in randomized trials.

To evaluate the efficacy and toxicity of two different etoposide (VP-16) dosages (30 or 45 mg/kg) in combination with busulfan/cyclophosphamide as conditioning therapy followed by stem cell transplantation in acute myeloid leukemia (AML), 90 patients with AML received either 30 mg/kg (n = 60) or 45 mg/kg (n = 30) etoposide in combination with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). The stem cell source was allogeneic related bone marrow (BM) (n = 53), allogeneic unrelated BM (n = 5), allogeneic unrelated peripheral blood (PBSC) (n = 2), syngeneic BM (n = 2), autologous BM purged (n = 9) or unpurged (n = 9), autologous PBSC (n = 10). Fifty-six patients (62%) were in first CR, 26 (29%) were > first CR, and eight (9%) were transplanted in relapse. Principal toxicities in both groups were mucositis and hepatotoxicity. Forty-five mg/kg etoposide resulted in greater hepatic toxicity (P = 0.03), and a higher incidence of VOD (23 vs 12%, P = 0.04) and acute GVHD grade III/IV (13 vs 5%, NS). The treatment-related mortality was 17% in the 30 mg/kg group and 33% in the 45 mg/kg group, mainly due to infections, intestinal pneumonia and GVHD. Hematological recovery of leukocytes 1/nl was comparable in both groups (17 vs 16 days). After a median follow-up of 16 months 19% in the 30 mg/kg group and 23% in the 45 mg/kg group relapsed. In patients who had undergone allogeneic related bone marrow transplantation in first CR no relapses occurred after a median follow-up of 3 years. For all patients the 3-year estimated disease-free survival was 62% in the 30 mg/kg group and 40% in the 45 mg/kg group (P = 0.03). For patients in first CR who underwent allogeneic related stem cell transplantation the 3 year disease-free survivals were 80% and 66%, respectively (P = 0.4). We conclude that etoposide 30 mg/kg or 45 mg/kg in combination with busulfan/cyclophosphamide is a highly active regimen for bone marrow transplantation of patients with AML with a low relapse rate. However, conditioning with 30 mg/kg rather than 45 mg/kg etoposide resulted in less toxicity and a better overall survival due to a lower transplant-related mortality. Bone Marrow Transplantation (2000) 26, 711-716.

Early postoperative infections and septic complications are predominant causes of morbidity and mortality in patients following orthotopic liver transplantation (OLTx). Prophylactic granulocyte colony-stimulating factor (G-CSF) administration after OLTx was found to decrease the number of sepsis episodes and sepsis-related mortality. Since polymorphonuclear neutrophils (PMNs) are one of the major determinants of antimicrobial defense, alteration of their functions may influence the development of sepsis in these patients. Therefore, we investigated in vitro whether or not priming with G-CSF affects the neutrophils' respiratory burst (RB) in immunosuppressed liver-transplanted patients. Venous blood was drawn from liver allograft recipients (n=12) between the 5th and 15th day postoperatively. Patients without clinical signs of infection or rejection were included in this study. Leukocytes were obtained as supernatant following sedimentation and incubated with 1000 IE ml-1 G-CSF. The RB was measured by the intracellular oxidation of non-fluorescent dihydrorhodamine to the fluorescent rhodamine by flow cytometry. The results were expressed as a percentage of increasing stimulation compared to the control responses, which are made up of the percentage of cells with RB reaction after stimulation with phorbol ester (PMA), bacteria (E. coli), or the combination of a cytokine (TNF-alpha) and a bacterial peptide (FMLP) in the absence of G-CSF. In vitro priming with G-CSF resulted in significantly increased activity of the RB after PMA (from 71.7% to 85.6%) and TNF-alpha/FMLP (from 58.4% to 72.7%) stimulation. These data demonstrate that G-CSF in vitro augments the RB of PMNs, thereby suggesting a possible therapeutic role for G-CSF as immunomodulating agent during bacterial and fungal infections following OLTx.

