First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma.

PURPOSE: To evaluate the efficacy of first-line chemotherapy (CT) in preventing external-beam radiotherapy (EBR) and/or enucleation in patients with retinoblastoma (Rbl). PATIENTS AND METHODS: Twenty-four patients with newly diagnosed unilateral or bilateral Rbl received CT associated with local treatment (LT). Two to five courses of etoposide and carboplatin were administered at 3- to 4-week intervals, depending on tumor response, and were completed each time by LT. RESULTS: Tumor response was observed in all eyes. Twenty-one of 24 patients showed a complete response (CR) that persisted at a median follow-up (FU) of 31 months (range, 4 to 41 months). Among the three patients who relapsed, two were lost to FU and one died of progressive disease. CR was achieved by CT and LT alone in 15 (71.4%) of 21 patients with less advanced disease (groups I to III). Six other patients with advanced disease (groups IV and V) experienced treatment failure and needed salvage treatment by EBR and/or enucleation. The difference between the two patient groups with regard to disease stage was statistically significant (P <.0001). EBR could be avoided in 13 (68.4%) of 19 patients, who presented with groups I to III (15 eyes) and group V (one eye) disease, whereas enucleation could be avoided in only two (40%) of five. CONCLUSION: CT combined with intensive LT is effective in patients with groups I to III Rbl, permitting the avoidance of EBR in the majority of these young children and, thus, reducing the risk of long-term sequelae. This is in contrast with the disappointing results for patients with groups IV and V Rbl, in whom EBR and/or enucleation was needed.

An adapted model of ex vivo vein perfusion: the key to understand vessel wall remodeling

Objective: Saphenous vein graft bypass remains the salvage option when¦endovascular procedure has failed or was contraindicated due to extensive¦occlusive lesions. However, pathological wall remodeling leading leading to¦graft failure is one of the most limiting factors of this therapy. Therefore, the¦understanding of this remodeling process of human vein is essential to the design¦of future effective therapeutics and it requires an adapted model of ex-vivo vein¦perfusion.¦Methods: We have developed an ex vivo vein support system (EVVSS), which¦uses standardized and controlled hemodynamic parameters for the pulsatile¦perfusion of saphenous vein segments. The morphological and molecular¦parameters involved in the remodeling process under an arterial shear stress¦associated to low (7 mm Hg) or high (70 mm Hg) pressure conditions can be¦analyzed.¦Results: Histomorphometric analysis showed that the vein segments perfused¦during 7 days under high pressure undergo a significant neointima development¦compared to veins exposed to low pressure conditions. The application of an¦arterial shear stress in the vein under low pressure induced an elevation of the¦MMP-2 and MMP-9 expression, activity and transcription. The application of¦higher pressure is associated to increased MMP2 expression and transcription¦and MMP9 transcription. TIMP1 expression and transcription were initiated by¦the application of an arterial shear stress but not modified by the modification¦of the pressure. However, TIMP2 expression was increased under high¦pressure conditions but its transcription was inhibited by arterial shear stress,¦independently of the pressure. The values of transcription and expression of¦PAI-1 were not modified by high pressure. Eph-B4 transcription and expression¦were significantly decreased under arterial shear stress.¦Conclusion: These data show that our EVVSS is a valuable setting to study¦ex vivo remodeling of human saphenous veins submitted to arterial conditions.¦The intimal hyperplasia as well as MMP 2, 9 and TIMP 2 seem to be influenced¦by the pressure.

Transanal endoscopic microsurgery resection of rectal tumors: outcomes and recommendations.

