Treatment and outcome in metastatic lobular breast cancer in the prospective German research platform OPAL.

PURPOSE: Evidence about routine treatment and outcome of patients with invasive lobular cancer (ILC) is limited, especially regarding metastatic disease. Here we present prospective real-world data of patients with metastatic ILC (mILC) as compared to patients with metastatic invasive ductal cancer (mIDC) receiving systemic therapy in routine care in Germany. METHODS: Prospective data on patient and tumor characteristics, treatments, and outcomes of patients with mILC (n = 466) and mIDC (n = 2100), recruited between 2007 and 2021 into the Tumor Registry Breast Cancer/OPAL were analyzed. RESULTS: Compared to mIDCs, patients with mILC were older at start of first-line treatment (median 69 vs. 63 years) and had more often lower grade (G1/G2: 72.8% vs. 51.2%), hormone receptor (HR)-positive (83.7% vs. 73.2%) and less often HER2-positive (14.2% vs. 28.6%) tumors, which metastasized more frequently to the bone (19.7% vs. 14.5%) or peritoneum (9.9% vs. 2.0%), and less frequently to the lungs (0.9% vs. 4.0%). Median OS of patients with mILC (n = 209) and mIDC (n = 1158) was 30.2 months [95% confidence interval (CI) 25.3, 36.0] and 33.7 months [95% CI 30.3, 37.9], respectively. Multivariate survival analysis did not show a significant prognostic impact of the histological subtype [HR mILC vs. mIDC 1.18 (95% CI 0.97-1.42)]. CONCLUSION: Overall, our real-world data confirm clinicopathological differences between mILC and mIDC breast cancer patients. Despite patients with mILC presenting with some favorable prognostic factors, ILC histopathology was not associated with a better clinical outcome in multivariate analysis, suggesting the need for more tailored treatment strategies for patients with the lobular subtype.

A multicentre, randomised, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer (DESIREE).

BACKGROUND: Stomatitis is one of the main reasons to discontinue everolimus in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). To decrease stomatitis and subsequently early treatment discontinuations or dose reductions, the DESIREE trial investigated the use of a stepwise dose-escalation schedule of everolimus (EVE esc). PATIENTS AND METHODS: DESIREE is a phase II, multicentre, randomised, double-blind, placebo-controlled trial in patients with HR+/HER2- mBC and progression/relapse after nonsteroidal aromatase inhibitor treatment. Patients were randomised to EVE esc (2.5 mg/day, week 1; 5 mg/day, week 2; 7.5 mg/day, week 3; 10 mg/day, weeks 4-24) or everolimus 10 mg/day (EVE 10mg) for 24 weeks plus exemestane. The primary endpoint was the incidence of stomatitis episodes grade ≥2 within 12 weeks of treatment. The secondary endpoints included toxicity, relative total dose intensity (RTDI) and quality of life (QoL). RESULTS: A total of 160 patients were randomised and 156 started treatment (EVE esc: 80; EVE 10mg: 76). The median age of patients was 64 years (range 33-85), 56.3% patients in the EVE esc arm versus 42.1% in the EVE 10mg arm had liver metastasis (P = 0.081) and 62.5% versus 51.3% received over one metastatic therapy line (P = 0.196). Within 12 weeks, the incidence of stomatitis episodes grade ≥2 was significantly lower in the EVE esc arm compared with the EVE 10mg arm (28.8% versus 46.1%; odds ratio 0.47, 95% confidence interval 0.24-0.92; P = 0.026). Toxicity was in line with the known safety profile without new safety concerns. The median RTDI was 91.1% in the EVE esc arm versus 80.0% in the EVE 10mg arm (P = 0.329). Discontinuation rate in the first 3 weeks was 6.3% versus 15.8%, respectively (P = 0.073). QoL was comparable between the two treatment arms. CONCLUSIONS: A dose-escalation schema of everolimus over 3 weeks can be successfully used to reduce the incidence of high-grade stomatitis in the first 12 weeks of treatment in patients with HR+/HER2- mBC. TRIAL REGISTRATION: ClinicalTrials.govNCT02387099; https://clinicaltrials.gov/ct2/show/NCT02387099.

[Investigation of the practical use of a vaccination device ("Pullet Vaccinator") for young layers]. / Untersuchungen zum Einsatz des Impfautomaten "Pullet Vaccinator" in der Junghennenaufzucht.