Objective: Superoxide production by polymorphonuclear neutrophils (PMNs) under cyclosporin A (CsA) therapy following kidney transplantation is impaired. We investigated if the respiratory burst of PMNs is similarly depressed in patients undergoing CsA treatment following orthotopic liver transplantation (OLTx). Additionally, the in vitro influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the superoxide anion production was examined during the respiratory burst. Patients: 10 patients after OLTx and 10 healthy blood donors (control group). Measurements and results: PMNs were stimulated with bacteria (Escherichia coli) or a combination of tumour necrosis factor alpha (TNFα) and N-formyl-methionyl-leucyl-phenylalanine (FMLP). The respiratory burst was measured by oxidation of non-fluorescent dihydrorhodamine to the fluorescent rhodamine by means of flow cytometry. No differences in respiratory bursts from OLTx patients compared to those from healthy blood donors could be seen. Under TNFα/FMLP stimulation, the respiratory burst was significantly increased after in vitro incubation with GM-CSF (500 U ml–1) in patients following OLTx (from 58.2 to 74.5 %) as well as in the control group (from 47.4 to 61.9 %). Conclusions: Our results demonstrate that superoxide production is not impaired under CsA treatment following OLTx. The respiratory burst of these patients' PMNs can even be augmented by GM-CSF in vitro.

We investigated an intensified conditioning regimen including fractionated total body irradiation (12 Gy), etoposide (30–45 mg/kg) and cyclophosphamide (120 mg/kg), followed by autologous (n = 5), allo-related (n = 13) or allo-unrelated (n = 6) bone marrow (n = 22) or peripheral stem cell (n = 2) transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. One patient received busulfan (16 mg/kg) instead of TBI. Nineteen patients were transplanted in 1CR, two in 2CR, one in 1PR and two in relapse. Major toxicity was mucositis grade II according to the Bearman scale in all patients. The treatment-related mortality was 25%, mainly due to infection or GVHD after allogeneic transplantation. After a median follow-up of 45 months (range 2–93), nine patients (37.5%) remain alive in CR. Nine patients (37.5%) relapsed and eight (33.3%) of these subsequently died. After autologous transplantation, four of five patients (80%) relapsed and died. Late relapse was seen after allogeneic, as well as autologous transplantation, at 33 and 59 months, respectively. The Kaplan–Meier estimate of leukemia-free survival for all patients is 38% at 3 years (95% CI: 18–58%) and 35% at 5 years (95% CI: 15–55%). For allogeneic transplants in first CR (n = 15) the estimate of disease-free survival was 46% at 3 years (95% CI: 19–73%) and 34% at 5 years (95% CI: 17–51%). Patients aged below 30 years had a better estimated overall survival at 3 years (61% vs 11%, P

Patients with primary refractory or relapsed acute myeloid leukemia (AML) who undergo intensive salvage chemotherapy carry a high risk of treatment failure due to infectious complications and early relapses. The study presented here assessed the effect of granulocyte colony-stimulating factor (G-CSF) on the duration of post-treatment neutropenia, the incidence of infection-related deaths, and the disease-free and overall survival. Sixty-eight evaluable patients with relapsed and refractory AML received G-CSF 5 microg/kg per day subcutaneously starting 2 days after the completion of salvage treatment with the S-HAM regimen, consisting of high-dose cytosine arabinoside twice daily on days 1, 2, 8, and 9 and mitoxantrone on days 3, 4, 10, and 11. Ninety-one patients who were treated with the identical S-HAM regimen but without G-CSF support during a preceding study served as controls. The application of G-CSF resulted in a significant shortening of critical neutropenia of less than 500 microl (36 vs. 40 days; p = 0.008), which translated into a trend towards a lower early death rate (21% vs. 30%) and an increase of complete remissions (56% vs. 47%, p=0.11). In patients younger than 60 years a significant prolongation of time to treatment failure (159 vs. 93 days, p=0.038) and of duration of disease-free survival (203 vs. 97 days, p=0.003) was observed. These results indicate a beneficial effect of G-CSF on early mortality as well as on long-term outcome when administered after S-HAM salvage therapy for advanced AML.

Trotz vieler unterschiedlicher neuer Therapieversuche, stellt das postoperative ANV auch heute noch ein nicht gelostes Problem dar. 1988 wurde Urodilatin (URO), ein natriuretisches Peptid, aus dem menschlichen Urin isoliert. Nachdem 2 nicht kontrollierte, klinische Studien mit URO zur Prophylaxe und Therapie des ANV nach Herz- bzw. Lebertransplantation (HTx, LTx) mit Erfolg durchgefuhrt wurden, initiierten wir diese erste doppelblinde, Plazebo-kontrollierte Studie zur Therapie des ANV nach LTx. Wir verglichen 5 URO (20 ng/kg KG/min) mit 4 Plazebopatienten. Eines der folgenden Einschluskriterien muste innerhalb von 7 Tagen nach LTx erfullt sein: Diuretika-resistente Oligurie/Anurie (

