Expected impact of applying new 2013 AHA/ACC cholesterol guidelines criteria on the recommended lipid target achievement after acute coronary syndromes.

BACKGROUND: 2013 AHA/ACC guidelines on the treatment of cholesterol advised to tailor high-intensity statin after ACS, while previous ATP-III recommended titration of statin to reach low-density lipoprotein cholesterol (LDL-C) targets. We simulated the impact of this change of paradigm on the achievement of recommended targets. METHODS: Among a prospective cohort study of consecutive patients hospitalized for ACS from 2009 to 2012 at four Swiss university hospitals, we analyzed 1602 patients who survived one year after recruitment. Targets based on the previous guidelines approach was defined as (1) achievement of LDL-C target < 1.8 mmol/l, (2) reduction of LDL-C ≥ 50% or (3) intensification of statin in patients who did not reach LDL-C targets. Targets based on the 2013 AHA/ACC guidelines approach was defined as the maximization of statin therapy at high-intensity in patients aged ≤75 years and moderate- or high-intensity statin in patients >75 years. RESULTS: 1578 (99%) patients were prescribed statin at discharge, with 1120 (70%) at high-intensity. 1507 patients (94%) reported taking statin at one year, with 909 (57%) at high-intensity. Among 482 patients discharged with sub-maximal statin, intensification of statin was only observed in 109 patients (23%). 773 (47%) patients reached the previous LDL-C targets, while 1014 (63%) reached the 2013 AHA/ACC guidelines targetsone year after ACS (p value < 0.001). CONCLUSION: The application of the new 2013 AHA/ACC guidelines criteria would substantially increase the proportion of patients achieving recommended lipid targets one year after ACS. Clinical trial number, NCT01075868.

Helical tomotherapy in the treatment of anal canal cancer: 3-year clinical experience

Objective: To report a single-center experience treating patients with squamous- cell carcinoma of the anal canal using helical Tomotherapy (HT) and concurrent chemotherapy (CT).Materials/Methods: From October 2007 to February 2011, 55 patients were treated with HT and concurrent CT (5-fluorouracil/capecitabin and mitomycin) for anal squamous-cell carcinoma. All patients underwent computed- tomography-based treatment planning, with pelvic and inguinal nodes receiving 36 Gy in 1.8 Gy/fraction. Following a planned 1-week break, primary tumor site and involved nodes were boosted to a total dose 59.4 Gy in 1.8 Gy/fraction. Dose-volume histograms of several organs at risk (OAR; bladder, small intestine, rectum, femoral heads, penile bulb, external genitalia) were assessed in terms of conformal avoidance. All toxicity was scored according to the CTCAE, v.3.0. HT plans and treatment were implemented using the Tomotherapy, Inc. software and hardware. For dosimetric comparisons, 3D RT and/or IMRT plans were also computed for some of the patients using the CMS planning system, for treatment with 6-18 MV photons and/or electrons with suitable energies from a Siemens Primus linear accelerator equipped with a multileaf collimator.Locoregional control and survival curves were compared with the log-rank test, and multivariate analysis by the Cox model.Results: With 360-degree-of-freedom beam projection, HT has an advantage over other RT techniques (3D or 5-field step-and-shot IMRT). There is significant improvement over 3D or 5-field IMRT plans in terms of dose conformity around the PTV, and dose gradients are steeper outside the target volume, resulting in reduced doses to OARs. Using HT, acute toxicity was acceptable, and seemed to be better than historical standards.Conclusions: Our results suggest that HT combined with concurrent CT for anal cancer is effective and tolerable. Compared to 3D RT or 5-field step-andshot IMRT, there is better conformity around the PTV, and better OAR sparing.

Stability of the Helical TomoTherapy Hi·Art II detector for treatment beam irradiations.

The Hi·Art II Helical TomoTherapy (HT) unit is equipped with a built-in onboard MVCT detector used for patient imaging and beam monitoring. Our aim was to study the detector stability for treatment beam measurements. We studied the MVCT detector response with the 6 MV photon beam over time, throughout short-term (during an irradiation) and long-term (two times 50 days) periods. Our results show a coefficient of variation ≤ 1% for detector chambers inside the beam (excluding beam gradients) for short- and long-term response of the MVCT detector. Larger variations were observed in beam gradients and an influence of the X-ray target where degradation was found. The results assume that an 'air scan' procedure is performed daily to recalibrate the detector with the imaging beam. On short term, the detector response stability is comparable to other devices. Long-term measure- ments during two 50-day periods show a good reproducibility. 

Vectorisation intra-oculaire [Drug delivery to target the posterior segment of the eye].

