The role of radiation therapy in Hodgkin disease: experience and controversy. The 54th annual Janeway Lecture: 1989.

BACKGROUND. Beginning in 1970, a series of patients with Hodgkin disease were treated at the University of Minnesota, after staging laparotomy, with radiation therapy (RT) for Stage I, II, and IIIA Hodgkin disease. This report is an analysis of the results of the treatment and of treatment modifications. METHODS. From 1970 to 1974, all patients were treated with standard RT. In 1975, an analysis of these patients indicated that patients with large mediastinal mass (LMM) and patients with Stage IIIA spleen-positive (IIIAS+) disease had a higher recurrence rates than patients without these factors. Subsequently, a schema of radical radiation therapy (RRT) was devised, which included low-dose lung RT for patients with LMM and low-dose liver RT for patients with IIIAS+ disease. RESULTS. Analysis of the results of the two treatments indicates that the use of low-dose lung RT in patients with LMM and low-dose liver RT in patients with IIIAS+ Hodgkin disease produced survival and recurrence-free survival results equivalent to those achieved by use of combined modality treatment (CMT) or chemotherapy (CT) alone. CONCLUSIONS. The use of RT with whole lung and liver irradiation for patients with LMM and IIIAS+ Hodgkin disease, respectively, produces results that are equivalent to those of CMT or CT alone with the advantage of a decreased incidence of second malignant neoplasms. In addition, patients who do not respond to initial RT have a greater chance of being saved with chemotherapy than do patients initially treated with CMT of being saved with RT. The authors suggest that radical RT is the treatment of choice for patients with LMM and/or IIIAS+ Hodgkin disease.     

Failure to find a relationship between mnestic skills of octogenarians and aluminum in drinking water

Summary High concentrations of aluminum (>80 g/l) in drinking water have been related to an elevated incidence of Alzheimer's disease. Mnestic and naming skills of residents living for >15 years in districts with high (98 g/l) or low (4 g/l) aluminum concentrations [Al] in the drinking water were evaluated in a population survey by examining 800 residents aged 81 to 85 using the mnestic subtest of the Mini Mental Status test (Zurich variant). The mnestic and naming performance of the octogenarians did not differ between the high- and low-content-areas. Since 73% of dementias are at least partly caused by Alzheimer's disease in the area examined and because the short test used discriminates demented from healthy octagenarians as well as tests involving extensive examinations, the findings of this study suggest with a high probability that the [Al] of drinking water is not an essential factor in the pathogenesis of senile dementia. The serum [Al] the urinary [Al] and the urinary [Al]/creatinine ratio were measured twice in ten clinically diagnosed Alzheimer patients and ten controls in both areas. No significant difference was found, which confirms the negative epidemiological findings.Parts of this study were presented at the joint meeting of the Swedish and Swiss Neurological Association in Interlaken, Switzerland, on May 22, 1990     

Managing the Impact of Immunogenicity in an Era of Immunotherapy: From Bench to Bedside

Biotherapeutics have revolutionized our ability to treat life-threatening diseases. Despite clinical success, the use of biotherapeutics has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs). The multifactorial nature of immunogenicity has prevented a standardized approach for assessing this and each of the assessment methods developed so far does not exhibit high enough reliability to be used alone, due to limited predictiveness. This prompted the Roche Pharma Research and Early Development (pRED) Immunogenicity Working Group to establish an internal preclinical immunogenicity toolbox of in vitro/in vivo approaches and accompanying guidelines for a harmonized assessment and management of immunogenicity in early development. In this article, the complex factors influencing immunogenicity and their associated clinical ramifications are discussed to highlight the importance of an end-to-end approach conducted from lead optimization to clinical candidate selection. We then examine the impact of the resulting lead candidate categorization on the design and implementation of a multi-tiered ADA/immunogenicity assay strategy prior to phase I (entry into human) through early clinical development. Ultimately, the Immunogenicity Toolbox ensures that Roche pRED teams are equipped to address immunogenicity in a standardized manner, paving the way for lifesaving products with improved safety and efficacy.     