Interstitial pneumonia caused by Herpes simplex virus type 1 (HSV-1) is a severe complication of orthotopic liver transplantation (LTX). The records of patients were reviewed who had an LTX at the age of 16 years or older between 1991 and 1994 with a mean follow-up of 21 months (range, 10 to 44 months). Six patients were included who had fever of38 degrees C, deterioration of arterial blood gases, radiological evidence of interstitial pneumonia and proof of HSV-1 in bronchoalveolar lavage fluid. All patients were anti-HSV-IgG positive before LTX. All patients were successfully treated with intravenous acyclovir, mechanical ventilation and reduced immunosuppression. Three patients who received cyclosporin A had a rejection which was successfully treated by switching to FK 506. Four patients were discharged in good health. One patient died 36 months after LTX of an unrelated cause. One patient died of urosepsis on postoperative day 139. Acyclovir together with mechanical ventilation and reduced immunosuppression proved to be an effective treatment for HSV-1 pneumonia following LTX.

The immunosuppressive effect of a monoclonal antibody (moAb), BT563, directed to the alpha-chain of the IL-2R (CD25), was analyzed in a prospective nonrandomized trial and a prospective randomized trial. Primary objectives were evaluation of the incidence of acute rejections and infections; secondary objectives were safety and tolerability of the moAb. A total of 28 patients were enrolled (phase II) to receive 10 mg/day of BT563 (12 days) as immunoprophylaxis in combination with cyclosporine, azathioprine, and low-dose steroids. Subsequently 32 patients were randomly assigned (phase III) to receive BT563 (10 mg/day) for 12 days or ATG (5 mg/kg/day) for 7 days in addition to cyclosporine and low-dose steroids. No side effects of the BT563 treatment were noted. The actuarial survival was 82% at 12 months in the phase II trial and 92% at 12 months in both arms of the phase III trial. There was one acute rejection in the phase II trial. No acute rejections were noted in the BT arm of the phase III trial and 5 acute rejections were treated in the ATG arm. In the phase II trial 7 infectious episodes were observed, while one infection was seen in the BT arm and 7 in the ATG arm of the triple immunosuppression phase III trial. In all patients circulation of coated CD25+ lymphocytes was observed during BT563 treatment; there was no evidence of depletion or modulation of CD25+ cells. Mean serum levels of BT563 ranged from 1.6 to 7.6 microgram/ml throughout the therapy. An antimurine response was seen in 82% (phase II) and 100% (phase III) of the patients. Antirabbit antibodies were found in 56% of the patients treated with ATG. Analysis of the antimurine response specificity revealed in 56% blocking anti-isotypic antibodies and only in 3% of the patients an anti-idiotypic response. The data of the study presented suggest that therapy with an anti IL-2R moAb is at least equal to ATG application according to the incidence of acute rejections and infections.

Regulatory roles of insulin and glucagon in hepatic metabolism and function are well described. However, little is known about implications of host pancreatic hormones in primary function of grafted liver. This study aimed to investigate it in relation to hepatic mitochondrial function. Insulin, c-peptide, and glucagon in peripheral blood were monitored for 2 days in clinical liver transplantation by a continuous sampling technique to avoid influences of hormonal oscillation. In grafts with immediate function (n = 10), smooth increase of arterial ketone body ratio reflecting hepatic intramitochondrial redox state was accompanied by increased c-peptide and decreased glucagon, resulting in the increase of c-peptide/glucagon ratio. In other functioning grafts (n = 20), where ketone body ratio was rather lower, increased glucagon level, observed also during anhepatic phase, resulted in the slower increase of c-peptide/glucagon ratio. These were accompanied by increased free fatty acid and ketone body levels. In primary nonfunction (n = 4), rapid increase of c-peptide accompanied by hyperglycemia resulted in the accelerated increase of c-peptide/ glucagon ratio, but ketone body ratio did not show any increase. Insulin/c-peptide ratio also showed a rapid increase. These findings suggest that the increase of insulin/glucagon ratio in portal blood, potentially influenced by recipient condition, is associated with the recovery of mitochondrial energy metabolism in survived hepatic grafts. However, this relationship does not work in failed grafts, where irreversible impairment of energy metabolism is attributed to graft itself.

