Modelling Bone Mineral Density in Swiss Breast Cancer Patients Treated with Letrozole, Tamoxifen and Sequences of Letrozole and Tamoxifen in the BIG 1-98 Study (SAKK 21/07).

Background: Bone health is a concern when treating early stage breast cancer patients with adjuvant aromatase inhibitors. Early detection of patients (pts) at risk of osteoporosis and fractures may be helpful for starting preventive therapies and selecting the most appropriate endocrine therapy schedule. We present statistical models describing the evolution of lumbar and hip bone mineral density (BMD) in pts treated with tamoxifen (T), letrozole (L) and sequences of T and L. Methods: Available dual-energy x-ray absorptiometry exams (DXA) of pts treated in trial BIG 1-98 were retrospectively collected from Swiss centers. Treatment arms: A) T for 5 years, B) L for 5 years, C) 2 years of T followed by 3 years of L and, D) 2 years of L followed by 3 years of T. Pts without DXA were used as a control for detecting selection biases. Patients randomized to arm A were subsequently allowed an unplanned switch from T to L. Allowing for variations between DXA machines and centres, two repeated measures models, using a covariance structure that allow for different times between DXA, were used to estimate changes in hip and lumbar BMD (g/cm2) from trial randomization. Prospectively defined covariates, considered as fixed effects in the multivariable models in an intention to treat analysis, at the time of trial randomization were: age, height, weight, hysterectomy, race, known osteoporosis, tobacco use, prior bone fracture, prior hormone replacement therapy (HRT), bisphosphonate use and previous neo-/adjuvant chemotherapy (ChT). Similarly, the T-scores for lumbar and hip BMD measurements were modeled using a per-protocol approach (allowing for treatment switch in arm A), specifically studying the effect of each therapy upon T-score percentage. Results: A total of 247 out of 546 pts had between 1 and 5 DXA; a total of 576 DXA were collected. Number of DXA measurements per arm were; arm A 133, B 137, C 141 and D 135. The median follow-up time was 5.8 years. Significant factors positively correlated with lumbar and hip BMD in the multivariate analysis were weight, previous HRT use, neo-/adjuvant ChT, hysterectomy and height. Significant negatively correlated factors in the models were osteoporosis, treatment arm (B/C/D vs. A), time since endocrine therapy start, age and smoking (current vs. never).Modeling the T-score percentage, differences from T to L were -4.199% (p = 0.036) and -4.907% (p = 0.025) for the hip and lumbar measurements respectively, before any treatment switch occurred. Conclusions: Our statistical models describe the lumbar and hip BMD evolution for pts treated with L and/or T. The results of both localisations confirm that, contrary to expectation, the sequential schedules do not seem less detrimental for the BMD than L monotherapy. The estimated difference in BMD T-score percent is at least 4% from T to L.

Double-blind comparison of indapamide with a placebo in hypertensive patients treated by practicing physicians.

The antihypertensive effect of indapamide (2.5 mg/day) was compared to that obtained with a placebo in a controlled trial carried out by 11 physicians in their private practice. Thirty-one patients with uncomplicated essential hypertension were included. After a run-in period of 3 weeks without any treatment, either indapamide (n = 16) or a placebo (n = 15) were administered for 8 weeks in double-blind fashion. Blood pressure decreased in both groups. In patients treated with indapamide, systolic pressure was significantly lower than in those given the placebo at 3 out of the 4 follow-up visits; diastolic pressure, however, was significantly lower only at the end of the trial. Both the active drug and the placebo were well tolerated. No significant change in body weight, plasma potassium and uric acid occurred during the study in either group of patients. It appears therefore that indapamide, at a dose which apparently has no major diuretic effect, may be useful for practitioners in managing patients with mild to moderate hypertension.