PURPOSE: Transanal endoscopic microsurgery provides a minimally invasive alternative to radical surgery for excision of benign and malignant rectal tumors. The purpose of this study was to review our experience with transanal endoscopic microsurgery to clarify its role in the treatment of different types of rectal pathology. METHODS: A prospective database documented all patients undergoing transanal endoscopic microsurgery from October 1996 through June 2008. We analyzed patient and operative factors, complications, and tumor recurrence. For recurrence analysis, we excluded patients with fewer than 6 months of follow-up, previous excisions, known metastases at initial presentation, and those who underwent immediate radical resection following transanal endoscopic microsurgery. RESULTS: Two hundred sixty-nine patients underwent transanal endoscopic microsurgery for benign (n = 158) and malignant (n = 111) tumors. Procedure-related complications (21%) included urinary retention (10.8%), fecal incontinence (4.1%), fever (3.8%), suture line dehiscence (1.5%), and bleeding (1.5%). Local recurrence rates for 121 benign and 83 malignant tumors were 5% for adenomas, 9.8% for T1 adenocarcinoma, 23.5% for T2 adenocarcinoma, 100% for T3 adenocarcinoma, and 0% for carcinoid tumors. All 6 (100%) recurrent adenomas were retreated with endoscopic techniques, and 8 of 17 (47%) recurrent adenocarcinomas underwent salvage procedures with curative intent. CONCLUSIONS: Transanal endoscopic microsurgery is a safe and effective method for excision of benign and malignant rectal tumors. Transanal endoscopic microsurgery can be offered for (1) curative resection of benign tumors, carcinoid tumors, and select T1 adenocarcinomas, (2) histopathologic staging in indeterminate cases, and (3) palliative resection in patients medically unfit or unwilling to undergo radical resection.

Severe and steroid-resistant Crohn's disease.

Patients with moderate to severe disease and patients with steroid-refractory or steroid-dependent disease differ in their management, as the latter groups usually include patients with less acute situations. Systemic corticosteroids represent the mainstay of the management of moderate to severe disease and remain the first-line therapy in this setting. Infliximab is the choice alternative for patients who do not respond to steroids or in whom steroids are contraindicated. Purine analogues, methotrexate and infliximab have shown efficacy in achieving steroid-free remission in patients with steroid-refractory or -dependent disease. Other fast-acting immunosuppressors showed little benefit. Surgery may be indicated in this setting. Nataluzimab may prove useful in patients refractory to infliximab.

Multiplex ultra-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification in human plasma of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, anidulafungin, and caspofungin.

Therapeutic drug monitoring (TDM) may contribute to optimizing the efficacy and safety of antifungal therapy because of the large variability in drug pharmacokinetics. Rapid, sensitive, and selective laboratory methods are needed for efficient TDM. Quantification of several antifungals in a single analytical run may best fulfill these requirements. We therefore developed a multiplex ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method requiring 100 μl of plasma for simultaneous quantification within 7 min of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, caspofungin, and anidulafungin. Protein precipitation with acetonitrile was used in a single extraction procedure for eight analytes. After reverse-phase chromatographic separation, antifungals were quantified by electrospray ionization-triple-quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. Deuterated isotopic compounds of azole antifungals were used as internal standards. The method was validated based on FDA recommendations, including assessment of extraction yields, matrix effect variability (<9.2%), and analytical recovery (80.1 to 107%). The method is sensitive (lower limits of azole quantification, 0.01 to 0.1 μg/ml; those of echinocandin quantification, 0.06 to 0.1 μg/ml), accurate (intra- and interassay biases of -9.9 to +5% and -4.0 to +8.8%, respectively), and precise (intra- and interassay coefficients of variation of 1.2 to 11.1% and 1.2 to 8.9%, respectively) over clinical concentration ranges (upper limits of quantification, 5 to 50 μg/ml). Thus, we developed a simple, rapid, and robust multiplex UPLC-MS/MS assay for simultaneous quantification of plasma concentrations of six antifungals and two metabolites. This offers, by optimized and cost-effective lab resource utilization, an efficient tool for daily routine TDM aimed at maximizing the real-time efficacy and safety of different recommended single-drug antifungal regimens and combination salvage therapies, as well as a tool for clinical research.

The effectiveness and safety of rescue treatments in 108 patients with steroid-refractory ulcerative colitis with sequential rescue therapies in a subgroup of patients.