Regulatory roles of insulin and glucagon in hepatic metabolism and function are well described. However, little is known about implications of host pancreatic hormones in primary function of grafted liver. This study aimed to investigate it in relation to hepatic mitochondrial function. Insulin, c-peptide, and glucagon in peripheral blood were monitored for 2 days in clinical liver transplantation by a continuous sampling technique to avoid influences of hormonal oscillation. In grafts with immediate function (n = 10), smooth increase of arterial ketone body ratio reflecting hepatic intramitochondrial redox state was accompanied by increased c-peptide and decreased glucagon, resulting in the increase of c-peptide/glucagon ratio. In other functioning grafts (n = 20), where ketone body ratio was rather lower, increased glucagon level, observed also during anhepatic phase, resulted in the slower increase of c-peptide/glucagon ratio. There were accompanied by increased free fatty acid and ketone body levels. In primary nonfunction (n = 4), rapid increase of c-peptide accompanied by hyperglycemia resulted in the accelerated increase of c-peptide/glucagon ratio, but ketone body ratio did not show any increase. Insulin/c-peptide ratio also showed a rapid increase. These findings suggest that the increase of insulin/glucagon ratio in portal blood, potentially influenced by recipient condition, is associated with the recovery of mitochondrial energy metabolism in survived hepatic grafts. However, this relationship does not work in failed grafts, where irreversible impairment of energy metabolism is attributed to graft itself.

During the course of chronic myeloid leukemia (CML) progression to blast crisis (BC) is thought to be caused by genetic instability such as cytogenetic aberrations in addition to the translocation t(9;22)(q34;q11). We have shown previously that major route ACA indicate an unfavorable outcome (Fabarius et al., Blood 2011). We now investigate whether there is a correlation in time between appearance of major route ACA and increase in blast count. Methods: Cytogenetic data and blast count in the peripheral blood were available from 1,290 CML patients recruited to the German CML-studies III (621 patients) and IIIa (669 patients) from January 1995 to January 2004. Treatments were interferon-alpha-based or related allogeneic stem cell transplantation (HSCT). Presence of ACA and major route ACA was considered as a time-dependent covariate. Multivariate proportional hazards models were estimated taking Euro CML score, study III vs. IIIa and stem cell transplantability into account. Cumulative incidences of blast increases were calculated starting at the date of the first ACA or major route ACA, respectively, regarding death as a competing risk. Patients were censored at the date of HSCT with an unrelated donor. Results: 1,287 patients were evaluable with median observation times of 13 and 12 years and a 10-year survival of 48% and 61% in CML studies III and IIIa, respectively. 258 patients progressed to BC with a cumulative 10-year incidence of 20%. 195 patients displayed ACA during the course of disease. 45 patients (15.7%) showed ACA already at diagnosis. 44 patients showed unbalanced minor route, 29 balanced minor route aberrations, 23 -Y. 109 patients showed major route aberrations including 10 with other prior ACA. In a multivariate analysis on 1,257 patients, patients with ACA had a hazard ratio (HR) for a blast increase of between 2.0-2.2 (p 5 years after the diagnosis of any ACA the cumulative incidence for a blast increase was 30% (95%- confidence interval (CI): 23-38%), of a major route ACA 40% (95%- CI: 28-49%). The 6-year probability of death without blast increase was 10%. 14 additional patients received an unrelated transplant of which 6 died. We conclude that ACA, particularly major route ACA, precede an increase of blasts. Major route ACA have to be considered as a prognostic indicator for disease progression at any time. Table 1. Blast increase to HR (univariate): ACA vs. no ACA HR(multivariate)*: ACA vs. no ACA HR (univariate): major route ACA vs. no major route ACA HR (multivariate)*: major route ACA vs. no major route ACA ≥30% 2.409 2.139 2.646 2.203 ≥20% 2.413 2.144 2.656 2.211 ≥15% 2.415 2.161 2.868 2.426 ≥10% 2.416 2.160 2.799 2.357 ≥5% 2.286 2.047 2.719 2.278 ≥1% 2.209 1.999 3.171 2.684 *adjusted to Euro-Score, study (III vs. IIIa) and transplantability Disclosures Saussele: ARIAD: Honoraria; BMS: Honoraria, Other: Travel grant, Research Funding; Pfizer: Honoraria, Other: Travel grant; Novartis Pharma: Honoraria, Other: Travel grant, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Scheid:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Baerlocher:Geron Corporation: Research Funding; Novartis: Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Müller:BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Pfirrmann:BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria. Baccarani:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hehlmann:BMS: Consultancy; Novartis Pharma: Research Funding.

