Thoracic wall involvement by Hodgkin disease and non-Hodgkin lymphoma: CT evaluation

Thoracic computed tomographic (CT) scans of 250 patients with newly diagnosed or recurrent lymphoma revealed thoracic wall involvement in 24 patients (11 with Hodgkin disease, 13 with non-Hodgkin lymphoma). Thoracic wall involvement occurred without contiguous mediastinal or parenchymal involvement in 17 patients. Of these, 13 patients had masses beneath the pectoralis muscles or within the breast, and four had masses arising from the ribs. Five additional patients had mediastinal masses with thymic involvement and parasternal extension through the thoracic wall. Pulmonary parenchymal lymphoma with thoracic wall invasion was noted in the remaining two patients. In five of nine patients receiving radiation therapy, treatment plans were modified by CT demonstration of thoracic wall lymphoma.     

Immunomodulatory effects of the HIV-1 gp120 protein on antigen presenting cells: implications for AIDS pathogenesis

Antigen presenting cell (APC) function is central to the development of an effective anti-viral immune response. Among APC, monocytes, macrophages and dendritic cells (DC) form the principal non-T cell compartment involved in in vivo HIV infection, and these cells play important and well-established roles in multiple aspects of viral pathogenesis. HIV infection may result in APC defects, which could ultimately contribute to the loss of CD4+ T cell responses observed early in HIV infection, when the CD4+ T cell number is still within the normal range. Extensive in vitro studies have demonstrated that the envelope glycoproteins of HIV-1 exert profound influences on various cell populations of the immune system, including hematopoietic progenitors, T and B lymphocytes, monocytes/ macrophages and DC, as well as on neuronal cells. The demonstration of the presence of envelope proteins both free in the circulation and bound to the surface of CD4+ cells suggests that gp120 interactions with non-infected cells can influence cellular functions in vivo, thus contributing to the immunopathogenesis of AIDS. This paper provides an overview of the present knowledge on gp120 binding, signal transduction triggering and interference with macrophage and DC functions and it highlights the importance of this interaction in the pathogenesis of AIDS.     

Long-term course of treatment-seeking Vietnam veterans with posttraumatic stress disorder: mortality, clinical condition, and life satisfaction

This study is a 6-year longitudinal study of 51 treatment-seeking male veterans with combat-related posttraumatic stress disorder. Measures of PTSD and psychiatric symptomatology, social functioning, and program impact were assessed at admission to an inpatient treatment program, at 18 months, and 6 years later. Previous studies had shown that the treatment program's impact on course of illness had been negligible. The sample showed an extremely high mortality rate of 17% over 6 years. The remaining veterans showed improvement in violence and alcohol and drug use, but an increase in hyperarousal symptoms and social isolation. Nearly three-fourths had had an inpatient hospitalization. Veterans' self-ratings, in contrast, indicated significant improvement in all areas of functioning except employment, as well as an overall positive view of the impact of the program on their lives. Results indicate that the majority of the veteran sample had experienced some improvement in their ability to cope with their chronic illness, decreasing their use of violence and substance abuse but still were experiencing high levels of symptomatology. The extremely high mortality rate, however, provides a somber reminder of the seriousness of this disorder.     

Advances in the combination of radiation therapy and chemotherapy against cancer

From June 5 through June 8, 2004, the American Society of Clinical Oncology held its 45th Annual Meeting in New Orleans, Louisiana, USA. The meeting was devoted to the presentation of advances in management of malignant diseases with a variety of therapeutic modalities. The meeting brings together investigators, clinicians, policy makers and professionals interested in the science and impact of novel treatments on cancerous disease. This report will examine the advances in combined modality approaches (i.e., the use of radiation therapy and chemotherapy) for the treatment of malignant disease. This review will summarize the advances reported in the use of chemoradiation for sarcomas and tumors of the genitourinary tract, brain, gastrointestinal tract, breast and lung.     

