University Hospital of Grenoble

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Chaikh A.,University Hospital of Grenoble | Chaikh A.,France HADRON National Research Infrastructure | Balosso J.,France HADRON National Research Infrastructure | Balosso J.,Joseph Fourier University
Translational Lung Cancer Research | Year: 2017

Background: To apply the equivalent uniform dose (EUD) radiobiological model to estimate the tumor control probability (TCP) scores for treatment plans using different radiobiological parameter settings, and to evaluate the correlation between TCP and physical quality indices of the treatment plans. Methods: Ten radiotherapy treatment plans for lung cancer were generated. The dose distributions were calculated using anisotropic analytical algorithm (AAA). Dose parameters and quality indices derived from dose volume histograms (DVH) for target volumes were evaluated. The predicted TCP was computed using EUD model with tissue-specific parameter (a=-10). The assumed radiobiological parameter setting for adjuvant therapy [tumor dose to control 50% of the tumor (TCD50) =36.5 Gy and γ50=0.72] and curative intent (TCD50=51.24 Gy and γ50=0.83) were used. The bootstrap method was used to estimate the 95% confidence interval (95% CI). The coefficients (ρ) from Spearman's rank test were calculated to assess the correlation between quality indices with TCP. Wilcoxon paired test was used to calculate P value. Results: The 95% CI of TCP were 70.6-81.5 and 46.6-64.7, respectively, for adjuvant radiotherapy and curative intent. The TCP outcome showed a positive and good correlation with calculated dose to 95% of the target volume (D95%) and minimum dose (Dmin). Consistently, TCP correlate negatively with heterogeneity indices. Conclusions: This study confirms that more relevant and robust radiobiological parameters setting should be integrated according to cancer type. The positive correlation with quality indices gives chance to improve the clinical out-come by optimizing the treatment plans to maximize the Dmin and D95%. This attempt to increase the TCP should be carried out with the respect of dose constraints for organs at risks. However, the negative correlation with heterogeneity indices shows that the optimization of beam arrangements could be also useful. Attention should be paid to obtain an appropriate optimization of initial plans, when comparing and ranking radiotherapy plans using TCP models, to avoid over or underestimated for TCP outcome. © Translational lung cancer research. All rights reserved.

Van Der Velden S.K.,Erasmus University Rotterdam | Pichot O.,University Hospital of Grenoble | Van Den Bos R.R.,Erasmus University Rotterdam | Nijsten T.E.C.,Erasmus University Rotterdam | And 2 more authors.
European Journal of Vascular and Endovascular Surgery | Year: 2015

Objectives This study evaluated how patient characteristics and duplex ultrasound findings influence management decisions of physicians with specific expertise in the field of chronic venous disease. Methods Worldwide, 346 physicians with a known interest and experience in phlebology were invited to participate in an online survey about management strategies in patients with great saphenous vein (GSV) reflux and refluxing tributaries. The survey included two basic vignettes representing a 47 year old healthy male with GSV reflux above the knee and a 27 year old healthy female with a short segment refluxing GSV (CEAP classification C2sEpAs2,5Pr in both cases). Participants could choose one or more treatment options. Subsequently, the basic vignettes were modified according to different patient characteristics (e.g. older age, morbid obesity, anticoagulant treatment, peripheral arterial disease), clinical class (C4, C6), and duplex ultrasound findings (e.g. competent terminal valve, larger or smaller GSV diameter, presence of focal dilatation). The authors recorded the distribution of chosen management strategies; adjustment of strategies according to characteristics; and follow up strategies. Results A total of 211 physicians (68% surgeons, 12% dermatologists, 12% angiologists, and 8% phlebologists) from 36 different countries completed the survey. In the basic case vignettes 1 and 2, respectively, 55% and 40% of participants proposed to perform endovenous thermal ablation, either with or without concomitant phlebectomies (p <.001). Looking at the modified case vignettes, between 20% and 64% of participants proposed to adapt their management strategy, opting for either a more or a less invasive treatment, depending on the modification introduced. The distribution of chosen management strategies changed significantly for all modified vignettes (p <.05). Conclusions This study illustrates the worldwide variety in management preferences for treating patients with varicose veins (C2-C6). In clinical practice, patient related and duplex ultrasound related factors clearly influence therapeutic options. © 2014 European Society for Vascular Surgery.

