[The 1933 resignation of Prof. Gotthold Herxheimer as chairman of the German Society of Pathology in a new light : Pathology in National Socialism]. / Der Rücktritt Prof. Gotthold Herxheimers als Vorsitzender der Deutschen Pathologischen Gesellschaft 1933 in neuem Licht : Pathologie im Nationalsozialismus.

The article offers a new approach to the retirement of Herxheimer as head of the German Society of Pathology in 1933 and frames it in a new context. The result is that the German Society of Pathology of the time contributed to National Socialism and supported it. Herxheimer became a victim, but his tragic fate was partly self-inflicted. This article is based on the methods of historical and cultural studies.

Possibility of differentiation of cochlear electrodes in radiological measurements of the intracochlear and chorda-facial angle position.

Due to an increasing number of cochlear implantations, quality control has become more important. In addition to intraoperative biophysical measurements, radiological imaging is another possibility. An upcoming technique regarding this is Cone Beam CT (CBCT). Sixty-five data sets (35 Nucleus Contour Advance-Cochlear; 30 Flex Soft-MedEl) of postoperative imaging by CBCT (Accu-I-tomo F17, Morita, Kyoto, Japan) underwent further evaluation. Insertion angle, height of the cochlea, distance of the electrode to the medial or lateral wall, angle between chorda tympani and facial nerve and the precise position of the electrode cable in the facial-chordal angle were determined. The typical difference between the perimodiolar and lateral course of the electrodes could also be shown in radiological measurements. This demonstrates the accuracy and advantage of CBCT in visualisation of small structures with fewer metal artifacts. Furthermore, in 75% of patients, the angle of the chorda and facial nerve could be visualised. Significant differences in dependence of the electrode type for the relation of them to the facial nerve could be seen. In conclusion, CBCT achieves reliable visualisation and detailed imaging-based measurements of the intracochlear position of different cochlea electrodes. Additionally, clinically known differences can be reproduced. Even visualisation of the position of the electrode in the chorda-facial angle is possible. Therefore, CBCT is a useful tool in intra- and postoperative control of cochlear implants.

Efficacy, toxicity and mortality of autologous SCT in multiple myeloma patients with dialysis-dependent renal failure.

Numerous studies have reported the feasibility and safety of autologous SCT (ASCT) in patients with multiple myeloma (MM) and mild to moderate renal impairment, but there are limited data in dialysis-dependent patients. In this retrospective study, we reviewed the toxicities and efficacy outcomes of 33 MM patients with dialysis-dependent renal failure who underwent ASCT at our institution from 1998 to 2012. The most common grade 3 non-hematologic toxicities were mucositis (49%), infection (15%) and bleeding (6%). Atrial dysrhythmias (24%) and delirium (30%) of all grades were also common. Hematologic toxicities included febrile neutropenia (88%); and RBC and platelet transfusions were required by 71 and 100% of patients, respectively. Transplant-related mortality (TRM) was high at 15%, predominantly caused by septic shock. Response to ASCT was at least VGPR (very good PR) in 50%, PR in 46.2% and stable disease (SD) in 3.8%. Median OS was 5.6 years, comparable to our overall institutional data. Overall, seven patients became dialysis independent. We conclude that ASCT can be an effective treatment for dialysis-dependent MM patients, with high response rates and survival. However, toxicities and a high TRM are observed indicating that further studies are needed to enhance the safety of this approach.

[Clinical aspects of transoral laser surgery and neck dissection for oro- and hypopharyngeal cancer in elderly patients]. / Klinische Aspekte der transoralen Laserchirurgie und Neck-Dissection bei Oro- und Hypopharynxkarzinomen im fortgeschrittenen Lebensalter.

BACKGROUND: The number of elderly patients with head and neck cancer is increasing. However, there are few valid data on postoperative course after head and neck cancer surgery in elderly patients. The aim of this study was to evaluate the oncological outcome of elderly patients after surgical treatment for oro- and hypopharyngeal cancer. MATERIAL AND METHODS: The clinical data of 81 patients, separated into two age groups (62 < 65 years vs. 19 ≥ 65 years), were retrospectively analysed. The cohort comprised T1 and T2 oro- and hypopharyngeal cancer patients, who had undergone primary treatment with transoral laser surgery and neck dissection. Overall and disease-free survival times of the patients were analysed. Additionally, comorbidities and perioperative complications were compared between the two age groups. Median follow-up time was 5.9 years. RESULTS: Comparison of different clinical and histopathological data revealed no significant differences between the age groups. The Kaplan-Meier method revealed no significant difference in disease-free survival between the age groups (p = 0.52). Age had no effect on disease-free survival in uni- or multivariate analysis (p = 0.53 vs. 0.94). Surgery-related complications were observed in 13 patients (16 %), 11 cases of which concerned the younger group of patients. CONCLUSION: Transoral laser surgery and neck dissection can lead to satisfactory oncological and surgical outcomes in elderly patients with oro- and hypopharyngeal cancer.