Retinal diseases are nowadays the most common causes of vision threatening in developed countries. Therapeutic advances in this field are hindered by the difficulty to deliver drugs to the posterior segment of the eye. Due to anatomical barriers, the ocular biodisponibility of systemically administered drugs remains poor, and topical instillation is not adequate to achieve therapeutic concentrations of drugs in the back of the eye. Ocular drug delivery has thus become one of the main challenges of modern ophthalmology. A multidisciplinary research is being conducted worldwide including pharmacology, biomaterials, ophthalmology, pharmaceutics, and biology. New promising fields have been developed such as implantable or injectable slow release intravitreal devices and degradable polymers, dispersed polymeric systems for intraocular drug delivery, and transscleral delivery devices such as iontophoresis, osmotic pumps or intra-scleraly implantable materials. The first clinical applications emerging from this research are now taking place, opening new avenues for the treatment of retinal diseases.

Systèmes de délivrance des médicaments pour le segment antérieur: bases fondamentales et applications cliniques [Drug delivery systems to target the anterior segment of the eye: fundamental bases and clinical applications].

The development of new drug delivery systems to target the anterior segment of the eye may offer many advantages: to increase the biodisponibility of the drug, to allow the penetration of drug that cannot be formulated as solutions, to obtain constant and sustained drug release, to achieve higher local concentrations without systemic effects, to target more specifically one tissue or cell type, to reduce the frequency of instillation and therefore increase the observance and comfort of the patient while reducing side effects of frequent instillation. Several approaches are developed, aiming to increase the corneal contact time by modified formulation or reservoir systems, or by increasing the tissue permeability using iontophoresis. To date, no ocular drug delivery system is ideal for all purposes. To maximize treatment efficacy, careful evaluation of the specific pathological condition, the targeted Intraocular tissue and the location of the most severe pathology must be made before selecting the method of delivery most suitable for each individual patient.

Toll-like receptor 3 expressed by melanoma cells as a target for therapy?

PURPOSE: The immunomodulatory properties of Toll-like receptors (TLR) agonists have inspired their use as experimental adjuvants for vaccination of cancer patients. However, it is now well recognized that TLR expression is not restricted to immune cells but can also be found in many cell types, including those giving rise to tumors. It is therefore mandatory to explore the potential effects of TLR triggering directly on tumor cells. EXPERIMENTAL DESIGN: In the present work, we have investigated TLR3 protein expression in melanoma cell lines derived from patients, and analyzed the effects of TLR3 agonists on tumor cell survival. Moreover, we used RNA interference to stably knock down TLR3 expression and study the involvement of this receptor in dsRNA-induced effects on melanoma cells viability. RESULTS: Human melanoma cells can express functional TLR3 protein. Interestingly, the engagement of the receptor by TLR3 agonists can directly inhibit cell proliferation and induce tumor cell death when combined to treatment with either type I IFN or protein synthesis inhibitors. These effects were shown by RNA interference to be largely dependent on TLR3. Moreover, TLR3-mediated cell death involves the activation of caspases and engages both extrinsic and intrinsic apoptotic pathways. CONCLUSION: TLR3 protein can be expressed in human melanoma cells, where it can deliver proapoptotic and antiproliferative signaling. Altogether, these results suggest that TLR3 agonists represent very promising adjuvants for cancer vaccines not only based on their well-described immunostimulatory properties, but also due to their newly identified cytostatic and cytotoxic effects directly on tumor cells.

ALK inhibitors in the treatment of advanced NSCLC.

Pharmacologic agents that target protein products of oncogenes in tumors are playing an increasing clinical role in the treatment of cancer. Currently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. Subsequently other genetic abnormalities with "driver" characteristics - implying transforming and tumor maintenance capabilities have been extensively reported in several small distinct subsets of NSCLC. Among these rare genetic changes, anaplastic lymphoma kinase (ALK) gene rearrangements, most often consisting in a chromosome 2 inversion leading to a fusion with the echinoderm microtubule-associated protein like 4 (EML4) gene, results in the abnormal expression and activation of this tyrosine kinase in the cytoplasm of cancer cells. This rearrangement occurs in 2-5% of NSCLC, predominantly in young (50 years or younger), never- or former-smokers with adenocarcinoma. This aberration most commonly occurs a independently of EGFR and KRAS gene mutations. A fluorescent in situ hybridization assay was approved by the US Food and Drug Administration (FDA) as the standard method for the detection of ALK gene rearrangement in clinical practice and is considered the gold standard. Crizotinib, a first-in-class dual ALK and c-MET inhibitor, has been shown to be particularly effective against ALK positive NSCLC, showing dramatic and prolonged responses with low toxicity, predominantly restricted to the gastro-intestinal and visual systems, and generally self-limiting or easily managed. However, resistance to crizotinib inevitably emerges. The molecular mechanisms of resistance are currently under investigation, as are therapeutic approaches including crizotinib-based combination therapy and novel agents such as Hsp90 inhibitors. This review aims to present the current knowledge on this fusion gene, the clinic-pathological profile of ALK rearranged NSCLC, and to review the existing literature on ALK inhibitors, focusing on their role in the treatment of NSCLC.

