[Impact of IMRT for neoadjuvant rectal cancer?] / Quel apport de la modulation d'intensité pour la radiothérapie des cancers du rectum ?

The standard management of locally advanced rectal tumors as cT3-T4 and/or N0/N1 is based on preoperative treatment combining radiotherapy of 45 to 50Gy and chemotherapy based on 5-fluorouracil. Intensity-modulated radiotherapy has already shown its interest compared to conformal radiotherapy in other locations, like in pelvic cancer. The role of intensity-modulated radiotherapy in the pre/postoperative treatment of rectal cancers is not a standard of care. Published studies showed its feasibility with the objective of less toxicity with equivalent efficacy.

Impact of the method chosen for the analysis of recurrences after radiotherapy for head and neck cancers: volume-based, point-based and combined methods.

Intensity modulated radiation therapy for head and neck is a complex technique. Inappropriate delineation and/or dose distribution can lead to recurrences. Analysis of these recurrences should lead to improve clinical practice. For several years, different methods of analysis have been described. The purpose of this review is to describe these different methods and to discuss their advantages and limitations. The first published methods used a volume-based approach studying the entire volume of recurrence according to initial target volumes, or dose distribution. The main limitation of these methods was that the volume of recurrence studied was dependent on the delay in diagnosis of that recurrence. Subsequently, other methods used point-based approaches, conceptualizing recurrence either as a spherical expansion from a core of radioresistant cells (center of mass of recurrence volume) or using a more clinical approach, taking into account tumor expansion pathways. More recently, more precise combined methods have been described, combining the different approaches. The choice of method is decisive for conclusions on the origin of recurrence.

Sustainable neurosurgical training around the globe. A review and outline.

Sharing an equal and quality neurosurgical training across the globe without exclusion may seem utopian. However, such training is possible through educational opportunities and the ongoing digital revolution. The aim is to present the current state of neurosurgery training and education methods indicating strengths, weaknesses and opportunities. The thoughts, comments and suggestions of the authors are based on their academic experiences, training missions around the world and particularly in low- and middle-income countries by pointing out the French experience. The learning must be interactive and programmed over time, integrating varied courses and activities. Virtual reality and neurosurgical simulation need to be developed. The content of the teaching including e-learning must be evidence-based and peer-reviewed. Pedagogical training of trainers is fundamental. It is critical to evaluate the training under real working conditions. The optimization of human resources should create economies of scale that would attenuate the financial burden. The commitment of the teams, tutoring are success factors.

[Intra and extra hepatic cholangiocarcinomas radiation therapy]. / Place de la radiothérapie des cholangiocarcinomes intra- et extrahépatiques.

Cholangiocarcinomas are digestive tumors whose incidence remains low and have poor prognosis. The benefits of adjuvant radiochemotherapy and radiotherapy have never been demonstrated in any phase III randomized controlled trial. Chemotherapy with capecitabine 6 months is the standard of care in adjuvant setting. Radiochemotherapy is validated in R1 patients. It is not recommended in neoadjuvant situations given the lack of evidence. Chemotherapy and radiochemotherapy are validated in adjuvant or locally advanced diseases. Stereotactic radiation therapy offers an interesting perspective, at the cost of significant digestive toxicities, requiring evaluation in randomized trials.

Hypofractionated stereotactic radiotherapy for large brain metastases: Optimizing the dosimetric parameters.