Impaired bortezomib binding to mutant ß5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells.

Proteasome inhibition is a novel treatment for several hematological malignancies. However, resistance to the proteasome inhibitor bortezomib (BTZ, Velcade) is an emerging clinical impediment. Mutations in the ß5 subunit of the proteasome, the primary target of BTZ, have been associated with drug resistance. However, the exact mechanism by which these mutations contribute to BTZ resistance, is still largely unknown. Toward this end, we here developed BTZ-resistant multiple myeloma (8226) and acute lymphoblastic leukemia (CCRF-CEM) cell line models by exposure to stepwise increasing concentrations of BTZ. Characterization of the various BTZ-resistant cells revealed upregulation of mutant ß5 subunit of the proteasome. These newly identified ß5-subunit mutations, along with previously described mutations, formed a mutation cluster region in the BTZ-binding pocket of the ß5 subunit, that of the S1 specificity pocket in particular. Moreover, we provide the first evidence that the mechanism underlying BTZ resistance in these tumor cells is impaired binding of BTZ to the mutant ß5 subunit of the proteasome. We propose that proteasome subunit overexpression is an essential compensatory mechanism for the impaired catalytic activity of these mutant proteasomes. Our findings further suggest that second-generation proteasome inhibitors that target the α7 subunit of the proteasome can overcome this drug resistance modality.

High-dose chemotherapy and auto-SCT in elderly patients with Hodgkin's lymphoma.

Our purpose was to assess efficacy and toxicity of high-dose chemotherapy (HDCT) and ASCT in patients with relapsed and refractory Hodgkin's lymphoma (HL) aged 60 years and older and compare the results with a group of younger HL patients treated in a similar manner. We identified 15 consecutive patients, with HL aged 60 years and older who underwent HDCT (etoposide 60 mg/kg+ melphalan 160 mg/m(2)) and ASCT at our institution from May 2001 to March 2008. The results were compared with a cohort of 157 younger HL patients treated in a similar manner from January 1999 to December 2006. After a median follow-up of 2.5 years, PFS at 3 years after ASCT was 73% (95% confidence interval (CI) 37-90) for the older group and 56% (95% CI 46-64) for the younger group (P=0.45); OS after ASCT was 88% (95% CI 39-98) for the older group and 84% (95% CI 75-90) for the younger group (P=0.80). No transplant-related deaths were seen. Our study suggests that ASCT is feasible for selected elderly patients with HL, giving similar results to younger patients in terms of survival and toxicity.

Disposition and toxicity of trabectedin (ET-743) in wild-type and mdr1 gene (P-gp) knock-out mice.

Trabectedin is a novel anticancer drug active against soft tissue sarcomas. Trabectedin is a substrate for P-glycoprotein (P-gp), which is encoded by mdr1a/1b in rodents. Plasma and tissue distribution, and excretion of [(14)C]-trabectedin were evaluated in wild-type and mdr1a/1b(-/-) mice. In parallel, we investigated the toxicity profile of trabectedin by serial measurements of blood liver enzymes and general pathology. [(14)C]-trabectedin was extensively distributed into tissues, and rapidly converted into a range of unknown metabolic products. The excretion of radioactivity was similar in both genotypes. The plasma clearance of unchanged trabectedin was not reduced when P-gp was absent, but organs under wild type circumstances protected by P-gp showed increased trabectedin concentrations in mdr1a/1b(-/-) mice. Although hepatic trabectedin concentrations were not increased when P-gp was absent, mdr1a/1b(-/-) mice experienced more severe liver toxicity. P-gp plays a role in the in vivo disposition and toxicology of trabectedin.

Predictors of mortality in patients undergoing autologous hematopoietic cell transplantation admitted to the intensive care unit.

Between January 2001 and July 2006, 1013 patients received autologous hematopoietic cell transplants (AHCT) at Canada's largest transplant center. In this retrospective cohort study of AHCT patients admitted to the intensive care unit (ICU), we describe the outcomes following ICU admission and the variables measured in the first 24 h of ICU admission associated with overall ICU mortality. Results indicate a 3.3% ICU admission rate (n=34) with 13 deaths (1% overall mortality rate, 38% in ICU mortality rate). The worst outcome was in AL amyloid patients of whom 28% were admitted to the ICU, with an ICU mortality rate of 55%. The Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE II) score in the first 24 h were statistically associated with mortality by univariate analysis. Other variables measured at 24 h and associated with ICU mortality included multiorgan failure, mechanical ventilation, inotropic support >4 h and Gram-negative sepsis. Our data indicate that ICU admission in the autotransplant population is rare and that it is influenced by underlying diagnosis, with AL amyloid patients having the highest risk. Our observations may assist clinical decision-making regarding the continuation of intensive care delivered 24 h after ICU admission.