Medical treatment of hypertension in Switzerland. The 2009 Swiss Hypertension Survey (SWISSHYPE).

OBJECTIVES: Despite a broad and efficient pharmacological antihypertensive armamentarium, blood pressure (BP) control is suboptimal and heterogeneous throughout Europe. Recent representative data from Switzerland are limited. The goal of the present survey was therefore to assess the actual control rate of high BP in Switzerland in accordance with current guidelines. The influence of risk factors, target organ damage and medication on BP levels and control was also evaluated.METHODS : A cross-sectional visit-based survey of ambulatory hypertensive patients was performed in 2009 in Switzerland. 281 randomly selected physicians provided data on 5 consecutive hypertensive patients attending their practices for BP follow-up. Data were anonymously collected on demographics, comorbidities and current medication, and BP was recorded. Subsequent modification of pharmacological antihypertensive therapy was assessed.RESULTS : Data from 1376 patients were available. Mean age was 65 +/- 12 years, 53.9% were male subjects. 26.4% had complicated hypertension. Overall, BP control (<140/90 mm Hg for uncomplicated and <130/80 mm Hg for complicated hypertension) was achieved in 48.9%. Compared to patients with complicated hypertension, BP control was better in patients with uncomplicated hypertension (59.4% vs. 19.2%, p < 0.001). As a monotherapy the most prescribed drug class were angiotensin receptor blockers (ARB, 41%), followed by angiotensin converting enzyme (ACE) inhibitors (21.5%), betablockers (20.8%) and calcium channel blockers (CCB, 10.8%). The most prescribed drug combinations were ARB + diuretic (30.1%) and ACE inhibitors + diuretic (15.3%). 46% were receiving a fixed drug combination. In only 32.7% of patients with uncontrolled hypertension was a change in drug therapy made.CONCLUSION : This representative survey on treated adult hypertensive patients shows that, compared to earlier reports, the control rate of hypertension has improved in Switzerland for uncomplicated but not for complicated, particularly diabetes-associated hypertension. ARBs and ACE inhibitors are the most prescribed antihypertensive drugs for monotherapy, whereas diuretics and ARBs were the most used for combination therapy.

Difficult-to-engage patients: a specific target for time-limited assertive outreach in a Swiss setting.

OBJECTIVE: Assertive community treatment (ACT) failed to develop in Europe, and its efficacy is debated. In Lausanne, Switzerland, ACT focuses on difficult-to-engage patients and aims to facilitate linkage with outpatient care through time-limited interventions. This study aimed to evaluate the applicability and efficiency of time-limited ACT. METHODS: We retrospectively assessed social, clinical, and functional outcomes and motivation for treatment in 75 consecutively seen subjects treated between 2000 and 2002. RESULTS: With 70% of the interventions lasting less than 6 months, we observed significant improvement in most clinical and social problems, in collaboration, in motivation for treatment, and in social network support, despite high baseline levels of clinical and social problems. The number of hospitalizations decreased significantly. CONCLUSIONS: Time-limited ACT is a useful treatment for difficult-to-engage patients with severe clinical and social problems, and it facilitates linkage to care. This narrower target for ACT may facilitate its implementation in Europe.

Safety concerns about CCR5 as an antiviral target.

PURPOSE OF REVIEW: Clinical trials of CCR5 antagonists attest to their efficacy and tolerance in HIV treatment. However, there has been debate on their long-term safety because of the role of CCR5 in innate immunity. This review highlights gaps in our understanding of epidemiology of infections that are modulated by CCR5, in particular, in HIV-infected individuals. RECENT FINDINGS: In the mouse model, CCR5 has a role in the response against pathogens as diverse as Toxoplama gondii, West Nile virus, Mycobacterium tuberculosis, herpes simplex virus, Trypanosoma cruzi, Cryptococcus neoformans, Chlamydia trachomatis, Listeria, and plasmodia. In human cohorts, individuals carrying the defective CCR5Delta32 allele present an increased susceptibility to flavivirus (West Nile virus and tickborne encephalitis virus). The selective pressures that led to the spread of loss-of-function CCR5 mutations in humans (CCR5Delta32), and in mangabeys (CCR5Delta24) are not understood. SUMMARY: The recent availability of CCR5 antagonists has raised concern that genetic, biological, or chemical CCR5 knockout, although beneficial against some pathogens (i.e. HIV), could be deleterious for other processes implicated in pathogen response. The consequences of long-term pharmaceutical intervention on CCR5 should be carefully assessed through rigorous postmarketing surveillance.