PURPOSE: Stereotactic radiotherapy plays a major role in the treatment of brain metastases (BM). We aimed to compare the dosimetric results of four plans for hypofractionated stereotactic radiotherapy (HFSRT) for large brain metastases. MATERIAL AND METHODS: Ten patients treated with upfront NovalisTx® non-coplanar multiple dynamic conformal arcs (DCA) HFSRT for≥25mm diameter single BM were included. Three other volumetric modulated arc therapy (VMAT) treatment plans were evaluated: with coplanar arcs (Eclipse®, Varian, VMATcEclipse®), with coplanar and non-coplanar arcs (VMATncEclipse®), and with non-coplanar arcs (Elements Cranial SRS®, Brainlab, VMATncElements®). The marginal dose prescribed for the PTV was 23.1Gy (isodose 70%) in three fractions. The mean GTV was 27mm3. RESULTS: Better conformity indices were found with all VMAT techniques compared to DCA (1.05 vs 1.28, P<0.05). Better gradient indices were found with VMATncElements® and DCA (2.43 vs 3.02, P<0.001). High-dose delivery in healthy brain was lower with all VMAT techniques compared to DCA (5.6 to 6.3 cc vs 9.4 cc, P<0.001). Low-dose delivery (V5Gy) was lower with VMATncEclipse® or VMATncElements® than with DCA (81 or 94 cc vs 110 cc, P=0.02). CONCLUSIONS: NovalisTx® VMAT HFSRT for≥25mm diameter brain metastases provides the best dosimetric compromise in terms of target coverage, sparing of healthy brain tissue and low-dose delivery compared to DCA.

Impact of an Education Programme on IBD Patients' Skills: Results of a Randomised Controlled Multicentre Study [ECIPE].

BACKGROUND: Better patient knowledge on inflammatory bowel disease [IBD] could improve outcome and quality of life. The aim of this study was to assess if an education programme improves IBD patients' skills as regards their disease. METHODS: The GETAID group conducted a prospective multicentre randomised controlled study. IBD patients were included at diagnosis, or after a significant event in the disease course. Patients were randomised between 'educated' or control groups for 6 months. Education was performed by trained health care professionals. A psycho-pedagogic score [ECIPE] was evaluated by a 'blinded' physician at baseline and after 6 and 12 months [M6 and M12]. The primary endpoint was the increase of ECIPE score at M6 of more than 20%. RESULTS: A total of 263 patients were included in 19 centres (male:40%; median age:30.8; Crohn's disease [CD]:73%). Of these, 133 patients were randomised into the educated group and 130 into the control group. The median relative increase in ECIPE score at M6 was higher in the educated group as compared with the control group (16.7% [0-42.1%] vs 7% [0-18.8%], respectively, p = 0.0008). The primary endpoint was met in 46% vs 24% of the patients in the educated and control groups, respectively [p = 0.0003]. A total of 92 patients met the primary endpoint. In multivariate analysis, predictors of an increase of at least 20% of the ECIPE score were randomisation in the educated group (odds ratio [OR] = 2.59) and no previous surgery [OR = 1.92]. CONCLUSIONS: These findings support the set-up of education programmes in centres involved in the management of IBD patients.

[Concurrent chemoradiotherapy for head neck cancers. Should organs at risk dose constraints be revisited ?] / Chimioradiothérapie concomitante des cancers des voies aérodigestives supérieures. Faut-il revoir les contraintes de dose dans les organes à risque ?

Concurrent chemoradiotherapy improves the outcome of locally advanced head and neck cancers and the current reference chemotherapy is cisplatin. These results are obtained at the cost of increased toxicities. To limit the risk of toxicity, organ at riskdose constraints have been established starting with 2D radiotherapy, then 3D radiotherapy and intensity-modulated radiotherapy. Regarding grade ≥3 acute toxicities, the scientific literature attests that concurrent chemoradiotherapy significantly increases risks of mucositis and dysphagia. Constraints applied to the oral mucosa volume excluding the planning target volume, the pharyngeal constrictor muscles and the larynx limit this adverse impact. Regarding late toxicity, concurrent chemoradiotherapy increases significantly the risk of postoperative neck fibrosis and hearing loss. However, for some organs at risk, concurrent chemotherapy appears to increase late radiation induced effect, even though the results are less marked (brachial plexus, mandible, pharyngeal constrictor muscles, parotid gland). This additional adverse impact of concomitant chemotherapy may be notable only when organs at risk receive less than their usual dose thresholds and this would be vanished when those thresholds are exceeded as seems to be the situation for the parotid glands. Until the availability of more robust data, it seems appropriate to apply the principle of delivering dose to organs at risk as low as reasonably achievable.