G-CSF-stimulated BM progenitor cells supplement suboptimal peripheral blood hematopoietic progenitor cell collections for auto transplantation.

Peripheral blood hematopoietic progenitor cells (PBHC) are the standard source of support for high-dose chemotherapy because of faster recovery of marrow function. Unfortunately, a proportion of patients are unable to mobilize adequate progenitors to proceed to autologous hematopoietic cell transplant (AHCT). Granulocyte-CSF-stimulated BM-derived hematopoietic progenitor cells (BMHC) may circumvent this problem. From 1999 to 2006, 52 patients (cases) with AML, Hodgkin (HL) or non-Hodgkin's lymphoma (NHL) in whom PBHC mobilization failed underwent a G-CSF-stimulated bone marrow harvest and proceeded to AHCT. Their outcome was compared with 422 patients (controls) with AML, HL and NHL undergoing AHCT using only PBHC. Twenty-three patients received BMHC alone and 29 patients received a combination of PBHC and BMHC. Median engraftment time for neutrophils (>0.5 x 10(9)/l) and platelets (>20 x 10(9)/l) were 14 and 27 days, but significantly longer when compared with controls (11 days, 11 days, P<0.0001). Patients receiving both PBHC and BMHC had faster engraftment, when compared with those receiving BMHC alone (P<0.001). In conclusion, performing an AHCT using G-CSF-stimulated BMHC in patients failing PBHC collection is feasible with faster engraftment seen in patients receiving both BMHC and PBHC over BMHC alone.

Invasive pneumococcal disease in adult hematopoietic stem cell transplant recipients: a decade of prospective population-based surveillance.

Prospective population-based surveillance to assess the epidemiology of invasive pneumococcal disease (IPD) in hematopoietic stem cell transplant (HSCT) patients is limited and a comparison to the general population is lacking. By using a population-based Invasive Bacterial Diseases Network surveillance program, we studied the incidence, clinical significance, serotypes and antimicrobial resistance of IPD in a large cohort of adult HSCT patients and the general population. Streptococcus pneumoniae isolates and patient data were collected prospectively from 1995 to 2004. We identified 14 cases of IPD (based on sterile site isolates) in our HSCT population over a 10-year period. This translated to an incidence rate of 347 infections per 100 000 persons per year. This compared to an incidence of 11.5 per 100 000 persons per year in the general population (regression ratio=30.2; 95% confidence interval (CI) 17.8-50.8, P<0.00001). If nonsterile site isolates (respiratory tract) were included, the incidence rate in transplant patients was 446 per 100 000 persons per year. Serotypes 23F and 6B were most common; 100 and 69.2% of isolates were a serotype included in the pneumococcal polysaccharide and conjugate vaccines, respectively. The antimicrobial resistance rates were high, especially for trimethoprim/sulfamethoxazole. HSCT recipients are at significantly greater risk for IPD than the general population. Preventative strategies are necessary.

Beta-blockers do not impair the cardiovascular benefits of endurance training in hypertensives.

Aerobic physical exercise is broadly recommended as a helpful adjunct to obtain blood pressure control in hypertension. Beta-blockade interacts with heart rate, sympathetic tone, maximal workload and local lactate production. In the present randomized-controlled study, we compared the cardiovascular effects of an endurance training programme in elderly hypertensives with or without beta-blockers and developed a first approach to determine a lactate-based training heart rate in presence of beta-blockade. Fifty-two patients (23 with beta-blocker, 29 without beta-blocker) > or =60 years with systolic 24-h ambulatory blood pressure (ABP) > or =140 mm Hg and/or antihypertensive treatment were randomly assigned to sedentary activity or a heart-rate controlled 12-week treadmill exercise programme (lactate 2.0 mmol/l). In the exercise group, the training significantly decreased systolic and diastolic 24-h ABP, blood pressure on exertion (100 W) and increased endothelium-dependent vasodilation (flow-mediated vasodilation, FMD) and physical performance both in the presence and absence of beta-blockade (P<0.05 each). The extent of ABP reduction did not significantly differ in the presence or absence of beta-blockade (Delta systolic ABP 10.6+/-10.5 vs 10.6+/-8.8 mm Hg, Delta diastolic ABP 5.7+/-8.6 vs 5.8+/-4.0 mm Hg). Mean training heart rate was significantly lower in the patients on beta-blockers (97.2+/-7.7 vs 118.3+/-7.5/min, P<0.001). Lactate-based aerobic endurance training evokes comparable cardiovascular benefits in the presence and absence of beta-blockade including a marked improvement of endothelial function. In the present study, target training heart rate with beta-blockers is about 18% lower than without.