BACKGROUND: Among patients with steroid-refractory ulcerative colitis (UC) in whom a first rescue therapy has failed, a second line salvage treatment can be considered to avoid colectomy. AIM: To evaluate the efficacy and safety of second or third line rescue therapy over a one-year period. METHODS: Response to single or sequential rescue treatments with infliximab (5mg/kg intravenously (iv) at week 0, 2, 6 and then every 8weeks), ciclosporin (iv 2mg/kg/daily and then oral 5mg/kg/daily) or tacrolimus (0.05mg/kg divided in 2 doses) in steroid-refractory moderate to severe UC patients from 7 Swiss and 1 Serbian tertiary IBD centers was retrospectively studied. The primary endpoint was the one year colectomy rate. RESULTS: 60% of patients responded to the first rescue therapy, 10% went to colectomy and 30% non-responders were switched to a 2(nd) line rescue treatment. 66% of patients responded to the 2(nd) line treatment whereas 34% failed, of which 15% went to colectomy and 19% received a 3(rd) line rescue treatment. Among those, 50% patients went to colectomy. Overall colectomy rate of the whole cohort was 18%. Steroid-free remission rate was 39%. The adverse event rates were 33%, 37.5% and 30% for the first, second and third line treatment respectively. CONCLUSION: Our data show that medical intervention even with 2(nd) and 3(rd) rescue treatments decreased colectomy frequency within one year of follow up. A longer follow-up will be necessary to investigate whether sequential therapy will only postpone colectomy and what percentage of patients will remain in long-term remission.

Amputations du membre inférieur [Amputations of the lower extremity]

Still nowadays amputations are frequently performed in our country. In diabetic patients the incidence of an amputation is 25 times higher than in the normal population. All possibilities of revascularisation or limb salvage must be excluded by a multidisciplinary approach before choosing an amputation. Once the decision is taken the good level of amputation and the correct technique have to determined. The goal of this article is to describe which clinical and paraclinical parameters will help the surgeon to choose the best level of amputation, which techniques are to be used for the amputation and to finally give some information about re-education and the fitting of an orthesis or prosthesis.

Giant extraskeletal myxoid chondrosarcoma of the thigh treated by wide extraarticular resection and reconstruction with a tumor prosthesis

Introduction: Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue tumour with a high risk for local recurrence and metastases. While this entity is resistant to radio- or chemo-therapy, wide resection remains the treatment of choice. Case report: A 60 year old man presented to our service with a large mass in his right thigh, slowly evolving over the past 7 years. His main complaint was the volume of his thigh. Imaging showed a 23x13x14 cm tumour in the quadriceps, eroding the cortical bone and with potential contamination of the knee joint. The risk of a pathological fracture was estimated considerable. A CT-guided core-needle biopsy revealed a FNCLCC grade 2 EMC. A thoraco-abdominal CT scan showed multiple pulmonary metastases. Due to the palliative situation with a very slow disease progression, a wide extraarticular resection of the distal femur and reconstruction with a megaprosthesis were performed. Extensive skin necrosis necessitated three revision procedures for débridement and confection of a pediculated lateral gastrocnemius muscle flap. No complementary treatment was possible for the pulmonary metastases. At 18 months follow-up, he walked without crutches, was able to do his activities of daily living. He was painfree and highly satisfied with the result. During the follow-up, slow progression of the pulmonary metastases was noted, which remained asymptomatic. Conclusion: Extraskeletal myxoid chondrosarcoma is a rare soft tissue tumour, and wide excision remains the treatment of choice. Whenever possible, limb salvage should be proposed to preserve function and quality of life.

Traitement de l'ischémie critique chronique des membres inférieurs en 2014 [Treatment of critical lower limb ischemia].

Critical limb ischemia is a major public health problem in our western countries due to the epidemia of (diabesity). The outcome of patients suffering from critical limb ischemia reains poor with an amputation free survival rate at one year of about 50%. The treatment should be multidiciplinary and done in emergency in specialized centers to ensure the limb salvage: this management should be centered aroud 3 axis: the screening of the cardiovascular risk factors, the best medical treatment and the invasive approaches. Due to multiple endovascular technical innovations, more frail patients with com plex diseases can be treated with good results. Therefore, the endovascular treatment is essential in the management of such patients by vascular surgeons.