Chronomics: circadian and circaseptan timing of radiotherapy, drugs, calories, perhaps nutriceuticals and beyond

We suggest a putative benefit from timing nutriceuticals (substances that are both nutrients and pharmaceuticals) such as antioxidants for preventive or curative health care, based on the proven merits of timing nutrients, drugs, and other treatments, as documented, i.a., in India. The necessity of timing melatonin, a major antioxidant, is noted. A protocol to extend the scope of chronoradiotherapy awaits testing. Imaging in time by mapping rhythms and broader time structures, chronomes, for earliest diagnoses, for example detection of vascular disease risk, is recommended. The study of rhythms and broader chronomes leads to a dynamic functional genomics, guided by imaging in time of free radicals and antioxidants, amongst many other variables.     

Review of 125 SiteSelect stereotactic large-core breast biopsy procedures

Advances in stereotactic breast biopsies have introduced a variety of devices that yield different sizes of tissue samples. The choice of biopsy device should be based on which technique is most likely to yield a definitive diagnosis at the time of the initial biopsy. This is a prospective study of 104 patients who underwent a total of 125 stereotactic breast biopsies using the SiteSelect large-core biopsy device. From May 1999 to June 2001, 104 patients underwent 125 stereotactic breast biopsies with the SiteSelect large-core biopsy device. One hundred four 15 mm SiteSelect biopsies, eighteen 10 mm SiteSelect biopsies, and three 22 mm SiteSelect biopsies were performed. Atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) were found in 15% of the biopsies and infiltrating cancer was found in another 15% of the biopsies. Seventy-eight percent of the ADH and 90% of the DCIS lesions were associated with indeterminate calcifications noted on mammogram. Two of the 22 mm SiteSelect excisions yielded a specimen that contained the entire cancer with clear surgical margins. All of the patients with DCIS or invasive carcinoma underwent definitive surgical and adjuvant therapy. The sensitivity and specificity of SiteSelect in this series of patients was 100%. The SiteSelect biopsy procedure is safe, well tolerated by patients, and can be performed under local anesthesia. SiteSelect is comparable to an open excisional biopsy in its ability to obtain adequate tissue for accurate diagnosis, but excises significantly less normal surrounding breast tissue. Based on the data, indications for primary use of SiteSelect are indeterminate calcifications on mammogram, rebiopsy of a vacuum-assisted biopsy site that yielded atypia on pathologic examination, and complete excision of a lesion suspicious for invasive carcinoma in order to assess actual size and margin status.     

Genetics and clinical practice in rheumatology

The dramatic advances made recently in human genome research are fueling considerable interest in genetic testing. A specific feature of genetic testing is that the results are final and impact not only the patient, but also the entire family. Those elements should be factored into the risk/benefit ratio evaluation. In France, legislation the differentiates diagnostic tests in symptomatic patients from predictive tests in asymptomatic patients with affected family members. Only multidisciplinary groups with both clinical and genetic expertise can order predictive tests. In all cases the physician must sign a statement that informed consent was obtained from the patient prior to testing. The test must be done in an accredited laboratory and the result communicated by the physician to the patient. Patient confidentiality must be respected, particularly regarding family members. In monogenic diseases, the diagnostic weight of genetic testing is often considerable, although the limitations should be borne in mind. In multifactorial diseases, genetic testing seeks to identify risk factors that are usually associated with a low level of risk. The result should be interpreted in the light of the clinical presentation, family history, and genetic background. The predictive value is closely dependent on the clinical presentation but is generally limited, most notably when family members are affected. Great care should be taken to avoid causing undue anxiety among individuals with positive test results. Diseases that illustrate these aspects include Paget's disease of bone, of which inherited variants caused by a mutation in a single gene on chromosome 5 have been identified recently, and rheumatoid arthritis, which is a multifactorial disease.     