Autologous stem cell transplantation in primary systemic amyloidosis: the impact of selection criteria on outcome.

Autologous stem cell transplantation (ASCT) for primary systemic amyloidosis (AL) produces high hematologic and organ responses. However, treatment-related mortality remains high and reported series are subject to selection bias. In all, 48 of 80 amyloid patients referred to our center had AL in the absence of myeloma, 26 of these 48 were deemed transplant candidates and 20 actually underwent ASCT. Transplant-related mortality has fallen from 50 to 20% since January 1999 due to better patient selection and prophylactic measures. Intent-to-treat organ responses were renal (46%), cardiac (25%) and liver (50%). Organ responses in patients who survived transplantation were renal (75%), cardiac (40%) and liver (100%). The 3-year OS post-ASCT was 56% with improved outcome predicted by a better performance status (P=0.08), normal ALP (P=0.08), nephrotic syndrome (P=0.01) and the absence of severe hypotension (P=0.01). The 3-year OS for all referred patients was 44% and this was not significantly better for transplant candidates. Patients with significant hypotension (systolic blood pressure < or =90 mmHg) or poor performance status (ECOG >2) have an exceedingly high treatment-related mortality and should not be transplanted. For those undergoing ASCT, organ response rates appear promising, but conclusive evidence of improved survival for this select group of patients is still lacking and will require randomized trials.

Sequential changes in compliance and resistance after bolus administration or slow infusion of surfactant in preterm infants.

OBJECTIVE: As bolus instillation of surfactant can lead to acute pulmonary, hemodynamic and cerebral side effects, we tested whether pulmonary mechanics and gas exchange differ between slow surfactant infusion and bolus administration. DESIGN AND SETTING: Prospective, randomized pilot study in a tertiary care university hospital. PATIENTS AND METHODS: Of 20 consecutive preterm infants (27-35 weeks' gestation) with severe respiratory distress syndrome) who were enrolled 14 with bovine surfactant finally were analyzed. INTERVENTIONS: Six treatments were administered by slow endotracheal surfactant infusion and eight as a bolus. Static compliance (C(stat)) and resistance (R(rs)) were measured every 3 min. RESULTS: C(stat) first decreased and then increased in both groups. In the infusion group C(stat) after 90 min was significantly higher than after bolus treatment but not after 15 or 45 min. R(rs) increased about threefold, with large fluctuations in the bolus group. After 90 min PaO(2)/FIO(2) had increased from 111+/-44 to 254+/-69 in the bolus group and from 86+/-40 to 238+/-102 in the infusion group, but early FIO(2) reduction and increase in PaO(2)/FIO(2) seemed delayed in the infusion group. CONCLUSIONS: Very slow infusion of natural surfactant is at least as effective as bolus instillation in terms of improvement in C(stat) and oxygenation after 90 min. However, until 90 min the course of C(stat) and indices of gas exchange seem superior after bolus therapy. Because R(rs) is substantially increased, long expiratory times are required to yield complete exhalation.

Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy.

Limb girdle muscular dystrophy is a group of clinically and genetically heterogeneous disorders inherited in an autosomal recessive or dominant mode. Caveolin-3, the muscle-specific member of the caveolin gene family, is implicated in the pathogenesis of autosomal dominant limb girdle muscular dystrophy 1C. Here we report on a 4-year-old girl presenting with myalgia and muscle cramps due to a caveolin-3 deficiency in her dystrophic skeletal muscle as a result of a heterozygous 136G-->A substitution in the caveolin-3 gene. The novel sporadic missense mutation in the caveolin signature sequence of the caveolin-3 gene changes an alanine to a threonine (A46T) and prevents the localization of caveolin-3 to the plasma membrane in a dominant negative fashion. Caveolin-3 has been suggested to interact with the dystrophin-glycoprotein complex, which in striated muscle fibers links the cytoskeleton to the extracellular matrix and with neuronal nitric oxide synthase. Similar to dystrophin-deficient Duchenne muscular dystrophy, a secondary decrease in neuronal nitric oxide synthase and alpha-dystroglycan expression was detected in the caveolin-3-deficient patient. These results implicate an important function of the caveolin signature sequence and common mechanisms in the pathogenesis of dystrophin-glycoprotein complex-associated muscular dystrophies with caveolin-3-deficient limb girdle muscular dystrophy.