Intersphincteric resection for low rectal cancer: the risk is functional rather than oncological. A 25-year experience from Bordeaux.

AIM: There are few data evaluating the long-term outcomes of intersphincteric resection (ISR), especially the impact of inclusion of more juxtapositioned and intra-anal tumours on oncological and functional outcomes. We compared the oncological and functional results of patients treated by total mesorectal excision and ISR for low rectal cancer over a 25-year period. METHOD: This is a retrospective study from a single institution evaluating results of ISR over three periods: 1990-1998, 1999-2006 and 2007-2014. Patients treated by partial or total ISR, with or without neoadjuvant chemoradiotherapy, for low rectal cancer (≤ 6 cm from the anal verge) were included. We compared postoperative morbidity, quality of surgery and oncological and functional outcomes in the time periods studied. RESULTS: Of 813 patients operated on for low rectal cancer, 303 had ISR. Tumour stage did not differ; however, the distance of the tumour from the anorectal junction decreased from 1 to 0 cm (P < 0.001) and the distal resection margin shortened from 25 to 10 mm (P < 0.001) from 1990 to 2014. The postoperative morbidity and quality of surgery did not change significantly over time. The 5-year local recurrence (4.3% vs 5.9% vs 3.5%; P = 0.741) and disease-free survival (72% vs 71% vs 75%; P = 0.918) did not differ between the three time periods. Functional results improved during the last period; however, overall 42% of patients experienced major bowel dysfunction. CONCLUSION: Pushing the envelope of sphincter-saving resection in ultra-low rectal cancer reaching or invading the anal sphincter did not compromise oncological and functional outcomes. The main limitation of the ISR procedure appears to be functional rather than oncological, suggesting that bowel rehabilitation programmes should be developed.

Delayed coloanal anastomosis: an alternative option for restorative rectal cancer surgery after high-dose pelvic radiotherapy for prostate cancer.

AIM: Restorative total mesorectal excision (TME) for rectal cancer after high-dose pelvic radiotherapy for prostate cancer has been reported to provide an unacceptable rate of pelvic sepsis. In a previous publication we proposed that delayed coloanal anastomosis (DCAA) should be performed in this situation. The present study aimed to assess the feasibility and outcomes of this strategy. METHOD: Between 2000 and 2018, 1094 men were operated on for rectal cancer in our institution. All men with T2/T3 mid and low rectal cancer with preoperative radiotherapy and restorative TME were considered for this study (n = 416). Patients with external-beam high-dose radiotherapy (EBHRT) for prostate cancer (70-78 Gy) were identified and compared with patients with conventional long-course chemoradiotherapy (CRT) followed by TME. We compared our already published historical cohort (2000-2012), including arm A (CRT + TME; n = 236) and arm B (EBHRT + TME; n = 12), with our early cohort (2013-2018), including arm C (CRT + TME; n = 158) and arm D (EBHRT + TME-DCAA; n = 10). The end-points were morbidity, pelvic sepsis, reoperation rate and quality of the specimen. RESULTS: Overall morbidity was not significantly different between groups. Pelvic sepsis decreased from 50% (arm B) to 10% (arm D) with the use of DCAA (P = 0.074), and was similar between arms A, C and D. Quality of the specimen was not significantly different between the four groups. CONCLUSION: Our results suggest that TME with DCAA in patients with previous EBHRT is feasible, with the same postoperative pelvic sepsis rate as conventional CRT.

[Preoperative intensity-modulated radiotherapy of rectal cancers: Relevance and modalities]. / Radiothérapie avec modulation d'intensité préopératoire des cancers rectaux : intérêt et application.

Preoperative radiotherapy boosted by chemotherapy is a recommended treatment in locally advanced rectal cancers. This treatment is delivered by three dimensional conformal irradiation, which is usually well tolerated but can induce potential toxicity such as rectitis, cystitis and hematologic adverse effects. Intensity-modulated radiotherapy, widely available nowadays, allows optimization of volume covering and sparing of organs at risk such as bladder and bone marrow. This review presents relevant clinical situations and requirements for a beneficial and safe preoperative irradiation of rectal cancers by intensity-modulated technique. This technique is compared to three-dimensional conformal radiotherapy.