A pilot study was performed in patients after liver transplantation (Ltx) to examine the effect of continuous intravenous urodilatin (URO, CDD/ANP-95-126)-infusion as an alternative therapy of acute renal failure (ARF) resistant to conventional therapy. Eight patients who developed ARF after liver transplantation and fulfilled requirements for haemodialysis/haemofiltration were treated. After URO infusion was started, renal function improved and all patients developed a strong diuresis and natriuresis within 2-4 h. The extracellular expansion due to sodium and water retention in anuric/oliguric ARF lead to an increased central venous pressure (CVP) and elevated blood pressure. During the URO infusion CVP declined and systolic, as well as diastolic, blood pressure were stable. In six patients where haemodialysis/haemofiltration could be avoided, serum creatinine (SC) and blood urea nitrogen (BUN) declined during URO treatment and creatinine clearance (CC) also improved significantly. Fluid and electrolyte disturbances changed promptly and normalized. This was in concordance with renal excretion of electrolytes. Two patients still required haemodialysis/haemofiltration. The six patients who did not require haemodialysis/haemofiltration after URO treatment normalized concerning their renal function and did well in a control period of 12 weeks. The study shows that continuous low dose URO infusion may present a new concept for treatment of postoperative acute renal failure resistant to conventional therapy.

Ten cases of classic centrocytic lymphoma as defined in the Kiel classification system were investigated for their immunophenotype, their proliferation activity and by means of molecular diagnostics. The findings were compared to those obtained from a group of nine cases of anaplastic centrocytic lymphoma. Both groups showed virtually identical immunohistochemical characteristics with positivity for CD5 and negativity for CD10 and CD23. In the group of anaplastic centrocytic lymphoma, there were considerably higher proliferation indices as documented by staining for the Ki-67 antigen, up to 80% of the tumour cells being positive. Moreover, the cases of anaplastic centrocytic lymphoma had bcl-1 gene rearrangements in eight out of nine cases compared with three out of 10 cases of classic centrocytic lymphoma. DNA analysis was not able to detect bcl-2 gene rearrangement in any case, pointing to a difference compared with lymphomas of germinal centre origin. The coincidence of anaplastic and sometimes blast-like morphology of the tumour cells, high proliferation index and a rearranged bcl-1 gene in nearly all cases of anaplastic centrocytic lymphoma support their classification as high-grade malignant variants of centrocytic lymphoma and suggest a possible role for the bcl-1 locus not only in the origin but also in the progression of centrocytic lymphomas.

PURPOSE A prospective phase II study was conducted to evaluate the efficacy of dexamethasone, carmustine, etoposide, cytarabine, and melphalan (Dexa-BEAM) as salvage chemotherapy for patients with Hodgkin's disease. PATIENTS AND METHODS Fifty-five patients progressing on or relapsing after eight- or 10-drug chemotherapy (cyclophosphamide, vincristine, procarbazine, and prednisone plus doxorubicin, bleomycin, vinblastine, and dacarbazine [COPP+ABVD] or COPP+ABV+ifosfamide, methotrexate, etoposide, and prednisone [IMEP]) were treated with Dexa-BEAM. Patients who responded after two cycles of Dexa-BEAM either continued treatment for another two to three cycles or received high-dose chemotherapy/autologous bone marrow transplantation (HDCT/ABMT) with cyclophosphamide, etoposide, and carmustine (BCNU) (CVB) as conditioning regimen. RESULTS Seventeen patients (31%) achieved a complete remission and 16 (29%) a partial remission, resulting in a response rate of 60% (95% confidence interval, 46% to 73%). Progressive disease developed in 18 patients. Toxicity of Dexa-BEAM was acceptable with pronounced, but temporary World Health Organization (WHO) grade III/IV granulocytopenia and thrombocytopenia occurring in more than 90% of all courses. Two patients died of sepsis during granulocytopenia. Three prognostic subgroups could be distinguished: (1) patients progressing on initial chemotherapy, (2) patients relapsing within 12 months, and (3) patients with late relapses. The response rates for these groups were 52%, 60%, and 83%, and the median survival duration 12, 29, and 40+ months, respectively. In a nonrandomized comparison, the survival of patients who responded to two cycles of Dexa-BEAM and had additional cycles of Dexa-BEAM (n = 14) was not different from those responding patients who underwent HDCT/ABMT (n = 19). However, the power to detect a 20% survival difference was only 33% in this comparison. CONCLUSION Dexa-BEAM is an effective salvage treatment for patients with Hodgkin's disease who fail to respond to multidrug chemotherapy. Efficacy and toxicity are comparable to HDCT/ABMT and underline the need for prospective randomized trials to define better the role of HDCT with and without ABMT in these patients.