Interobserver and intraobserver variability of apparent diffusion coefficient measurements in treated malignant hepatic lesions: measurements in the whole lesion versus in the area with the most restricted diffusion

Purpose: The increase of apparent diffusion coefficient (ADC) in treated hepatic malignancies compared to pre-therapeutic values has been interpreted as treatment success; however, the variability of ADC measurements remains unknown. Furthermore, ADC has been usually measured in the whole lesion, while measurements should be probably centered on the area with the most restricted diffusion (MRDA) as it represents potential tumoral residue. Our objective was to compare the inter/intraobserver variability of ADC measurements in the whole lesion and in MRDA. Material and methods: Forty patients previously treated with chemoembolization or radiofrequency were evaluated (20 on 1.5T and 20 on 3.0T). After consensual agreement on the best ADC image, two readers measured the ADC values using separate regions of interest that included the whole lesion and the whole MRDA without exceeding their borders. The same measurements were repeated two weeks later. Spearman test and the Bland-Altman method were used. Results: Interobserver correlation in ADC measurements in the whole lesion and MRDA was as follows: 0.962 and 0.884. Intraobserver correlation was, respectively, 0.992 and 0.979. Interobserver limits of variability (mm2/sec*10-3) were between -0.25/+0.28 in the whole lesion and between -0.51/+0.46 in MRDA. Intraobserver limits of variability were, respectively: -0.25/+0.24 and -0.43/+0.47. Conclusion: We observed a good inter/intraobserver correlation in ADC measurements. Nevertheless, a limited variability does exist, and it should be considered when interpreting ADC values of hepatic malignancies.

Cytokines and hs-CRP levels in individuals treated with low-dose aspirin for cardiovascular prevention: a population-based study (CoLaus Study).

Pro-inflammatory cytokines and high-sensitive C-reactive protein (hs-CRP) are associated with increased risk for cardiovascular disease. Low-dose aspirin for CV prevention is reported to have anti-inflammatory effects. The aim of this study was to determine the association between pro-inflammatory cytokines and hs-CRP levels and low-dose aspirin use for cardiovascular prevention in a population-based cohort (CoLaus Study). We assessed blood samples in 6085 participants (3201 women) aged 35-75years. Medications' use and indications were recorded. Among aspirin users (n=1'034; 17%), overall low-dose users (351; 5.8%) and low-dose for cardiovascular prevention users (324; 5.3%) were selected for analysis. Pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α were assessed by a multiplex particle-based flow cytometric assay and hs-CRP by an immunometric assay. Cytokines and hs-CRP were presented in quartiles. Multivariate analysis adjusting for sex, age, smoking status, body mass index, diabetes mellitus and immunomodulatory drugs showed no association between cytokines and hs-CRP levels and low-dose aspirin use for cardiovascular prevention, either comparing the topmost vs. the three other quartiles (OR 95% CI, 0.84 (0.59-1.18), 1.03 (0.78-1.32), 1.10 (0.83-1.46), 1.00 (0.67-1.69) for IL-1β, IL-6, TNF-α and hs-CRP, respectively), or comparing the topmost quartile vs. the first one (OR 95% CI, 0.87 (0.60-1.26), 1.19 (0.79-1.79), 1.26 (0.86-1.84), 1.06 (0.67-1.69)). Low-dose aspirin use for cardiovascular prevention does not impact plasma pro-inflammatory cytokine and hs-CRP levels in a population-based cohort.

A randomised controlled pilot study comparing Mepitel(®) and SurfaSoft(®) on paediatric donor sites treated with Recell(®).

This randomized controlled pilot study examined the effects of a silicone net dressing (Mepitel(®)) and a monofilament polyamide woven dressing (SurfaSoft(®)) on the rate of epithelialisation and epidermal maturation, pain, and ease of dressing removal on paediatric donor sites treated with epithelial cell suspension (ReCell(®)). Fifteen children (1-15 years) admitted for acute or reconstructive burns procedures in a tertiary referral hospital in Australia were randomly assigned to the experimental group, Mepitel(®) (n=8) and to the control group, SurfaSoft(®) (n=7). All donor sites were treated with ReCell(®) and covered with the assigned dressing. Measurements of rate of epithelialisation and epidermal maturation, pain, and ease of dressing removal were recorded every two days until the wound was healed. Results showed that there was no difference in the rate of epidermal maturation between the two groups. Less pain and force to remove the dressing was shown in the Mepitel(®) group when compared to SurfaSoft(®). The rate of epithelialisation was found to be an unreliable measure. Although additional research is required to support the results of this study, these results suggest that Mepitel's(®) pliable, self-adhesive and atraumatic properties may improve healing of ReCell(®) treated donor sites with less pain at dressing changes. This pilot study provides a strong base for further research in this area.