The need for combination antihypertensive therapy to reach target blood pressures: what has been learned from clinical practice and morbidity-mortality trials?

Pharmacological treatment of hypertension represents a cost-effective way for preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment blood pressure (BP) should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (&lt; 130/80 mmHg) if diabetes or renal disease co-exists. Most of the time such targets cannot be reached using monotherapies. This is especially true in patients who exhibit a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases BP control. Such preparations are not only efficacious, but also well tolerated, and some fixed low-dose combinations have a tolerability profile similar to placebo. This is for instance the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has recently been shown in controlled interventional trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving macrovascular stiffness. Fixed-dose combinations are becoming more and more popular and are even proposed by current hypertension guidelines as a first-line option to treat hypertensive patients.

Tertiary treatment of pulp and paper mill effluents

Työn tavoitteena oli selvittää mitä käsittelyvaihtoehtoja on olemassa jäteveden puhdistamon tertiäärikäsittelyyn ja miten suuri tarve paperi- ja selluteollisuuden prosessivesien puhdistukseen on. Tarkoituksena oli saada käsitys koko tertiäärikäsittelystä eri näkökulmista. Lopuksi läpikäytiin tertiäärikäsittelymenetelmiä ja etsittiin mahdollisia uusia menetelmiä, joita voitaisiin käyttää jäteveden tertiääripuhdistukseen. Ensimmäisenä työssä on perehdytty jäteveden koostumukseen paperi- ja selluteollisuudessa ja puhdistukseen ilmastetulla aktiivilietemenetelmällä, jotta tertiäärikäsittely ymmärrettäisiin konseptina paremmin. Lisäksi työssä selvitettiin tertiäärikäsittelyn tarvetta ja vaihtoehtoja sen käyttämättä jättämiselle teollisuuden ja muun ympäristöä vahingoittavan toiminnan ympäristönäkökohdat huomioonottaen. Lyhyiden menetelmäesitysten jälkeen kiteytetään tertiäärikäsittelyn ympäristönäkökohdatja vaihtoehdot sen käytölle yhteenvetona, jossa otetaan huomioon myös viranomaisten, yrityksen ja BAT referenssien sisältämä tieto tertiäärikäsittelystä. Työn kokeellinen osa sisältää erään tertiäärikäsittelysovelluksenrakentamisen, koekäytön ja laboratorioanalyysien yhteenvedon. Lisäksi menetelmää verrataan kustannus-tehokkuudeltaan vastaavien menetelmien kanssa. Tarkoituksena oli löytää jäteveden tertiäärikäsittelyyn sopiva laitteisto, jonka toimintaanei sisältyisi kemikaalien annostelua ja sitä käytettäisiin lähinnä jätevedenpuhdistamon ongelmatilanteiden väliaikaiseksi ratkaisuksi. Mahdollisesti se voisi toimia myös jatkuvatoimisesti veden kirkastuksessa. Diplomityössä rakennettu laitteisto, jota käytettiin myös pilot koeajoissa, ei ollut paras mahdollinen laitteisto tertiäärikäsittelyn toteuttamiseksi paperi- ja selluteollisuudessa, mutta kilpailukykyinen muiden laitteistojen kanssa. Laitteiston toimintaperiaate on kuitenkin käyttökelpoinen tietyin varauksin ja sitä voidaan käyttää vedenpuhdistamiseen.