Two patients with persistent disease after allografting for multiple myeloma received donor T-cell lymphocyte infusion (DLI) (1.5 x 10(8) and 7 x 10(7)) to induce a graft-vs.-myeloma effect for further tumour regression after withdrawal of immunosuppression. The interval between stem cell transplantation and DLI was 8 and 14 months respectively. Both patients converted from partial to complete remission, lasting 12+ and 28+ months. Immunofixation became negative after 3 and 4 months. The main toxicity was grade II and III acute graft-vs.-host disease (GvHD) and limited or extensive chronic GvHD in each patient. We conclude that DLI induced further tumour reduction in patients with persistent disease after allografting for multiple myeloma.

In the early postoperative period after liver transplantation a possible neurotropic side effect of middle-chain triglycerides used for total parenteral nutrition (TPN) was evaluated by EEG and Glasgow Coma Scale. Group I: no fat for TPN; Group II: 0.7 g/kg body weight (BW) and day, of MCT/LCT emulsion; Group III: 1.5 g/kg BW and day, of MCT/LCT emulsion. Only on postoperative day 5/6 significant differences in distribution of background activity in the EEG were seen between Group I and II. Patients in Group I showed more pathological EEG patterns (Mann-Whitney-U-test p less than 0.05). Per discriminant analysis an influence of applicated fatty acids on the registered background activity could be excluded. Instead an underlying rejection of the graft in 7 of 10 patients could be made responsible for deterioration of the EEG pattern. Following the presented data a negative neurotropic effect of MCT/LCT emulsions in the described dosages can be negated.

In a prospective multicenter trial the efficiency of the response-adapted COP-BLAM/IMVP-16 protocol to induce complete remissions (CR) in high-grade malignant non-Hodgkin’s lymphomas as well as the prognostic relevance of adjuvant radiotherapy were investigated. From 1986–1989, 548 patients (median age 56 years) with stage II–IV (Ann Arbor) disease were treated with five cycles of COP-BEAM followed by two cycles of IMVP-16. If only a partial remission was obtained at the time of first restaging (RS) after three cycles (delayed response), treatment was switched to IMVP-16 (two to five courses) immediately. Patients achieving CR by the second RS after chemotherapy were randomized to adjuvant radiotherapy or observation. Responses to chemotherapy were 63% CR in patients completing the second RS (N = 350) or 72% if patients achieving late CR by consolidating radiotherapy are added; responses were 58% or 65% if all deaths prior to the second RS are included (N = 50). Overall and relapse-free survival were 71% and 68% at one year and 63% and 61% at two years. Multivariate risk factor analysis proved the early (by first RS) CR response to possess predominant prognostic relevance for survival. A significant advantage of adjuvant radiotherapy over no further treatment for duration of CR is not yet discernible. These results emphasize the importance of a rapidly achieved CR, thus contributing to the design of future trials.

Zwischen 12/85 und 4/90 wurden 55 nach der aktualisierten Kiel-Klassifikation als mittelgroszellig pleomorph (mgrz pleo n = 19), groszellig pleomorph (grz pleo n = 21), groszellig anaplastisch Ki-1-po

One hundred and twenty-six patients were treated for 137 episodes of fungal infection with liposomal amphotericin B (AmBisome) at 43 investigational centres. Among the patients were 72 with malignancies, 17 organ transplant recipients, 20 patients with immunological disorders and 17 others. AmBisome treatment was instituted after toxicity from previous amphotericin B treatment in 49 cases, nephrotoxicity or renal insufficiency in 40 and failure of previous antifungal treatment in 41. One hundred and eight episodes were clinically evaluable; among these 52 were caused by Candida spp. and 34 by Aspergillus spp. Ninety-nine patients were treated for at least eight days with a maximum dose of 0.7-5 mg/kg/day. Among 64 cases with proven invasive fungal infection 58% were cured. Fungi were eradicated in 35 of 54 (65%) mycologically evaluable cases. The cumulative dose was 3.2 +/- 3.2 (mean +/- S.D.) in cases where fungi were eradicated in comparison with 3.3 +/- 2.3 g in cases where fungi persisted. The eradication rate was 83% for Candida spp. compared with 41% for Aspergillus spp. (P less than 0.01). Among 24 cases with presumptive invasive fungal infections 14 (58%) were cured. Candida spp. were eradicated in seven of ten of these cases. Among 11 cases with superficial fungal infections eight were cured and three improved. Candida spp. were eradicated in four of five patients. It is concluded that AmBisome is an effective antifungal agent in a majority of patients with invasive or superficial fungal infections.