Determination of the enantiomers of mianserin, desmethylmianserin, and 8-hydroxymianserin in the plasma and urine of mianserin-treated patients.

An HPLC method is presented which allows the measurement in the same run of the enantiomers of mianserin, desmethylmianserin, and 8-hydroxymianserin in plasma and urine of mianserin-treated patients. Limits of quantitation for the (S)- and (R)-enantiomers of mianserin and desmethylmianserin were 4 and 2.5 ng/ml, respectively, in plasma, and for the (S)- and (R)-enantiomers of mianserin, desmethylmianserin, and 8-hydroxymianserin 5, 2.5, and 5 ng/ml, respectively, in urine. The measured ratios of (S)-mianserin/(R)-mianserin and (S)-desmethylmianserin/(R)-desmethylmianserin in the plasmas of 10 mianserin-treated patients, all extensive metabolizers of debrisoquine as determined by CYP2D6 genotyping, varied, respectively, from 1.0 to 4.06 and from 0.19 to 0.64. As the enantiomers of mianserin differ in their pharmacological profile, these results could partially explain why, until now, no consistent relationship has been established between the therapeutic response and total [(S) + (R)] plasma levels of this antidepressant.

Myelin basic protein content of aggregating rat brain cell cultures treated with cytokines and/or demyelinating antibody: effects of macrophage enrichment.

The demyelinative potential of the cytokines interleukin-1 alpha (IL-1 alpha), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) has been investigated in myelinating aggregate brain cell cultures. Treatment of myelinated cultures with these cytokines resulted in a reduction in myelin basic protein (MBP) content. This effect was additively increased by anti-myelin/oligodendrocyte glycoprotein (alpha-MOG) in the presence of complement. Qualitative immunocytochemistry demonstrated that peritoneal macrophages, added to the fetal telencephalon cell suspensions at the start of the culture period, successfully integrated into aggregate cultures. Supplementing the macrophage component of the cultures in this fashion resulted in increased accumulation of MBP. The effect of IFN-gamma on MBP content of cultures was not affected by the presence of macrophages in increased numbers.

Bone mineral density in breast cancer patients treated with adjuvant letrozole, tamoxifen, or sequences of letrozole and tamoxifen in the BIG 1-98 study (SAKK 21/07).

BACKGROUND: The risk of osteoporosis and fracture influences the selection of adjuvant endocrine therapy. We analyzed bone mineral density (BMD) in Swiss patients of the Breast International Group (BIG) 1-98 trial [treatment arms: A, tamoxifen (T) for 5 years; B, letrozole (L) for 5 years; C, 2 years of T followed by 3 years of L; D, 2 years of L followed by 3 years of T]. PATIENTS AND METHODS: Dual-energy X-ray absorptiometry (DXA) results were retrospectively collected. Patients without DXA served as control group. Repeated measures models using covariance structures allowing for different times between DXA were used to estimate changes in BMD. Prospectively defined covariates were considered as fixed effects in the multivariable models. RESULTS: Two hundred and sixty-one of 546 patients had one or more DXA with 577 lumbar and 550 hip measurements. Weight, height, prior hormone replacement therapy, and hysterectomy were positively correlated with BMD; the correlation was negative for letrozole arms (B/C/D versus A), known osteoporosis, time on trial, age, chemotherapy, and smoking. Treatment did not influence the occurrence of osteoporosis (T score < -2.5 standard deviation). CONCLUSIONS: All aromatase inhibitor regimens reduced BMD. The sequential schedules were as detrimental for bone density as L monotherapy.