OBJECTIVE: To evaluate the safety of layer vaccination of the vaccination device "Pullet Vaccinator", its publicised increased operational safety and the practicality of the device using serological monitoring of the vaccination success. MATERIALS AND METHODS: In a first trial, two veterinarians experienced in the syringe method vaccinated hens using the syringe and the vaccination device, respectively. After 1 hour, the equipment was switched and both veterinarians continued to vaccinate for a further hour. The second trial proceeded as in the first trial, except with untrained persons. For each of the four vaccination groups (experienced/syringe; experienced/device; untrained/syringe; untrained/device), the number of vaccinated hens was counted and 20 hens were dissected from each group to compare the impact of both inoculation methods on the animals. To monitor vaccination success, blood was collected for serological screening. On the final blood collection day, further hens per group were dissected to evaluate possible long-term injuries. RESULTS: The vaccination device offers greater occupational safety compared to the syringe method. Vaccination injuries to the hens' breast muscles were more pronounced with the syringe application. For experienced persons, the number of vaccinated animals per hour was approximately doubled using the syringe compared to the device. For the untrained, a comparable number of vaccinated animals was recorded for both methods. Serological monitoring did not show any significant differences in antibody response to the vaccination between both methods. CONCLUSION AND CLINICAL RELEVANCE: In certain points, the device proved technically imperfect and should be revised for improved use in the field.

Simulating Magnetic Nanoparticle Behavior in Low-field MRI under Transverse Rotating Fields and Imposed Fluid Flow.

In the presence of alternating-sinusoidal or rotating magnetic fields, magnetic nanoparticles will act to realign their magnetic moment with the applied magnetic field. The realignment is characterized by the nanoparticle's time constant, τ. As the magnetic field frequency is increased, the nanoparticle's magnetic moment lags the applied magnetic field at a constant angle for a given frequency, Ω, in rad/s. Associated with this misalignment is a power dissipation that increases the bulk magnetic fluid's temperature which has been utilized as a method of magnetic nanoparticle hyperthermia, particularly suited for cancer in low-perfusion tissue (e.g., breast) where temperature increases of between 4°C and 7°C above the ambient in vivo temperature cause tumor hyperthermia. This work examines the rise in the magnetic fluid's temperature in the MRI environment which is characterized by a large DC field, B(0). Theoretical analysis and simulation is used to predict the effect of both alternating-sinusoidal and rotating magnetic fields transverse to B(0). Results are presented for the expected temperature increase in small tumors (~1 cm radius) over an appropriate range of magnetic fluid concentrations (0.002 to 0.01 solid volume fraction) and nanoparticle radii (1 to 10 nm). The results indicate that significant heating can take place, even in low-field MRI systems where magnetic fluid saturation is not significant, with careful The goal of this work is to examine, by means of analysis and simulation, the concept of interactive fluid magnetization using the dynamic behavior of superparamagnetic iron oxide nanoparticle suspensions in the MRI environment. In addition to the usual magnetic fields associated with MRI, a rotating magnetic field is applied transverse to the main B(0) field of the MRI. Additional or modified magnetic fields have been previously proposed for hyperthermia and targeted drug delivery within MRI. Analytical predictions and numerical simulations of the transverse rotating magnetic field in the presence of B(0) are investigated to demonstrate the effect of Ω, the rotating field frequency, and the magnetic field amplitude on the fluid suspension magnetization. The transverse magnetization due to the rotating transverse field shows strong dependence on the characteristic time constant of the fluid suspension, τ. The analysis shows that as the rotating field frequency increases so that Ωτ approaches unity, the transverse fluid magnetization vector is significantly non-aligned with the applied rotating field and the magnetization's magnitude is a strong function of the field frequency. In this frequency range, the fluid's transverse magnetization is controlled by the applied field which is determined by the operator. The phenomenon, which is due to the physical rotation of the magnetic nanoparticles in the suspension, is demonstrated analytically when the nanoparticles are present in high concentrations (1 to 3% solid volume fractions) more typical of hyperthermia rather than in clinical imaging applications, and in low MRI field strengths (such as open MRI systems), where the magnetic nanoparticles are not magnetically saturated. The effect of imposed Poiseuille flow in a planar channel geometry and changing nanoparticle concentration is examined. The work represents the first known attempt to analyze the dynamic behavior of magnetic nanoparticles in the MRI environment including the effects of the magnetic nanoparticle spin-velocity. It is shown that the magnitude of the transverse magnetization is a strong function of the rotating transverse field frequency. Interactive fluid magnetization effects are predicted due to non-uniform fluid magnetization in planar Poiseuille flow with high nanoparticle concentrations.

Heating in the MRI environment due to superparamagnetic fluid suspensions in a rotating magnetic field.