Between 1981 and 1988, thirty-nine patients with acute myeloid leukemia (AML) following a de novo myelodysplastic syndrome (n-MDS) were studied cytogenetically. The chromosomal aberration rate was 59%. The anomalies most often found were: complex (four or more) aberrations (n = 6), a 5q- chromosome (n = 6), monosomy 7 or a 7q- chromosome and trisomy 8 as the sole defect (n = 3). Incidence and types of chromosomal aberrations were approximately the same as in myelodysplastic syndromes and in 191 patients with de novo AML studied in our laboratory during the same period. But the cytogenetic pattern in AML post de novo MDS also shared certain similarities with chromosomal findings in 35 patients with secondary, therapy-induced (t) AML/MDS. In both these types of acute leukemia primary changes such as t(8;21), t(15;17) and inv (16) were not found; the frequency of AA-Karyotypes was high (70 and 66%) and the incidence of -5,5q- in AML post de novo MDS was more comparable with that found in t-AML/MDS than in de novo AML. Thus the chromosomal patterns seen in AML post de novo MDS indicate that these leukemias share similarities with both de novo and t-AML not only clinically but also cytogenetically.

Does procalcitonin (PCT) allow differentiation between infection and rejection following liver transplantation in the case of fever of unknown origin (FUO)?Open prospective trial.transplant intensive care unit at a university hospital.Forty patients after liver transplantation.Liver biopsy for diagnosis of rejection, transcutaneous aspiration cytology for monitoring of lymphocyte activation.Procalcitonin from EDTA plasma, APACHE II, Sepsis, score (Elbute and Stoner).Eleven patients suffered an infectious complication resulting in an increase in PCT levels (2.2-41.7 ng/ml). Eleven patients developed a rejection episode; none of these patients showed a rise in PCT levels. The statistical difference between PCT levels in rejection and infection was significant (p0.05) on the day of diagnosis.PCT allows differentiation between rejection and infection in the case of FUO. Elevation of PCT plasma levels develops early postoperatively due to operation trauma, and, in the case of FUO with no rise in PCT, a rejection may be suspected.

The pharmacokinetics of cefotaxime including formation of its active metabolite desacetyl-cefotaxime were assessed after liver transplantation in three groups of patients (four patients per group): --during the postoperative recovery phase (group 1), --during an episode of allograft nonfunction (group 2), --during an episode of allograft rejection (group 3). All patients received a single dose of 1 g cefotaxime intravenously. Concentrations of cefotaxime and its metabolite were determined in plasma and urine until 6 to 72 h after medication. The terminal half-life of cefotaxime increased and total clearance decreased due to an impairment of drug metabolism, mainly in patients with a nonfunctioning allograft and during rejection. Thus, no desacetyl-cefotaxime was detectable in urine of any patient and none in plasma of 2/4 patients with a nonfunctioning allograft. In addition, a moderate impairment of renal function in several patients contributed to the delayed elimination of cefotaxime and its metabolite. It can be concluded that liver function after transplantation is correlated with the ability to eliminate cefotaxime. Therefore, administration of half the normal dose is recommended particularly in patients with a nonfunctioning allograft or during rejection.

Cytogenetic studies were performed in 120 patients with de novo myelodysplastic syndrome (MDS) classified according to FAB criteria. Twenty-eight patients had refractory anemia (RA), 14 had refractory anemia with ring sideroblasts (RARS), 45 had refractory anemia with blast excess (RAEB), 19 had refractory anemia with blast excess in transformation (RAEB-t), and 14 had chronic myelomonocytic leukemia (CMMoL). Fifty patients (42%) had clonal chromosome anomalies at initial analysis. The most common cytogenetic anomalies were: 5q- (11 patients), trisomy 8 (nine patients), -7/7q- (6 patients), 12p- (five patients), followed by structural anomalies of chromosome 17 (four patients), and loss of Y chromosome (three patients). The prognostic value of chromosome anomalies was examined by comparison of the significance of single chromosome anomalies (34 patients) versus multiple cytogenetic changes (16 patients). Patients with multiple anomalies had a shorter survival (8 months) than patients with single anomalies (18 months) or those with a normal karyotype (36 months). All these differences were significant. The incidence of multiple anomalies was higher in patients with RAEB and RAEB-t than in those with RA, RARS, and CMMOL (p less than 0.05). However, no chromosome anomaly was specifically associated with any group of FAB classification. Transformation to acute leukemia was observed in 25% of patients with normal karyotype, 41% of patients with single anomalies, and 50% of patients with multiple changes. The incidence of leukemic transformation was significantly higher in patients with multiple anomalies than in those with a normal karyotype (p less than 0.05). Thus, in the present study, FAB classification and chromosome anomalies were of independent prognostic significance. Sequential cytogenetic studies were performed in 23 patients to correlate the cytogenetic and clinical findings during the course of the disease. Six of seven patients with transformation to acute leukemia showed a karyotypic evolution. These findings agree with the view that an unstable karyotype can be associated with a poor prognosis.