Selective alterations in natural killer cell subsets in patients with atopic dermatitis.

We examined the immunophenotypic characteristics of natural killer (NK) cell subsets in patients with severe atopic dermatitis (AD), rhinitis allergica (RA) and in healthy controls. Expression of CD16, CD56 and CD57 antigens on peripheral blood lymphocytes was evaluated by simultaneous double immunocytofluorometry. Our results showed significantly lower percentages of cells with CD16, CD56 and CD57 surface antigens in patients with AD. Furthermore subdivision of the AD group into two subgroups, AD1 and AD0 (with and without antigen-specific IgE antibodies against potent inhalative allergens, i.e. mite, grass, rye, birch, cat) revealed that patients of subgroup AD1 showed a more prominent decrease compared to that of subgroup AD0. Moreover, we found a significant negative correlation between the percentage of CD56 + CD16 + NK cells and total IgE levels in serum, which were significantly higher in patients of subgroup AD1 than in AD0. NK cell activity was deficient in patients with AD but there was no difference between both subgroups. These data indicate that considerable heterogeneity in immunologic regulation may exist in patients with AD with regard to their NK cell subsets.

Combined therapy of xenografts of human pancreatic carcinomas with rTNF-alpha and mitomycin C.

Based on previously published experimental studies in nude mice indicating that rTNF-alpha as well as mitomycin C are able to induce significant growth inhibition of xenotransplants of gastrointestinal and pancreatic carcinomas we have investigated the antitumor effects of rTNF-alpha (0.8 mg/kg daily for 21 days) and mitomycin C (2.4 mg/kg once weekly, day 1, 7, 14) as single drugs and in combination (0.8 + 2.4) in nude mice bearing xenografts of 4 human pancreatic carcinomas and 1 colorectal cancer. Serum CA 19-9 was measured additionally to tumor growth rate. The results demonstrate that combined treatment is more effective compared to rTNF-alpha and mitomycin C alone. Combined therapy resulted in a significant inhibition of tumor growth in 3 of 5 xenografts and in decrease of tumor volume to less than 50% of the initial values in 2 of 5 tumors. The results support the concept that combinations of cytokines with cytostatics might be of value for treatment of gastrointestinal and pancreatic cancer in vivo.

Cytokines and pancreatic cancer. Sensitivity of xenotransplants of predominantly pancreatic carcinomas to rIFN-gamma and rTFN-alpha in nude mice.

Ten xenotransplants of human gastrointestinal carcinomas (eight human pancreatic carcinomas) were assayed for their sensitivity to human rIFN-gamma and human rTNF-alpha in nude mice. Both substances demonstrated a dose and route dependent antitumoral activity in principle. However, the extent of response varied distinctly between the tested xenografts. rTNF-alpha was clearly superior to rIFN-gamma at systemic application of comparable doses (0.8 mg/kg/d). Intramural administration of both cytokines could cause cytotoxic effects and was significantly more effective than systemic administration that predominantly resulted in antiproliferation. Growth inhibition of rIFN-gamma or rTNF-alpha alone could be clearly enhanced by combining both cytokines. In addition, the results suggest: the possibility to enhance the effects of rIFN-gamma alone also by combination with nIL 2, as well as a decrease of the effects of rTNF-alpha with time of therapy.

[The computer as an aid in attention training--a clinico-experimental study]. / Der Computer als Hilfe beim Aufmerksamkeitstraining--Eine klinisch-experimentelle Studie.

Reported is the evaluation of a computer-directed training programme for visual attention, that is based on the results of experimental studies by Zubin (1975) and Shakow (1979). With reference to Zubin's model, this training programme addresses active maintenance of selective visual attention (in terms of "sustained attention"), applying Shakow's diagnostic research paradigm (with a preparatory stimulus, an RT stimulus, and a variable preparatory interval) in a behavioural setting (learning of strategies for attention) for clinical purposes. In a pre-post-study carried out for a three-week programme, the results of single case experiments showed a significant decrease of reaction time variability, which partly persisted in follow-up studies. It was found that attentional performance increased in both psychotic patients and patients with cerebral dysfunction. In the second phase of statistical validation on patients with psychotic attention deviations, both attention performance and transfer effects were verified. The behavioural training methods, which were implemented to foster attention, proved helpful in the majority of cases. For greater practicability, a programme version for use on the home computer has been developed. The study on the whole illustrates the growing utilization of computer technology in neuropsychological rehabilitation.