Should Koos grade I vestibular schwannomas be treated early with gamma knife surgery? A subgroup analysis in a series of 190 consecutive patients.

INTRODUCTION: Gamma knife surgery (GKS) for vestibular schwannomas (VS) has a long-term clinical and scientific track record. After a period of de-escalation of dose prescription, results show a high rate of tumor control with improvement of clinical outcome (less than 1% facial palsy, 50-70% hearing preservation). Régis et al. (J Neurosurg 2013;119 Suppl.:105-11) suggested recently that proactive GKS management in intracanalicular tumors is better than a « wait and see » strategy when hearing is still useful at the time of diagnosis. MATERIALS AND METHODS: Based on these previous findings, we prospectively analyzed 190 vestibular schwannomas (VS), treated with GKS as first intention over a period of 4 years (2010-2014). We concentrated on patient, tumor and dosimetric characteristics. Special attention was given on the dose to the cochlea and its impact in maintaining serviceable hearing. RESULTS: The mean follow-up period was 1.3years (range 0.6-3.6). Preoperative serviceable hearing was present in 63.11% patients. The mean maximal diameter was 15.1mm (range 5-29.5). The size and volume of the tumor corresponded to Koos grade I, II, III and IV in 15.9%, 34.8%, 45.4% and 3.8% of the cases, respectively. The mean target volume was 1.24cm(3) (0.017-7.8). The mean prescription isodose volume was 1.6 cc (0.032-8.5). The mean marginal dose was 12Gy (11-12). The mean maximal dose received by the cochlea in patients with GR class 1 and 2 was 4.1Gy (1.5-7.6). Our preliminary neuroradiological follow-up shows 97% tumor control, with 45% shrinkage. Patients presenting with GR class 1 and class 2 at baseline retained serviceable hearing in 85% of cases. Among the patients with a follow-up of at least one year, those with Koos I tumors had the highest probability to maintain identical level of hearing after GKS. CONCLUSION: Our preliminary data suggest that Koos I patients should be treated early with GKS, before tumor growth and/or hearing deterioration, as they have the highest probability of hearing preservation.

Hidradenitis suppurativa of the groin treated by radical excision and defect closure by medial thigh lift: aesthetic surgery meets reconstructive surgery.

INTRODUCTION: Hidradenitis suppurativa of the groin is a chronic, relapsing inflammatory disease of the skin and subcutaneous tissues. Radical surgical excision is the treatment of choice. Often split-skin grafting or wound healing by secondary intention are used for defect closure, sometimes with disfiguring results. We describe our experience with radical excision of localised inguinal hidradenitis suppurativa and immediate defect closure with a medial thigh lift. PATIENTS AND METHODS: Our hospital database was searched for all patients presenting to our institution for surgical treatment of hidradenitis suppurativa between 2001 and 2006. Only patients with hidradenitis confined to the groin were included. Exclusion criteria were simple abscess incisions, recurrence after previous grafting or flap surgery and extension of the disease outside the groin and presence of clinical signs of infection at the time of surgery. We documented patient demographics, sizes of defects, complications, time of follow-up, recurrences and patient satisfaction. RESULTS: A total of 8 patients with localised inguinal hidradenitis suppurativa were identified and 15 thigh lifts were performed. Defect size assessed on pathologic examination of the excised specimens averaged 15.9 cm x 4.3 cm x 1.3 cm (length x width x depth). All wounds but one healed primarily. Functional and aesthetic results were satisfactory. No major complications and no irritations of the genital area were observed. No recurrences were observed either. CONCLUSION: We propose the medial thigh lift to be considered for immediate defect closure after radical excision of localised inguinal hidradenitis suppurativa provided that no perifocal signs of infection are present after debridement.