In the presence of alternating-sinusoidal or rotating magnetic fields, magnetic nanoparticles will act to realign their magnetic moment with the applied magnetic field. The realignment is characterized by the nanoparticle's time constant, τ. As the magnetic field frequency is increased, the nanoparticle's magnetic moment lags the applied magnetic field at a constant angle for a given frequency, Ω, in rad/s. Associated with this misalignment is a power dissipation that increases the bulk magnetic fluid's temperature which has been utilized as a method of magnetic nanoparticle hyperthermia, particularly suited for cancer in low-perfusion tissue (e.g., breast) where temperature increases of between 4°C and 7°C above the ambient in vivo temperature cause tumor hyperthermia. This work examines the rise in the magnetic fluid's temperature in the MRI environment which is characterized by a large DC field, B(0). Theoretical analysis and simulation is used to predict the effect of both alternating-sinusoidal and rotating magnetic fields transverse to B(0). Results are presented for the expected temperature increase in small tumors (~1 cm radius) over an appropriate range of magnetic fluid concentrations (0.002 to 0.01 solid volume fraction) and nanoparticle radii (1 to 10 nm). The results indicate that significant heating can take place, even in low-field MRI systems where magnetic fluid saturation is not significant, with careful selection of the rotating or sinusoidal field parameters (field frequency and amplitude). The work indicates that it may be feasible to combine low-field MRI with a magnetic hyperthermia system using superparamagnetic iron oxide nanoparticles.

Diagnosis of acute pulmonary histoplasmosis by antigen detection.

BACKGROUND: Antigen detection, which has proven useful in diagnosis of disseminated histoplasmosis, has not been studied in acute pulmonary histoplasmosis (APH). Because treatment is indicated in most patients with moderately severe or severe APH, antigen detection for rapid diagnosis could be helpful. METHODS: Histoplasma antigen detection was evaluated in 130 patients with APH. RESULTS: Antigenuria was detected in 64.6%, antigenemia in 68.6%, and antibody in 64.3%. If both urine and serum specimens were tested, antigen was detected in 82.8%, of which 45.8% had antigenemia only; and if both antigen and antibody were measured, results were positive in 93.3%, of which antigen only was positive in 35.7%. CONCLUSIONS: Testing for antigenemia, antigenuria, and antibodies using the complement fixation test offers a sensitive, noninvasive method for diagnosis of APH.

Reduced complications during hemodialysis by automatic blood volume controlled ultrafiltration.

BACKGROUND: Intradialytic morbid events (IMEs, mostly hypotension) are frequent complications during hemodialysis (HD). This study investigated whether automatic feedback control via adjustment of the ultrafiltration rate reduces IME frequency. METHODS: In this multi-center cross-over study, 56 hypotension-prone patients were treated both with standard HD (sHD, applying a constant ultrafiltration rate) and HD applying a blood volume controlled ultrafiltration rate (cHD). The relative blood volume (RBV) was continuously monitored. The individual relative blood volume limit (RBVcrit ) was determined from the measured RBV during initial sHD. During cHD, the ultrafiltration rate was automatically adjusted to keep the actual RBV above RBVcrit. RESULTS: In 3,081 HD treatments, slightly fewer IMEs were observed during cHD than during sHD (0.785+/-0.613 versus 0.695+/-0.547 per treatment, P=0.144). Less symptomatic events were seen during cHD: -13% for symptomatic hypotension (0.594 versus 0.685 per treatment, P=0.120), and -32% for cramps (0.049 versus 0.072 per treatment, P=0.009). Thirty-one patients with the highest IME rate (IME in at least every second treatment) especially benefited from cHD: 1.185+/-0.554 versus 0.979+/-0.543 IME per treatment (P=0.004). The reduction in blood pressure (BP) and the increase in heart rate were lower during the treatments with cHD than with sHD: systolic BP: -18.8+/-26.7 versus -22.2+/-28.9 mmHg (P=0.007), diastolic BP: -7.8+/-14.8 versus -9.1+/-15.3 mmHg (P=0.064), heart rate: 1.8+/-10.4 versus 2.3+/-11.6 per minute (P=0.014). Neither treatment duration nor ultrafiltration volume was significantly different between cHD and sHD. CONCLUSION: For cHD, less intradialytic morbid events were observed than for sHD, and pre- to post-dialytic changes in blood pressure and heart rate were less pronounced.

Bulk flow in ferrofluids in a uniform rotating magnetic field.