Wastewater Treatment of Diesel Power Plant

Diplomityön tavoitteena on selvittää Wärtsilän dieselvoimalaitosten jätevedenkäsittelyn vallitseva tila. Tutkimuksessa keskitytään raskaspolttoöljykäyttöisiin voimalaitoksiin. Työssä selvitetään yleisimmät dieselvoimalaitosten jätevesille asetetut vaatimukset. Selvitys tehdään keräämälläja tutkimalla dieselvoimalaitosten jätevesille sovellettuja standardeja. Työssä selvitetään myös dieselvoimalaitokselta ulostulevan jäteveden laatu sekä nykyisen jätevedenkäsittelyjärjestelmän toiminta. Selvitys tehdään keräämällä ja tutkimalla yrityksen sisäisiä tietoja, sekä ottamalla ja analysoimalla jätevesinäytteitä. Näytteiden otto ja analysointi toteutetaan vierailemallakahdessa voimalaitoksessa sekä yhdessä muussa kohteessa. Jäteveden laatu ennen ja jälkeen käsittelyn määritetään. Myös öljynjalostusteollisuuden jätevedenkäsittelyä tarkastellaan kirjallisuuteen pohjautuen. Tarkastelun tavoitteena on hankkia tietoa jätevedenkäsittelystä kohteissa, joissa jäteveden laatu vastaa dieselvoimalaitoksella syntyvää jätevettä. Vertailun vuoksi myös öljynjalostusteollisuudelle asetetuttuja jätevesistandardeja tutkitaan. Lisäksi työssä tutkitaan myös joitakin muita jätevedenkäsittelymenetelmiä. Diplomityön tuloksena määritetään dieselvoimalaitosten jätevedenkäsittelyn tulevaisuuden haasteet ja mahdollisuudet.

Modern Gamma Knife radiosurgery of vestibular schwannomas: treatment concept, volumetric tumor response, and functional results.

The objective of the present study was longitudinal evaluation of the volumetric tumor response and functional results after Gamma Knife radiosurgery of vestibular schwannomas, performed according to the modern standards of treatment. From October 2003 to September 2007, 133 consecutive patients with vestibular schwannomas were treated according to the concept of robotic Gamma Knife microradiosurgery, which is based on precise irradiation of the lesion, sparing adjacent structures, and delivery of the high radiation energy to the target. Multiple small-sized isocenters located within the border of the neoplasm were applied. The mean marginal dose was 11.5 Gy (range, 11-12 Gy). In total, 126 cases with a minimum posttreatment follow-up of 2 years (range, 2-7 years; median, 4 years) were analyzed. Temporary enlargement was noted in 25 % of tumors at 6 months after radiosurgery. At 3 years of follow-up, tumor shrinkage, stabilization, and increase in volume were marked in 73 %, 23 %, and 4 % of cases, respectively. All progressing lesions spontaneously stabilized later on and did not require additional management. In 3 % of patients, transitory impairment of the facial nerve function was marked; however, neither its permanent dysfunction nor trigeminal neuropathy attributed to radiosurgery was noted. Impairment of hearing compared to its pretreatment level was revealed in 4 %, 12 %, 13 %, and 16 % of patients at 6 months, 1 year, 2 years, and 3 years after radiosurgery, respectively, and this trend was statistically significant (P = 0.0042). Overall, 77 % of patients with serviceable hearing before treatment preserved it 3 years thereafter. In conclusion, modern Gamma Knife radiosurgery provides effective and safe management of vestibular schwannomas. Nevertheless, possible temporary tumor enlargement, delay of its growth arrest, transient dysfunction of the cranial nerves, and gradual deterioration of hearing after irradiation should be always taken into consideration.

Helical tomotherapy for the treatment of anal canal cancer: a dosimetric comparison with 3D conformal radiotherapy.

AIMS AND BACKGROUND: The standard treatment of anal canal cancer (ACC) is combined chemotherapy and radiation therapy (RT), which is complex because of the shape of the target volumes and the need to minimize the irradiation of normal pelvic structures. In this study we compared the dosimetric results of helical tomotherapy (HT) plans with traditional 3D conformal RT (3DRT) plans for the treatment of ACC. METHODS AND STUDY DESIGN: Twelve patients (median age 57 years, range 38-83; F/M 8/4) treated with HT and concurrent chemotherapy for locally advanced ACC were selected. All had histologically confirmed squamous-cell carcinoma. A clinical target volume including the tumor and pelvic and inguinal lymph nodes was treated with HT to a total dose of 36 Gy in 1.8-Gy daily fractions. Then a sequential boost of 23.4 Gy in 1.8-Gy daily fractions (total dose 59.4 Gy) was delivered to the tumor and involved nodes. For all 12 patients, 3DRT plans were generated for comparison. Treatment plans were evaluated by means of standard dose-volume histograms. Dose coverage of the planning target volumes (PTVs), homogeneity index (HI), and mean doses to organs at risk (OARs) were compared. RESULTS: The coverage of PTV was comparable between the two treatment plans. HI was better in the HT vs. 3DRT plans (1.25 and 3.57, respectively; p<0.0001). HT plans resulted in better sparing of OARs (p<0.0001). CONCLUSIONS: HT showed superior target dose conformality and significant sparing of pelvic structures compared with 3DRT. Further investigation should determine if these dosimetric improvements will improve clinical outcomes regarding locoregional control, survival, and treatment-related acute and late morbidity.