A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition

Summary. Seven randomised comparative studies were conducted in healthy volunteers to compare the pharmacokinetic and pharmacodynamic profiles of selegiline hydrochloride in a new formulation designed for buccal absorption Zydis Selegiline (1.25–10mg) with conventional selegiline hydrochloride tablets conventional selegiline tablets (10mg). A total of 156 healthy volunteers participated in these studies. Plasma concentrations of selegiline and its primary metabolites, N-desmethylselegiline (DMS), l-amphetamine (AMT), and l-methamphetamine (MET) were measured using Gas Chromatography Mass Spectrometry (GCMS) and gas liquid chromatography (GLC) assays. Inhibition of monoamine-oxidase type B (MAO-B) and monoamine oxidase type A (MAO-A) activity was determined by measurement of as -phenylethylamine (PEA) by GCMS and 5-hydroxyindoleacetic acid (5-HIAA) by High Performance Liquid Chromatography (HPLC) assays. Almost a third (2.96mg) of a 10mg selegiline dose in Zydis Selegiline was absorbed pre-gastrically (predominantly buccally) within 1 minute. Mean [SD] area-under-the curve (AUC_0–) values following Zydis Selegiline 10mg (5.85 [7.31] ng·h/mL) were approximately five times higher than those following conventional selegiline tablets 10mg (1.16 [1.05] ng·h/mL). In contrast, plasma concentrations of metabolites were significantly (p<0.001) lower following Zydis Selegiline 10mg than following conventional selegiline tablets 10mg.Plasma concentrations of selegiline and its metabolites increased in a dose-dependent manner over the dose-range Zydis Selegiline 1.25–5mg. Bioavailability was determined using AUC and peak plasma concentrations (C_max). The C_max of selegiline was similar following administration of Zydis Selegiline 1.25mg (1.52ng/mL) or conventional selegiline tablets 10mg (1.14mg/mL). The range of values for AUC_0– and C_max following Zydis Selegiline 1.25mg were entirely contained within the range following conventional selegiline tablets 10mg, with a much higher variability of plasma selegiline concentrations occurring after conventional selegiline tablets than after Zydis Selegiline. As expected, peak plasma concentrations for DMS, AMT and MET were consistently lower after Zydis Selegiline 1.25mg (1.19, 0.34, 0.93ng/ml, respectively) than after conventional selegiline tablets 10mg (18.37, 3.60, 12.92ng/ml, respectively). A significant (r=0.0001) correlation between daily PEA excretion (a measure of brain MAO-B inhibition) and the log-transformed AUC_(0–t) for selegiline was demonstrated. Mean daily PEA excretion was similar following Zydis Selegiline 1.25mg and conventional selegiline tablets 10mg (13.0µg versus 17.6µg). In contrast, there was no correlation between PEA excretion and selegiline metabolites, indicating that selegiline metabolites do not significantly inhibit MAO-B. Urinary excretion of 5-HIAA (used as a marker for MAO-A inhibition) was unrelated to plasma concentrations of selegiline or DMS following single or repeat dosing of Zydis Selegiline 1.25mg or conventional selegiline tablets 10mg. However, comparison of treatment groups revealed a significantly lower excretion of 5-HIAA in the conventional selegiline tablets 10mg group than in the Zydis Selegiline 1.25mg group after repeated administration over 13 days.In summary, by reducing the opportunity for first-pass metabolism, the absorption of selegiline from Zydis Selegiline was more efficient and less variable than from conventional selegiline tablets. Compared with conventional selegiline tablets 10mg, Zydis Selegiline 1.25mg yielded similar plasma concentrations of selegiline and degree of MAO-B inhibition, but markedly reduced concentrations of the principal metabolites. Thus, the lower but equally MAO-B inhibitory dose of selegiline in Zydis Selegiline 1.25mg, which is associated with lower concentrations of potentially harmful metabolites, could offer a safer and more predictable treatment in the management of patients with Parkinsons disease.Present address: Cephalon UK Ltd., Surrey Research Park, Guildford, United KingdomPresent address: Biogen Ltd., Maidenhead, Berks, United KingdomPresent address: Safetymednet, Ruscombe, United KingdomPresent address: Oxford Glycosciences (UK) Ltd., Abingdon, United KingdomPresent address: Pfizer UK Ltd., High Wycombe, United KingdomReceived December 3, 2002; accepted June 30, 2003     

A new low-dose formulation of selegiline: clinical efficacy,patient preference and selectivity for MAO-B inhibition