Direct measurements of the bulk flow of a ferrofluid in a uniform rotating magnetic field were obtained using the ultrasonic velocity profile method. The fluid was observed to corotate with the field in a rigid-body-like fashion throughout the bulk of the container, except near the air-fluid interface, where it was observed to counterrotate. The results were found in qualitative agreement with the spin diffusion theory of Zaitsev and Shliomis [J. Appl. Mech. Tech. Phys. 10, 696 (1969)]10.1007/BF00907424.

Thrombin as a survival factor for cancer cells: thrombin activation in malignant effusions in vivo and inhibition of idarubicin-induced cell death in vitro.

OBJECTIVES: The aim of the experiments shown here, is to demonstrate exemplarily that thrombin can be a survival factor for malignant cells. METHODS: Activation of the coagulation system has been examined in patients with acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NHL) before and after chemotherapy as well as in malignant effusions of heavily pretreated patients with solid tumors. Thrombin receptor expression (PAR-I) has been examined on HL-60 cells; the effect ofthrombin on the proliferation of the cells and inhibition of apoptosis induction by idarubicin has been shown. RESULTS: Using fibrinopeptide A as an indirect parameter for thrombin activation, we found elevated levels in patients with AML and NHL before and a significant 2-fold increase after chemotherapy (p < 0.02 for the AML group; p < 0.0006 for the NHL group). Apparently, this does not only affect patients with hematological diseases, but also with solid tumors. In order to find out if the tumor cells directly activate thrombin, we examined malignant effusions of patients with different solid tumors. Comparing prothrombin fragment 1 + 2 in ascites and pleural effusions with the patients' serum levels, we found it significantly increased in all cases (mean of 1.96 +/- 0.5 nmol/l in the serum vs. 12.1 +/- 3.6 nmol/l in effusions; p < 0.001). The majority of patients presented elevated serum levels. Additionally, we incubated HL-60 cells (human promyelocytic leukemia) with thrombin prior to treatment with idarubicin. Expression of thrombin receptor (PAR-1) could be verified by FACS-analysis using a monoclonal antibody. HL-60 cells responded with increased proliferation to thrombin exposure with concentrations between 0.3 and 3 U/ml. This effect could be abolished by the addition of hirudin, demonstrating thrombin specificity. In these concentrations, thrombin was able to abrogate the induction of apoptosis by idarubicin completely (p < 0.005). CONCLUSIONS: Here we give evidence for the role of thrombin as a resistance factor for tumor cells towards chemotherapy. In the light of the fact that thrombin is regularly activated in cancer patients, these findings indicate that thrombin is a clinically relevant cellular resistance factor. A number of pre-clinical and clinical studies imply that inhibition of the coagulation system, e.g. by low-molecular weight heparins or warfarin, increases the effect of chemotherapy.

Fluorimetric multiparameter cell assay at the single cell level fabricated by optical tweezers.

A fluorimetric multi-parameter cell sensor at the single cell level is presented which makes it possible to observe the physiological behavior of different cell lines, different physiological parameters, and statistical data at the same time. Different cell types were immobilized at predefined positions with high accuracy using optical tweezers and adhesion promoting surface layers. The process is applicable to both adherent and non-adherent cells. Coating of the immobilization area with mussel adhesive protein was shown to be essential for the process. Intracellular proton and calcium concentrations in different cell classes were simultaneously imaged and the specific activation of T lymphocytes was demonstrated. This method should be especially useful for drug screening due to the small sample volume and high information density.

Optical tweezers in pharmacology.

Current applications of optical tweezers in pharmacology are presented. The manufacture of cellular biosensor arrays employing optical tweezers is reviewed. Using this technique, a new approach to cellular drug screening, based on single cells patterned with the laser tweezers was introduced. Specific stimulation of different immobilized, viable cells could be shown simultaneously. Furthermore, the usefulness of optical tweezers for analyzing the interactions of ligands with cellular membrane receptors is demonstrated. The laser tweezers could successfully be used to compare neuron interactions with glycoproteins of the extracellular matrix by applying the optical tweezers as picotensometer. The forces of interactions between polystyrene beads coated with different proteins of the extracellular matrix and the cell membrane receptors of cerebellar neurons from postnatal day 6 (P6) mice were measured. When antibodies to the extracellular matrix proteins were added, forces were significantly reduced for the corresponding antigens but not for the other glycoproteins. This proved the specificity of the measured interactions. Information regarding the receptor anchorage of tenascin-C could be deduced.