Schweizer A.,Novartis | Halimi S.,University Hospital of Grenoble | Halimi S.,Joseph Fourier University | Dejager S.,Novartis
Vascular Health and Risk Management | Year: 2014

A large proportion of Muslim patients with type 2 diabetes mellitus (T2DM) elect to fast during the holy month of Ramadan. For these patients hypo- and hyperglycemia constitute two major complications associated with the profound changes in food pattern during the Ramadan fast, and efficacious treatment options with a low risk of hypoglycemia are therefore needed to manage their T2DM as effectively and safely as possible. Dipeptidyl peptidase-4 (DPP-4) inhibitors modulate insulin and glucagon secretion in a glucose-dependent manner, and consequently a low propensity of hypoglycemia has consistently been reported across different patient populations with these agents. Promising data with DPP-4 inhibitors have now also started to emerge in patients with T2DM fasting during Ramadan. The objective of this review is to provide a comprehensive overview of the currently available evidence and potential role of DPP-4 inhibitors in the management of patients with T2DM fasting during Ramadan whose diabetes is treated with oral antidiabetic drugs, and to discuss the mechanistic basis for their beneficial effects in this setting. © 2014 Schweizer et al.

Pichot O.,University Hospital of Grenoble | De Maeseneer M.,University of Antwerp | De Maeseneer M.,Erasmus Medical Center
Perspectives in Vascular Surgery and Endovascular Therapy | Year: 2011

Nowadays, various surgical and endovenous methods are available to treat varicose veins. Theoretically, every technique is applicable to treat any kind of patient. However, it seems appropriate to consider the specific indications and limitations of each of the techniques. To choose the most appropriate treatment method, several issues have to be taken into account. The patient's reason for consulting and clinical condition will define the aim of the treatment. Anatomical and hemodynamic characterization of the varicose veins by means of duplex ultrasound will define the technical feasibility. Although a definitive algorithm still remains to be developed, some of the most important questions that should be included in a decision tree can already be proposed: Is high ligation necessary or at least justified? Is stripping or ablation necessary or at least justified, and in that case, what is the most appropriate technique to be used? All this should help us define a reasonable "à la carte" treatment for each patient. © The Author(s) 2011.

Galasso O.,University of Catanzaro | Jenny J.-Y.,University of Strasbourg | Saragaglia D.,University Hospital of Grenoble | Miehlke R.K.,Rhine Main Center for Joint Diseases
Orthopedics | Year: 2013

The use of a keel in the tibial component during modern primary total knee arthroplasty (TKA) has become common, and its cementation may affect the future performance of the prosthesis. Although proponents of cementing the entire tibial component argue that this technique provides better initial fixation and may prevent aseptic loosening, reasons exist to apply cement only to the tibial baseplate. In this study, 232 patients who underwent TKA using full or surface cementation of the tibial baseplate were evaluated at an average 5.6-year follow-up to assess survivorship and clinical results. The cumulative survival rate at 8 years was 97.1%. With revision of either component for any reason considered the endpoint, no significant difference was noted between full and surface cemented groups. Knee Society Score, range of motion, and femorotibial mechanical angle significantly increased postoperatively. Multivariate analysis revealed that good preoperative range of motion and Knee Society Scores were related to good postoperative range of motion and Knee Society Scores. Follow-up length was a negative predictor of postoperative Knee Society Score. The use of full or surface cementation of the baseplate was unrelated to the postoperative clinical outcomes. Clinical outcomes did not differ according to the tibial component cementation technique. The results of this study suggest that cementing the keel of the tibial component during primary TKA has no advantage for patients. Longer-term follow-up and proper patient randomization are required to confirm these findings.