Summary. Three studies were performed using a fast dissolving formulation of selegiline hydrochloride designed for buccal absorption Zydis Selegiline. The aim of the first study was to compare the therapeutic efficacy of Zydis Selegiline (1.25mg or 10mg) with conventional selegiline hydrochloride tablets conventional selegiline tablets (10mg) in patients with Parkinsons disease (PD) who were previously treated with conventional selegiline tablets as an adjunct to levodopa/dopamine agonist therapy. Patients were observed for 4 weeks to ensure that they were stable. Stable patients (n=197) were then randomised to continue with conventional selegiline tablets 10mg (n=68), or to treatment with Zydis Selegiline 1.25mg (n=64) or Zydis Selegiline 10mg (n=62) for 12 weeks in this randomised, parallel group study. A further aim was to establish the acceptability of Zydis Selegiline compared with conventional selegiline tablets. Patient preference for Zydis Selegiline was also evaluated in a second study, a single-dose, randomised, two-way crossover study conducted in patients with PD (n=148). Patients were stratified by the presence or absence of swallowing and salivation problems and were randomised to either Zydis Selegiline 5mg or a placebo fast-dissolving formulation. In a third study, the degree of potentiation of the tyramine pressor effect following Zydis Selegiline was compared with that following conventional selegiline tablets in healthy volunteers. A total of 24 healthy volunteers were randomised to receive Zydis Selegiline 1.25mg or conventional selegiline tablets 10mg for 14–16 days in an open-label, randomised parallel group study.Both Zydis Selegiline (1.25mg and 10mg) treatments were shown to be therapeutically equivalent to conventional selegiline tablets 10mg based on comparison of mean total Unified Parkinsons Disease Rating Scale (UPDRS) scores. Therapeutic equivalence was defined a priori as the 90% confidence interval (CI) for the difference in total UPDRS scores between groups to lie entirely within the range ±5. The difference (90% CI) in mean adjusted total UPDRS between Zydis Selegiline 1.25mg and conventional selegiline tablets 10mg was –2.50 (–4.84, –0.17), and for Zydis Selegiline 10mg and conventional selegiline tablets 10mg, 0.04 (–2.30, 2.38). For the motor subscores of the UPDRS, differences between adjusted means (90% CI) compared with the conventional selegiline tablets group were: Zydis Selegiline 1.25mg, –2.14 (–3.94, –0.33) and Zydis Selegiline 10mg, –0.90 (–2.70, +0.91). Patients who switched from conventional selegiline tablets to Zydis Selegiline 1.25mg showed a slight improvement in UPDRS scores following 12 weeks of treatment (standard error of difference 1.039; p=0.01).In the single-dose crossover study, most (61%) patients liked Zydis Selegiline 5mg; a significantly greater proportion than the null hypothesis of 50% (p<0.002). However, only 62 patients (46%) indicated that they liked the taste of Zydis Selegiline. Nevertheless, the proportion of patients who preferred Zydis Selegiline (65%) to their usual medication was significantly greater than the null hypothesis of 50% (p<0.001).Similar findings were demonstrated in the 12-week study where a higher proportion of patients who received up to 3 months of treatment indicated a preference for either Zydis Selegiline 1.25mg (90%) or Zydis Selegiline 10mg (86%) over conventional selegiline tablets 10mg. More than 90% of patients found Zydis Selegiline easy to take, with 61% rating it as extremely easy. Most (81%) patients taking Zydis Selegiline 1.25mg liked the taste compared with 45% taking Zydis Selegiline 5mg (in the previous study).Zydis Selegiline did not potentiate the tyramine effect: a pressor effect was elicited after 400mg tyramine both before and after 14 days of treatment with Zydis Selegiline 1.25mg. In contrast, after 14 days treatment with conventional selegiline tablets 10mg, the threshold dose required to elicit the tyramine pressor response was significantly (p<0.0001) reduced from 400mg to 200mg.In summary, Zydis Selegiline at doses of 1.25mg and 10mg was therapeutically equivalent to conventional selegiline tablets 10mg. The Zydis Selegiline formulation was well-liked by all patients, with most preferring Zydis Selegiline 1.25mg to their usual selegiline tablet. Furthermore, Zydis Selegiline was well tolerated and, unlike conventional selegiline tablets, appeared to retain specificity for inhibition of monoamine oxidase type B (MAO-B), since it did not potentiate the pressor response to tyramine.Present address: Cephalon UK Ltd., Surrey Research Park, Guildford, United KingdomPresent address: Safetymednet, Ruscombe, United KingdomPresent address: Oxford Glycosciences (UK) Ltd., Abingdon, United KingdomReceived December 3, 2002; accepted July 23, 2003