Purification and N-terminal sequence of beta-trace, a protein abundant in human cerebrospinal fluid.

beta-Trace, a protein that represents a major constituent of human cerebrospinal fluid with unknown function has been purified to apparent homogeneity by gel chromatography and electrophoresis. After sodium dodecylsulfate electrophoresis on polyacrylamide gels (SDS-PAGE) and Western blotting, the N-terminal sequence (28 amino acids) has been determined. The high degree of identity with the corresponding sequences of prostaglandin D synthetase from rat (68%) and human (93%) suggests a strong relationship if not identity with this enzyme. Thus, 30 years after its discovery beta-trace might unravel as a well-known protein of the prostaglandin metabolism.

Lateral retinacular release of the patella.

From October 1977 through January 1984, 2,330 arthroscopic procedures of the knee were performed by one of the authors (G.J.S.). Among these procedures, 35 lateral retinacular releases were performed through minimal, lateral incisions. Twenty-two knees in 22 patients were available for follow-up evaluation, and these cases were reviewed retrospectively. The average age of the patients at the time of surgery was 22.6 years. The average follow-up period was 48 months. The patients were divided into three subgroups on the basis of their preoperative diagnosis. Group I (eight knees) had a history of patellar dislocations; group II (seven knees) had recurrent patellar subluxation, identified by history and physical and radiographic examinations; and group III (seven knees) had patellar pain without a history of dislocations or subluxation and with no symptoms of instability. All of these patients underwent diagnostic arthroscopy and lateral retinacular release, as well as arthroscopic treatment of associated pathology. Postoperatively and at the time of followup, all patients were evaluated for pain, function and patellar instability. In 15 patients with a history of patellar dislocation or subluxation, 67% were found to have had significant improvement in their symptoms, which was borne out by the findings during physical examination. None was worse following treatment. Among the seven patients with no history of patellar dislocation or subluxation, only one of the seven had a satisfactory result. Based upon the findings of this study, it was concluded that arthroscopic lateral retinacular release is a reasonable, initial step in the surgical treatment of patellar dislocation or subluxation, resistant to conservative treatment. Its efficacy in cases of recalcitrant patellar pain without a history of instability is doubtful.

Role of bone grafting in correction of protrusio acetabuli by total hip arthroplasty.

A study of 27 hip arthroplasties derived from a pool of more than 200 total hip arthroplasties performed between 1976 and 1981 was conducted to assess the need for and benefits of bone grafting in the surgical management of protrusio acetabuli. The objective of surgery and the reason for augmentation by bone graft was to lateralize the acetabular component, normalize the center of rotation of the hip, and strengthen the deficient medial wall. Based on this study, the authors recommend: when protrusion is less than 5 mm in either direction and the medial wall is reasonably strong, bone graft is not indicated; in protrusion greater than 5 mm with a thin but intact medial wall, autogenous bone graft is indicated but artificial fixation devices need not be used; and a grossly deficient medial wall requires reconstruction with bone graft and additional fixation devices to achieve normalization of the center of rotation of the hip joint.

Circulating immune complexes in cancer patients receiving goat radiolocalizing antibodies to carcinoembryonic antigen.

The circulating radioactivity and antibody immunoreactivity in patients with diverse cancers who had received 131I-labeled goat antibodies to carcinoembryonic antigen (CEA) were studied by Sephadex G-200 column chromatography and with solid-phase (SP) immunoadsorbents containing anti-goat immunoglobulin G(IgG), anti-human IgG, anti-CEA, or CEA. Upon gel filtration, more than 80% of the plasma radioactivity was distributed between native IgG and an excluded macromolecular radioactive fraction (Pool I). The native IgG and Pool I radioactive peaks were immunoreactive with the SP anti-goat IgG and SP CEA to the same extent as was the radioantibody prior to injection. The circulating CEA in patients with elevated titers only partially bound the injected radioantibody since less than 50% of the latter chromatographed as Pool I. Up to 50% of the Pool I radioantibody from this group of patients was bound to the SP anti-CEA, whereas it was minimally reactive with the SP anti-human IgG. The clearance of radioantibody was similar between groups having different amounts of Pool I radioantibody, and injection of CEA radioantibody was not accompanied by a decrease in circulating antigen. Patients with lower CEA titers had the majority of the plasma radioactivity chromatographing as Pool I radioantibody which showed elevated binding to the SP anti-human IgG but not the SP anti-CEA. Tumor localization by photoscanning was observed in seven of eight and nine of nine patients who had circulating CEA-radioantibody and anti-immunoglobulin-radioantibody complexes, respectively. Thus, these studies demonstrate that CEA, as well as human antibody reactive with goat IgG, can form immune complexes in patients given injections of CEA radiolocalizing antibody. However, these complexes do not appear to prevent tumor radioimmunodetection.