Brichon P.-Y.,University Hospital of Grenoble | Poquet C.,University Hospital of Grenoble | Arvieux C.,University Hospital of Grenoble | Pison C.,University Hospital of Grenoble
Interactive Cardiovascular and Thoracic Surgery | Year: 2012

A 41-year-old woman had a jeopardizing air leak from an alveolar-pleural and transdiaphragmatic fistula with pulmonary cavitation, secondary to a severe postoperative abdominal sepsis. Her condition dramatically improved by introduction, in the lower bronchus, of a one-way endobronchial valve, leading to immediate cessation of air leakage and removal of extracorporeal membrane oxygenation, and thus avoiding a lower left lobectomy with myoplasty. Furthermore, removal of the valve nine weeks later led to near-complete recovery of the left lower lobe. © 2012 The Author 2012. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Context: Androgen-deprivation therapy (ADT) as an adjuvant to radiation therapy (RT) is an established treatment for locally advanced prostate cancer (PCa). Objective: To examine the established clinical evidence on the use of short-term and/or long-term adjuvant ADT plus external irradiation and discuss recent data devoted to the duration of ADT with RT. Evidence acquisition: During the 2010 Annual Congress of the European Association of Urology (EAU) in Barcelona, Spain, a satellite symposium was held on the individualised management of patients with PCa. This paper is based on one of the presentations given at the symposium. Data were retrieved from recent review articles, original articles, and abstracts on the use of ADT in the neoadjuvant and/or concomitant and adjuvant settings with RT in patients with locally advanced PCa. Evidence synthesis: A number of studies have evaluated the survival benefits of short-term and long-term adjuvant ADT with RT in locally advanced PCa. European Organisation for Research and Treatment of Cancer (EORTC) study 22863 demonstrated that immediate androgen suppression given during and for 3 yr after external irradiation improved disease-free survival (DFS) and overall survival (OS) of patients with locally advanced PCa out to 10 yr. The OS benefits of long-term adjuvant ADT with RT were subsequently shown in Radiation Therapy Oncology Group (RTOG) protocols 85-31 and 92-02. More recently, EORTC study 22961 provided a definitive observation that 6-mo androgen suppression in association with three-dimensional conformal RT (3D-CRT) resulted in inferior survival compared with RT and 3 yr of ADT in the treatment of locally advanced PCa. Not only was OS improved but there was a significant improvement in all parameters of progression-free survival (PFS). Conclusions: Locally advanced PCa should be managed with 3D-CRT plus concomitant and adjuvant 3-yr androgen suppression. Several studies have evaluated the survival benefits of short-term and long-term adjuvant androgen-deprivation therapy (ADT) with radiation therapy in locally advanced prostate cancer. Definitive evidence for the superior benefits of long-term (3 yr) ADT plus three-dimensional conformal radiotherapy was provided by European Organisation for Research and Treatment of Cancer study 22961. © 2010 European Association of Urology.

Aptel F.,University Hospital of Grenoble | Aptel F.,Joseph Fourier University | Lafon C.,French Institute of Health and Medical Research
International Journal of Hyperthermia | Year: 2015

Glaucoma is a common disease mainly due to an increase in pressure inside the eye, leading to a progressive destruction of the optic nerve, potentially to blindness. Intraocular pressure (IOP) is the result of a balance between production of liquid that fills the eye-aqueous humour-and its resorption. All treatments for glaucoma aim to reduce IOP and can therefore have two mechanisms of action: reducing aqueous humour production by the partial destruction or medical inhibition of the ciliary body-the anatomical structure responsible for production of aqueous humour-or facilitating the evacuation of aqueous humour from the eye. Several physical methods can be used to destroy the ciliary body, e.g. laser, cryotherapy, microwave. All these methods have two major drawbacks: they are non-selective for the organ to be treated and they have an unpredictable dose-effect relationship. High intensity focused ultrasound (HIFU) can be used to coagulate the ciliary body and avoid these drawbacks. A commercially available device was marketed in the 1980s, but later abandoned, essentially for technical reasons. A smaller circular device using miniaturised transducers was recently developed and proposed for clinical practice. Experimental studies have shown selective coagulation necrosis of the treated ciliary body. The first three clinical trials in humans have shown that this device was well tolerated and allowed a significant, predictable and sustained reduction of IOP. The aim of this contribution is to present a summary of the work concerning the use of HIFU to treat glaucoma. © 2014 Informa UK Ltd. All rights reserved.