Administration of hepatitis B immunoglobulin (HBIG) initially after liver transplantation of hepatitis B patients is considered important to prevent reinfection reliably. However, dosing schedules differ considerably between centers. We measured HBsAg, anti-HBs and HBV DNA kinetics to create a rational basis for dosing schemes.Thirteen patients (group A) received 10,000 IU HBIG in the anhepatic phase followed by 10,000 IU daily until HBsAg became negative, whereas five patients (group B) received 20,000 IU followed by 5000 IU every 30 min.HBsAg levels at time of transplantation ranged from 0.12 to 12,990 IU/ml. Correlations between initial HBsAg and HBIG required to decrease HBsAg below 1 IU/ml were high in groups A and B (r=0.97, p0.001; r=1.00, p0.001), as were correlations between initial HBsAg and HBIG required to raise anti-HBs above 1000 IU/l (r=0.94, p0.001; r=1.00, p0.001). In 11 HBV DNA-positive patients, DNA levels became negative in seven, and dropped by 2.5 log10 (mean) in the other four patients during immunoglobulin administration.In conclusion, required HBIG doses to decrease HBsAg and raise anti-HBs are determined by HBsAg levels at time of transplantation, not by HBV DNA levels. Shortened HBIG dosing intervals accelerate HBsAg decrease and anti-HBs increase. HBV DNA decreases rapidly during HBIG administration in most patients.

Enhanced recovery of patients after surgery ("ERAS") has become an important focus of perioperative management. From a metabolic and nutritional point of view, the key aspects of perioperative care include:•avoidance of long periods of pre-operative fasting;•re-establishment of oral feeding as early as possible after surgery;•integration of nutrition into the overall management of the patient;•metabolic control, e.g. of blood glucose;•reduction of factors which exacerbate stress-related catabolism or impair gastrointestinal function;•early mobilisation. Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and if necessary tube feeding (TF) offers the possibility of increasing or ensuring nutrient intake in cases where food intake is inadequate. These guidelines are intended to give evidence-based recommendations for the use of ONS and TF in surgical patients. They were developed by an interdisciplinary expert group in accordance with officially accepted standards and are based on all relevant publications since 1980. The guideline was discussed and accepted in a consensus conference. EN is indicated even in patients without obvious undernutrition, if it is anticipated that the patient will be unable to eat for more than 7 days perioperatively. It is also indicated in patients who cannot maintain oral intake above 60% of recommended intake for more than 10 days. In these situations nutritional support should be initiated without delay. Delay of surgery for preoperative EN is recommended for patients at severe nutritional risk, defined by the presence of at least one of the following criteria: weight loss >10-15% within 6 months, BMI

Summary. A livid, sharply defined enanthema of the oral mucosa with ulcerations on the soft palate in a patient presenting with de novo acute myeloid leukaemia with prolonged, therapy-induced granulocytopenia (lt 0.5 nl-1 for 113 days!) was diagnosed as geotrichosis. Geotrichum capitatum was identified both in vivo and in vitro. Pneumonic infiltrates in the upper lobes of both lungs were treated with amphotericin B infusions. Healing of the aforementioned enanthema was only achieved after addition of 5-fluorocytosine to therapy. Susceptibility determinations with several Geotrichum capitatum isolates led to the conclusion that amphotericin B was unsuitable as a therapeutic agent in this case. 5-Fluorcytosine and itraconazole exhibited superior antifungal and antimycotic activity. Zusammenfassung. Ein livides, scharf begrenztes Enanthem der Mundschleimhaut mit Ulzerationen am weichen Gaumen bei einer de novo akuten myeloischen Leukamie mit extrem langer, therapiebedingter Granulozytopenie (lt 0.5 nl-1uber 113 Tage!) wird als Geotrichose angesehen. Geotrichum capitatum wurde in vivo und in vitro nachgewiesen. Pneumonische Infiltrate in beiden Lungenoberlappen waren Anlas zu einer Infusionstherapie mit Amphotericin B. Eine Abheilung des obengenannten Enanthems wurde allerdings erst nach Umstellung der Therapie auf 5–Fluorcytosin-Infusionen erzielt. Resistenzbestimmungen mit mehreren Isolaten hinterliesen den Eindruck, das Amphotericin B als Therapeutikum hier nicht geeignet war. 5–Fluorcytosin und Itraconazol zeigten einen besseren antimyzetischen Effekt und antimykotische Wirksamkeit.