Viral- and myelin-specific cellular immune response in patients treated with natalizumab: a cross-sectional and a longitudinal prospective study

Introduction: Natalizumab, a monoclonal antibody binding to the alpha4 integrins, is efficient in preventing relapses and progression of disability in multiple sclerosis (MS) patients. However, a total of seven MS patients treated with natalizumab suffered from progressive multifocal leukoencephalopathy (PML), on a total of 53?000 patients (data of March 6, 2009) treated with this drug. PML is a disease affecting immunosuppressed people, which is caused by the polyomavirus JC (JCV). This virus produces a lytic infection of the oligodendrocytes. Yet, natalizumab cannot be considered as a classical immunosuppressant, such as suggested by the fact that no increased incidence of other opportunistic infections was reported with this drug. It has been postulated that, by closing the blood-brain, natalizumab might prevent JCV-specific CD8_ T cells to reach the CNS and perform immune surveillance. Alternatively, it has been suggested that this drug acts by releasing JCV from the bone marrow, one of its site of latency. In this study, we address the question whether there is an increased activity of JCV in the blood of natalizumab-treated MS patients. Material and Methods: In this prospective longitudinal study, we are following a cohort of 24 MS patients receiving monthly injections of natalizumab. Blood and urine are drawn every one to three months, up to 12 months. As a control group, we follow 16 MS patients treated with IFN-beta. For this control group, there are two time-points: before and 1094 months after treatment onset. We are analysing the viral (JCV-, EBV- and CMV-) as well as the myelin- (MOG-, MOBP-) specific cellular immune responses using proliferation and ELISPOT (IFNgamma) assays. For JCV, we study the response against VP1, the major capsid protein. For JCV VP1, MOG and MOBP, we use 15-mer peptides overlapping by 10 amino acids, thus eliciting CD4_ as well as CD8_ T cell response. These peptides encompasse the whole sequence of the proteins. For EBV and CMV, we use pools of immunodominant 8- to 10-mer peptides eliciting CD8_ T cells. At the same time-points, using RTPCR, we determine the presence of JCV DNA coding for the VP1 protein in the PBMC, plasma, and urine. Results: At the time of writing this abstract, 16 patients have reached the 9-month (T9), and 11 the T12 time-point. We expect that by the ISNV meeting in June 2009, 18 and 14 patients will be at T9 and T12, respectively. Virological and immunological results will be presented. 9th International Symposium on NeuroVirology 2_6 June 2009 39 J Neurovirol Downloaded from informahealthcare.com by Cantonale et Universitaire on 06/25/10 For personal use only. Conclusions: This ongoing longitudinal prospective study should tell us whether there is an enhanced JCV activity in the peripheral blood of patients on natalizumab. This work is supported by the FNS (PP00B-106716), the Swiss MS Society and a research grant from Biogen Dompe.

Six of 12 Relapsed or Refractory Indolent Lymphoma Patients Treated 10 Years Ago with 131I-Tositumomab Remain in Complete Remission.

The purpose of our study was to update the safety and efficacy results of radioimmunotherapy in relapsed or resistant indolent or transformed non-Hodgkin lymphoma. Methods: More than 9 y ago, we treated 12 indolent and 4 transformed, relapsed or refractory lymphoma patients with a single administration of nonmyeloablative therapy with tositumomab and I-131-tositumomab. The 16 patients had a mean of 3.1 (range, 1-6) previous chemotherapy and antibody treatments. Results: Six of 12 relapsed indolent lymphoma patients remain disease-free a mean of 9.8 y (range, 8.6-10.7 y) after radioimmunotherapy. Three of 4 transformed lymphoma patients progressed after radioimmunotherapy, and 1 patient had a partial response of 10 mo. Conclusion: Optimal patient benefit might be obtained in indolent lymphoma when administering radioimmunotherapy up-front in combination with chemotherapy and rituximab treatment. However, these results show that radioimmunotherapy alone achieved long-lasting remissions in 6 of 12 (50%) indolent lymphoma patients in relapse after 1 or multiple chemotherapies.

Les fractures du pilon tibial. Etude rétrospective à long terme de 51 fractures traitées par réduction sanglante et ostéosynthèse [Fractures of the tibial pilon. Long-term retrospective study of 51 fractures treated with open reduction and osteosynthesis].