Update of the BIPM comparison BIPM.RI(II)-K1.Cs-134 of activity measurements of the radionuclide 134Cs to include the 2008 results of the BEV (Austria), the 2009 result of the IRA (Switzerland) and the 2010 results of the NMISA (South Africa)

Purine nucleotide pyrophosphotransferase was purified to apparent homogeneity from a culture filtrate of Streptomyces morookaensis. It is a monomeric protein with a molecular weight of 24 000-25 000, and its isoelectric point is 6.9. The enzyme synthesizes purine nucleoside 5'-phosphate (mono, di, or tri) 3'-diphosphates such as pppApp, ppApp, pApp, pppGpp, ppGpp and pppIpp by transferring a pyrophosphoryl group from the 5'-position of ATP, dATP and ppApp to the 3'-position of purine nucleotides. The purified enzyme catalysed the formation of 435 mumol of pppApp and 620 mumol of pppGpp from ATP and GTP per min mg protein under the standard conditions. The enzyme requires absolutely a divalent cation for activity, and optimum pH for the enzyme activity lay above 10 for Mg2+, for Co2+ and Zn2+ from 9 to 9.5, and for Fe2+ from 7.5 to 8. The following Michaelis constants were determined: AMP, 2.78 mM; ADP, 3.23 mM; GMP, 0.89 mM; GDP, 0.46 mM and GTP, 1.54 mM, in the case of ATP donor. The enzyme is inhibited by guanine, guanosine, dGDP, dGTP, N-bromosuccinimide, iodacetate, sodium borate and mercuric acetate.

Adjuvant or radical fractionated stereotactic radiotherapy for patients with pituitary functional and nonfunctional macroadenoma.

Purpose: To evaluate the efficacy and toxicity of stereotactic fractionated radiotherapy (SFRT) for patients with pituitary macroadenoma (PMA).Methods and Materials: Between March 2000 and March 2009, 27 patients (male to female ratio, 1.25) with PMA underwent SFRT (median dose, 50.4 Gy). Mean age of the patients was 56.5 years (range, 20.3 - 77.4). In all but one patient, SFRT was administered for salvage treatment after surgical resection (transphenoidal resection in 23, transphenoidal resection followed by craniotomy in 2 and multiple transphenoidal resections in another patient). In 10 (37%) patients, the PMAs were functional (3 ACTH-secreting, 3 prolactinomas, 2 growth hormone-secreting and 2 multiple hormone-secretion). Three (11.1%) and 9 (33.3%) patients had PMA abutting and compressing the optic chiasm, respectively. Mean tumor volume was 2.9 +/- 4.6 cm(3). Eighteen (66.7%) patients had hypopituitarism prior to SFRT. The mean follow-up period after SFRT was 72.4 +/- 37.2 months.Results: Tumor size decreased for 6 (22.2%) patients and remained unchanged for 19 (70.4%) other patients. Two (7.4%) patients had tumor growth inside the prescribed treatment volume. The estimated 5-year tumor growth control was 95.5% after SFRT. Biochemical remission occurred in 3 (30%) patients with functional PMA. Two patients with normal anterior pituitary function before SFRT developed new deficits 25 and 65 months after treatment. The 5-year survival without new anterior pituitary deficit was thus 95.8%. Five patients with visual field defect had improved visual function and 1 patient with no visual defect prior to SFRT, but an optic chiasm abutting tumor, had a decline in visual function. The estimated 5-year vision and pituitary function preservation rates were 93.2% and 95.8%, respectively.Conclusions: SFRT is a safe and effective treatment for patients with PMA, although longer follow-up is needed to evaluate long-term outcomes. In this study, approximately 1 patient with visual field defect out of two had an improved visual.

Partial cricotracheal resection for pediatric subglottic stenosis: long-term outcome in 57 patients.

OBJECTIVE: We sought to assess the long-term outcome of 57 pediatric patients who underwent partial cricotracheal resection for subglottic stenosis. METHODS: Eighty-one pediatric partial cricotracheal resections were performed in our tertiary care institution between 1978 and 2004. Fifty-seven patients had a minimal follow-up time of 1 year and were included in this study. Evaluation was based on the last laryngotracheal endoscopy, the responses to a questionnaire, and a retrospective review of the patient's data. The following parameters were analyzed: decannulation rates, breathing, voice quality, and deglutition. RESULTS: A single-stage partial cricotracheal resection was performed in 38 patients, and a double-stage procedure was performed in 19 patients. Sixteen patients underwent an extended partial cricotracheal resection (ie, partial cricotracheal resection combined with another open procedure). At a median follow-up time of 5.1 years, the decannulation rates after a single- or double-stage procedure were 97.4% and 95%, respectively. Two patients remained tracheotomy dependent. One patient had moderate exertional dyspnea, and all other patients had no exertional dyspnea. Voice quality was found to improve after surgical intervention for 1 +/- 1.34 grade dysphonia (P < .0001) according to the adapted GRBAS grading system (Grade, Roughness, Breathiness, Asthenia, and Strain). CONCLUSIONS: Partial cricotracheal resection provides good results for grades III and IV subglottic stenosis as primary or salvage operations. The procedure has no deleterious effects on laryngeal growth and function. The quality of voice significantly improves after surgical intervention but largely depends on the preoperative condition.