Halimi S.,University Hospital of Grenoble | Raccah D.,University Hospital Sainte Marguerite | Schweizer A.,Novartis | Dejager S.,Novartis
Current Medical Research and Opinion | Year: 2010

Background: The prevalence of type 2 diabetes (T2DM) increases with age. Older patients have an increased likelihood for T2DM-related morbidity and mortality. The objective of this review is to provide an overview of the challenges in managing T2DM in the elderly, with an emphasis on prevention of hypoglycaemia and the role of the DPP-4 inhibitor vildagliptin in this patient population. Methods: A search of PubMed was conducted (from 2003 to 2010) to identify English-language articles relevant to the management of elderly patients with T2DM, with an emphasis on vildagliptin treatment. A limitation of this review is that it does not provide an overview of the entire class of dipeptidyl-peptidase-4 (DPP-4) inhibitors. Findings: Management of T2DM in elderly patients is complicated by numerous factors, including a high prevalence of cardiovascular risk factors and other comorbidities and a high frequency of polypharmacy issues. Hypoglycaemia may pose the greatest barrier to optimal glycaemic control in elderly patients, who are less likely to recognise and respond to hypoglycaemic episodes, leading to increased frequency and severity of events. Data on the DPP-4 inhibitor vildagliptin indicate that reductions in A1C in elderly patients are at least as good as those observed in younger patients and are achieved with minimal risk of hypoglycaemia. T2DM in older individuals is associated with relative hyperglucagonaemia and elevated postprandial glucose (PPG). Vildagliptin treatment appears to address both these defects. Vildagliptin improves the ability of α-and β-cells to respond appropriately to changes in plasma glucose levels. This, in the face of high glucose levels, results in reduced inappropriate glucagon secretion and PPG excursions. In the face of low glucose, however, the protective glucagon response is well-preserved. These factors help explain the efficacy and minimal risk of hypoglycaemia observed with vildagliptin in elderly patients. Conclusion: The elderly population with T2DM poses unique treatment challenges and have not been particularly well-represented in clinical trials, highlighting the need for additional studies to better define appropriate glucose targets and to ascertain the best strategies for achieving and maintaining appropriate glycaemic levels. Because vildagliptin does not expose patients to hypoglycaemic risk, it seems particularly suited to oral therapy of T2DM in the elderly. © 2010 Informa UK Ltd.