PURPOSE OF THE STUDY: Fracture of the tibial pilon is a rare injury and its treatment remains difficult. The aim of this study was to report the complications and long term results of internal fixation using a technique which respects soft tissues and in which little material was used. MATERIAL: From 1985 to 1990, 48 patients with 51 fractures of the tibial pilon were treated by open reduction and internal fixation. All patients were submitted to a clinical and radiological review. METHODS: Both the Rüedi/Allgöwer and the AO-classification were used and determined by standard X-rays. Surgical procedure was performed with a 2 or 3 1/3 tube AO-plates and the peroneus was always fixed if fractured. Intraoperative reconstruction was analyzed. Subjective and objective scoring were used according to Olerud and Molander and the ankle arthritis was scored according to the classification determined by the SOFCOT in 1992. RESULTS: A minimal follow-up of 1 year for all cases was obtained, based on our own files. Thirty-eight patients (40 fractures) were evaluated after an average period of 88 months (56 to 124 months). Five patients developed cutaneous infection, three developed deep infection and four developed superficial skin necrosis. One aseptic non-union necessitated reoperation after 14 months. Two ankles had joint fusion after 19 and 25 months respectively due to severe arthritis. In six cases infectious and non-infectious complications led to surgical revision. According to the Olerud and Molander score, 15 per cent of the results were excellent, 45 per cent were good, 30 per cent were fair and 10 per cent poor. DISCUSSION: Literature shows a wide range of results following this surgical procedure. This is due to the difference in the type of trauma, classification system used, material used for the internal fixation and method of evaluation. The classification system of Rüedi and Allgöwer is the most commonly used but has a rather subjective tendency, especially between type II and type III. Treatment is difficult, especially for comminutive fractures associated with soft tissue damage. In this case, open reduction and internal fixation could increase iatrogenic lesions. For this reason surgical procedure can be delayed for several days, little material is used and soft tissue manipulation is reduced to minimum. In other study reports, the use of external fixation with or without minimal internal fixation have produced less complications without improving long term results. CONCLUSION: Analysis and comparison of study reports are difficult because of the absence of consensus in classification system and evaluation methods. The AO-classification, apparently the most objective, will probably be more and more used in the future. Treatment must be adapted to the bony lesion and soft tissue damage. Open reduction and internal fixation must be reserved for a specific group of lesion.

Lipid and lipoprotein profile in HIV-infected patients treated with lopinavir/ritonavir as a component of the first combination antiretroviral therapy.

We characterized lipid and lipoprotein changes associated with a lopinavir/ritonavir-containing regimen. We enrolled previously antiretroviral-naive patients participating in the Swiss HIV Cohort Study. Fasting blood samples (baseline) were retrieved retrospectively from stored frozen plasma and posttreatment (follow-up) samples were collected prospectively at two separate visits. Lipids and lipoproteins were analyzed at a single reference laboratory. Sixty-five patients had two posttreatment lipid profile measurements and nine had only one. Most of the measured lipids and lipoprotein plasma concentrations increased on lopinavir/ritonavir-based treatment. The percentage of patients with hypertriglyceridemia (TG >150 mg/dl) increased from 28/74 (38%) at baseline to 37/65 (57%) at the second follow-up. We did not find any correlation between lopinavir plasma levels and the concentration of triglycerides. There was weak evidence of an increase in small dense LDL-apoB during the first year of treatment but not beyond 1 year (odds ratio 4.5, 90% CI 0.7 to 29 and 0.9, 90% CI 0.5 to 1.5, respectively). However, 69% of our patients still had undetectable small dense LDL-apoB levels while on treatment. LDL-cholesterol increased by a mean of 17 mg/dl (90% CI -3 to 37) during the first year of treatment, but mean values remained below the cut-off for therapeutic intervention. Despite an increase in the majority of measured lipids and lipoproteins particularly in the first year after initiation, we could not detect an obvious increase of cardiovascular risk resulting from the observed lipid changes.