Switchable hardening of a ferromagnet at fixed temperature

The intended use of a magnetic material, from information storage to power conversion, depends crucially on its domain structure, traditionally crafted during materials synthesis. By contrast, we show that an external magnetic field, applied transverse to the preferred magnetization of a model disordered uniaxial ferromagnet, is an isothermal regulator of domain pinning. At elevated temperatures, near the transition into the paramagnet, modest transverse fields increase the pinning, stabilize the domain structure, and harden the magnet, until a point where the field induces quantum tunneling of the domain walls and softens the magnet. At low temperatures, tunneling completely dominates the domain dynamics and provides an interpretation of the quantum phase transition in highly disordered magnets as a localization/delocalization transition for domain walls. While the energy scales of the rare earth ferromagnet studied here restrict the effects to cryogenic temperatures, the principles discovered are general and should be applicable to existing classes of highly anisotropic ferromagnets with ordering at room temperature or above.     

Radiation dosimetry in specific area radiography

An improved head-and-neck phantom was constructed from a human skull, cervical vertebrae, and Mix D, a mixture of wax, plastic, and metal oxides with x-ray absorbing and scattering properties similar to water and soft tissues. Lithium fluoride thermoluminescent dosimeters were calibrated and then exposed within the phantom. The doses at 17 anatomic sites were calculated for each of the 18 specific area radiographs in a complete intraoral radiographic survey.     

Can late survival of patients with moderate ischemic mitral regurgitation be impacted by intervention on the valve?

BACKGROUND: Ischemic mitral regurgitation is known to be associated with poor long-term outcome after coronary artery bypass grafting; however, our ability to alter that outcome with intervention on the valve is unclear. The decision to address the valve is most challenging for patients with only moderate mitral regurgitation, particularly with the popularization of off-pump surgery. We therefore reviewed early and late outcomes of patients undergoing revascularization with or without mitral valve surgery. METHODS: Patients with moderate mitral regurgitation undergoing revascularization with and without mitral surgery between January 1991 and September 1996 were identified retrospectively. Operative notes were reviewed and patients with structural valve disease excluded. Perioperative events and late outcomes as determined by telephone contact and search of the social security death index (survival data 97% complete) were compared. RESULTS: One hundred seventy-six patients with moderate mitral regurgitation underwent revascularization alone (n = 142) or with mitral repair or replacement (n = 34). Those undergoing revascularization alone had a higher serum creatinine, somewhat less mitral regurgitation, and lower New York Heart Association functional class preoperatively. Operative mortality was greater with valve surgery (21% vs 9%, p = 0.047). Actuarial survival of both groups at 5 years was similar (52% vs 58%, p = NS); however, when stratified by preoperative functional class, those with more advanced heart failure preoperatively had superior late survival if their mitral valve was intervened upon. CONCLUSIONS: The late survival of patients with ischemic mitral regurgitation undergoing coronary revascularization remains poor; however, intervention on the mitral valve appears to benefit those with symptomatic heart failure.     

IgG2/IgG4 subclass deficiency in a patient with chronic mucocutaneous candidiasis and bronchiectases

A 22-year-old man with chronic mucocutaneous candidiasis (CMC) and hypothyroidism developed severe bronchiectases following recurrent bronchopneumonia. Immunological investigations revealed IgG₂/IgG₄ subclass deficiency and absence of antibodies against pneumococcal and Haemophilus polysaccharides. Under regular immunoglobulin substitution every 3 weeks pulmonary symptoms improved markedly.     

Assessment of the bioactivity of antibodies against beta-amyloid peptide in vitro and in vivo

The accumulation of the beta-amyloid peptide (Abeta) is a central event in the pathogenesis of Alzheimer's disease (AD). Abeta removal from the brain by immune therapy shows promising potential for the treatment of patients with AD, although the mechanisms of the antibody action are incompletely understood. In this study we compared the biological activities of antibodies raised against various Abeta fragments for Abeta reduction in vitro and in vivo. Antibodies against Abeta enhanced the uptake of Abeta42 aggregates up to 6-fold by primary microglial cells in vitro. The kinetics of Abeta42 uptake varied considerably among antibodies. Based on the activity to mediate Abeta42 uptake by microglial cells, we identified a bioactive antibody that significantly reduced Abeta42 levels in the brains of transgenic mice with neuronal expression of an AD-related mutated amyloid precursor protein. This effect depended on the epitopes recognized by the antibody. Our data suggest that the ability to facilitate Abeta42 uptake by primary microglia cells in vitro can be used to predict the biological activity of the antibody by passive immunization in vivo. This protocol may prove useful for the rapid validation of the activity of antibodies designed to be used in immune therapy of AD.