News Article | October 26, 2016

Before your doctor starts sticking electrodes into your brain, it would be reasonable to hope that he or she knows precisely what will happen and why. But when it comes to deep brain stimulation (DBS) for Parkinson's disease, the only thing the experts can agree on is that it works. In DBS, millimetre-thin electrodes are implanted into the brain, aimed at a target smaller than a corn kernel, the location of which has been painstakingly mapped from imaging data. The electrodes deliver a mild stream of electrical jolts to the subthalamic nucleus that can control the debilitating motor symptoms that patients experience. Over the past few decades, the medical community has embraced this treatment. “The procedure is very safe and effective,” says Andres Lozano, a neurosurgeon at the University of Toronto in Canada. He estimates that around 10,000 people worldwide undergo DBS surgery for Parkinson's every year, with more than 140,000 people receiving implants so far. Yet little is known about how DBS restores normal function to the brain's motor circuitry. Progress is being made, however, and any advance in the understanding of the disease could yield major dividends in patient-specific care. “We are just blasting the brain with continuous stimulation at the moment, and it's amazing that such a crude intervention helps so much,” says Jill Ostrem, a neurologist at the University of California, San Francisco (UCSF). “Imagine what we could do if we could be more sophisticated and individualistic about this.” Perhaps the biggest obstacle is the continuing uncertainty about how Parkinson's causes the brain's circuits to malfunction. Most research into the neurophysiology of the disease has focused on the brain's 'motor circuit', which consists of the basal ganglia, the thalamus and part of the cortex that governs movement. As Parkinson's progresses, neurons in the basal ganglia that produce the neurotransmitter dopamine die, derailing the function of the motor circuit. “Dopamine plays the major role in setting the rules for neural activity,” says Lozano. “In the absence of that influence, the neurons start misbehaving and firing in a pattern that is pathological.” At first, researchers seeking an explanation for the neurons' misbehaviour favoured what was known as the 'rate model', which was developed in the 1980s. Neurologist Mahlon DeLong at Emory University in Atlanta, Georgia, proposed that parkinsonian symptoms arise from a higher rate of signalling in a region of the basal ganglia known as the subthalamic nucleus. DeLong thought that this increased neuronal firing was inhibiting other areas in the motor circuit, and reported that surgical disruption of the subthalamic nucleus relieved parkinsonian motor symptoms in monkeys1. In the 1990s, Alim-Louis Benabid and his colleagues, then at the University Hospital of Grenoble in France, used DeLong's findings as a foundation for the development of DBS for Parkinson's. Benabid's team demonstrated that high-frequency electrical stimulation, delivered by electrodes positioned near the subthalamic nucleus, eased motor symptoms such as rigidity2. Although the fundamentals of how DBS is given to people with Parkinson's have changed little since then, the rate model has largely fallen by the wayside. Instead, it seems that symptoms arise from a change in the normal firing patterns across the motor circuitry, rather than excessive firing at one point. The concept now is that the circuit is excessively synchronized, says Philip Starr, a neurosurgeon at UCSF. “Individual cells in the motor cortex and the basal ganglia that normally tend to fire independently now fire together,” Starr explains. In particular, Parkinson's researchers have identified high levels of β-band oscillation — brainwave activity occurring at around 15–30 hertz — within the basal ganglia. Such frequencies also occur in the healthy brain but become exaggerated in Parkinson's and seem to be associated with delayed or impaired conscious movement. Normally, dopamine-producing neurons in the basal ganglia prevent such synchronized rhythms from becoming established; in this 'pattern model', the loss of these neurons removes this safeguard. But researchers are still unclear how the disruptive β activity arises. One possibility is that the activity spills over from other connected regions of the brain. Neurologist Helen Bronte-Stewart, at Stanford University in California, says that the β activity that occurs routinely in the motor cortex could be transmitted by the long axons that extend from neurons in this region to the basal ganglia. Also unclear is how the β rhythm interferes with voluntary movement. Starr's group is exploring a phenomenon known as phase–amplitude coupling, which might have an important role in the process. According to this model, the parkinsonian motor cortex is forced to march in lockstep with β rhythms that emanate from the basal ganglia, rather than fire independently to enable normal physical movement. Against this backdrop, neuroscientists are at a loss as to why DBS works so well. When the rate model prevailed, researchers thought that DBS was directly inhibiting the excessive activity that DeLong, Benabid and their colleagues observed. But researchers have since shown that the electrical stimulation excites rather than inhibits neurons in the basal ganglia, sending neuroscientists back to the drawing board. “We had a situation where subthalamic stimulation was a mainstream therapy that had been done all over the world for ten years with great supporting evidence, but we didn't know how it worked anymore,” says Starr. Most current pattern-model theories go back to the idea that DBS breaks up the unhealthy rhythms in the motor circuitry by introducing irregular patterns of neuronal activity in the basal ganglia. “We're taking this pathological behaviour and quashing it,” says Lozano. “You seem to be better off with no output than with output that causes trouble.” But researchers are still struggling to understand how this loss of synchronization