Mycophenolic acid formulations in adult renal transplantation - update on efficacy and tolerability.

The description more than 30 years ago of the role of de novo purine synthesis in T and B lymphocytes clonal proliferation opened the possibility for selective immunosuppression by targeting specific enzymatic pathways. Mycophenolic acid (MPA) blocks the key enzyme inosine monophosphate dehydrogenase and the production of guanosine nucleotides required for DNA synthesis. Two MPA formulations are currently used in clinical transplantation as part of the maintenance immunosuppressive regimen. Mycophenolate mofetil (MMF) was the first MPA agent to be approved for the prevention of acute rejection following renal transplantation, in combination with cyclosporine and steroids. Enteric-coated mycophenolate sodium (EC-MPS) is an alternative MPA formulation available in clinical transplantation. In this review, we will discuss the clinical trials that have evaluated the efficacy and safety of MPA in adult kidney transplantation for the prevention of acute rejection and their use in new combination regimens aiming at minimizing calcineurin inhibitor toxicity and chronic allograft nephropathy. We will also discuss MPA pharmacokinetics and the rationale for therapeutic drug monitoring in optimizing the balance between efficacy and safety in individual patients.

Late outcome of spinal cord stimulation for unreconstructable and limb-threatening lower limb ischemia.

OBJECTIVES: To determine whether the initial benefits of spinal cord stimulation (SCS) treatment for critical limb ischemia (CLI) persist over years. DESIGN: Analysis of data prospectively collected for every CLI patient receiving permanent SCS. Follow-up range 12 to 98 months (mean 46+/-23, median 50 months). POPULATION: 87 patients (28% stage III, 72%stage IV) with unreconstructable CLI due (83%) or not (17%) to atherosclerosis and with an initial sitting/supine transcutaneous pO2 gradient >15 mmHg. METHODS: Assessment of actuarial patient survival (PS), limb salvage (LS) and amputation-free patient survival (AFPS). Analysis of the impact of 15 risk factors on long-term outcomes using the Fischer's exact test for categorical variables and the t test for continuous variables. RESULTS: Follow-up was complete for patient and limb survival. A single non-atherosclerotic patient died during follow-up. Among atherosclerotic patients PS decreased from 88% at 1y, to 76% at 3y, 64% at 5y and 57% at 7y. LS reached 84% at 1y, 78% at 2y, 75% at 3y and remained stable thereafter. Diabetes was found to affect LS (p<0.05) and heart disease to reduce PS (p<0.01). AFPS was reduced in heart patients (p<0.01), diabetics (p<0.05) and in patients with previous stroke (p<0.05). CONCLUSIONS: In CLI patients the beneficial effects of SCS persist far beyond the first year of treatment and major amputation becomes infrequent after the second year.

Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study.

Extranodal NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. No therapeutic strategy is currently identified in relapsing patients. We report the results of a French prospective phase II trial of an L-asparaginase-containing regimen in 19 patients with relapsed or refractory disease treated in 13 centers. Eleven patients were in relapse and 8 patients were refractory to their first line of treatment. L-Asparaginase-based treatment yielded objective responses in 14 of the 18 evaluable patients after 3 cycles. Eleven patients entered complete remission (61%), and only 4 of them relapsed. The median overall survival time was 1 year, with a median response duration of 12 months. The main adverse events were hepatitis, cytopenia, and allergy. The absence of antiasparaginase antibodies and the disappearance of Epstein-Barr virus serum DNA were significantly associated with a better outcome. These data confirm the excellent activity of L-asparaginase-containing regimens in extranodal NK/T-cell lymphoma. L-Asparaginase-based treatment should thus be considered for salvage therapy, especially in patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma warrants evaluation in prospective trials. This trial is registered at www.clinicaltrials.gov as #NCT00283985.