occurs, and the model is not yet universally accepted. Whatever the mechanism, the general belief is that the β-band-busting activity of DBS comes from stimulating the cells within the subthalamic nucleus of the basal ganglia. But neuroscientist Gordon Arbuthnott at the Okinawa Institute of Science and Technology in Japan and his colleagues have an alternative theory. They posit that stimulation excites the long axons that connect neurons in the motor cortex with those in the subthalamic nucleus, and that the effect is transmitted 'backwards' along these wires to the motor cortex, rather than 'forwards' into the basal ganglia. The hypothesis is that DBS disrupts unhealthy activity patterns in the motor cortex, and this region, in turn, stops the abnormal synchronization of β activity seen in the basal ganglia3, 4. “It seems as though there is a link between motor cortical activity, the loss of β rhythm and recovery,” Arbuthnott says. This would favour a model in which Parkinson's is driven by the motor cortex rather than by the basal ganglia. But research is still at an early stage — the supporting data have mostly come from animal models. Efforts to alleviate Parkinson's symptoms in humans with direct electrical stimulation of the motor cortex, rather than the basal ganglia, have proven disappointing. Unsolved mysteries about the mechanism aside, DBS works — and researchers are now customizing its delivery to individuals through a combination of clinical experience and technological progress. One of the hot questions concerns when during the course of the disease can DBS do the most good. Most people receive an implant after they have lived with medically managed Parkinson's for more than a decade, when disease progression has made their symptoms more difficult to control. A 2013 clinical trial called EARLYSTIM concluded that intervening a few years earlier might be beneficial5. The following year, a pilot study led by researchers at Vanderbilt University in Nashville, Tennessee, went further: they gave DBS to people who had been receiving medication for as little as six months6. Both studies provoked a backlash, partly because of the risks associated with neurosurgery, but also owing to fears that such patients might have been misdiagnosed and instead have a different, non-Parkinson's motor disorder. But some clinicians believe it is possible to identify those who are most likely to benefit from early intervention. “These are usually patients with early-onset, tremor-dominant Parkinson's disease,” says Bronte-Stewart. After DBS, she says, “many of them quit their meds and have a very good and stable response, and some of them are lucky enough to never develop cognitive impairment.” At the moment, DBS is an all-or-nothing proposition. It comprises a continuous dose of electrical stimulation at a fixed frequency that can be adjusted only by a specialist. More flexible approaches that are designed to fine-tune the timing, frequency and spatial distribution of the current could both boost the efficacy and reduce the downsides of DBS. Peter Brown, a neurologist at the University of Oxford, UK, is investigating patterned stimulation. Changing the timing of the electrical pulses can radically alter the effect of DBS on dysfunctional motor-circuit rhythms, he contends: “You can impede them by timing the stimulation appropriately, or you can worsen them by timing it wrong.” Peter Tass and colleagues at the Jülich Research Centre in Germany are pursuing a version of this approach called coordinated reset, which delivers stimulation sequentially to distinct subpopulations of subthalamic neurons. This approach has shown early promise, and Brown is impressed. “You can treat for a few sessions and there can be this prolonged, sustained improvement for several weeks,” he says. There are side effects with DBS, such as impaired speech, involuntary movements and cognitive impairment, and these can become especially problematic when stimulation is delivered non-stop. Brown likens it to “heating a room in your house all the time, come summer or winter”. His team is among several that are developing adaptive DBS, in which stimulation changes in response to physiological signals — essentially, installing a thermostat for the brain (see 'Deep brain thermostat'). The hard part is picking the right trigger. Brown's team is focusing on excessive β-band activity in the basal ganglia, and has shown that the adaptive approach delivers symptom relief that is equivalent to conventional DBS, while reducing the side effects7. Adaptive systems also consume less power — an important benefit given that standard batteries for current DBS last only 3–4 years and require a surgical procedure to replace. Meanwhile, Starr's team has identified signatures in the activity of motor-cortex neurons that predict the onset of parkinsonian symptoms, and devised an algorithm that initiates stimulation when these patterns are detected8. And Bronte-Stewart's team has developed an adaptive DBS platform that uses Bluetooth-enabled smartwatches to detect the onset of tremor and then signal to the stimulator to respond accordingly9. These adaptive approaches could also help to unlock some mysteries of the parkinsonian brain. Ostrem, for example, has been working with a new DBS system from Medtronic called the Activa PC+S, which allows flexible monitoring of brain activity before, during and after the onset of symptoms. Ostrem notes that these kinds of technologies, combined with accumulating data from high-resolution brain imaging and modelling efforts, could allow treatment regimens that target specific neurological malfunctions. “Parkinson's patients have similar symptoms, but there are probably many reasons why they develop,” she says. “It may be that DBS should not be applied in the exact same way to everyone.” Although it is important to uncover the mystery of how DBS works, improving the precision of treatment will at least remove some of the urgency from answering such questions.

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