[Reirradiation for head and neck squamous cell carcinoma: Indications and results]. / Réirradiations des carcinomes épidermoïdes des voies aérodigestives supérieures : indications et résultats.

Despite progress in the management of head and neck squamous cell carcinoma (HNSCC), a significant proportion of patients previously irradiated for head-and-neck cancer will develop locoregional recurrence or a second primary. Because of the heterogeneity of this population with respect to disease-related factors (localization, volume, recurrence or second primary, time interval from previous irradiation…) and patient-related factors (comorbidities, sequelae of previous irradiation…), the optimal reirradiation treatment remains to be defined. Salvage therapy using reirradiation, despite some encouraging results, has historically been avoided because of concerns regarding toxicity. The results of more recent studies using contemporary treatment techniques and conformal delivery methods such as intensity modulated radiation therapy (IMRT) or stereotactic radiotherapy (SBRT) have been somewhat more promising. The aim of this review is to discuss the reirradiation of HNSCC in terms of patient selection and modern radiotherapy techniques.

Management of gestational trophoblastic diseases in a low resource country: establishment of a national center and its results.

To describe the process of establishing a reference center for gestational trophoblastic diseases (GTD) in Senegal and to report its main results so far. We describe the history and establishment of the center, which is based on the experience of the main international centers. The adaptations made to patient follow-up are detailed, while we follow FIGO and WHO diagnostic and management criteria. Finally, we report our main results. Between 2011 and 2017, 878 files were registered at the Center. More than half of the women had no histological confirmation of GTD (60.8 %). The diagnosis was then based on ultrasound images or macroscopic examination of molar vesicles. Spontaneous remission occurred in 64.5 % of the cases, while gestational trophoblastic neoplasia developed in 23.5 %. The FIGO criteria were slightly adapted for hCG monitoring. Methotrexate was the drug of choice in the low-risk group (97.8 %), while the EMACO protocol was financially difficult for nearly half of the high-risk group. The overall remission rate was 83 % and the specific lethality 11.6 %. Our center has demonstrated the efficiency of centralizing the management of GTDs. Difficulty in access to hCG and antimitotic drugs makes management difficult. However, we have introduced alternative solutions that we are working to improve.

[Tolerance of hypofractionated stereotactic radiotherapy for hepatic tumours]. / Tolérance de l'irradiation stéréotaxique hypofractionnée des tumeurs hépatiques.

PURPOSE: The purpose of the study was to evaluate the outcomes of stereotactic radiation therapy for primary and secondary liver tumours in Jean-Perrin cancer centre (Clermont-Ferrand, France) in terms of efficacy and safety. MATERIALS AND METHODS: Between December 2013 and June 2016, 25 patients were included. Treatment was performed on a linear accelerator Novalis TX®. The prescription dose was 42 to 60Gy in three to five fractions. Local control at 1 year was evaluated with modified Response Evaluation Criteria in Solid Tumours (mRECIST) and RECIST criteria. Acute and late toxicity were evaluated with Common Terminology Criteria for Adverse Events (CTCAE) v4.0 criteria. RESULTS: Median follow-up was 10.5 months. Treatment tolerance was good with few side effects grade 3 or above, no acute toxicity and only one late toxicity. We have highlighted that hepatic artery haemorrhage was associated with the presence of a biliary prosthesis in contact with the artery (P=0.006) and in the irradiation field. There was no correlation with the dose delivered to the artery and hepatic artery haemorrhage. CONCLUSION: Stereotactic radiation therapy for liver tumours allows a good local control with few secondary effects. Caution should be exercised when treating patients with biliary prostheses in the vicinity of the target volume because there is a risk of haemorrhage of the hepatic artery in contact with the prosthesis.

[Toxicity of docetaxel, platine, 5-fluorouracil-based induction chemotherapy for locally advanced head and neck cancer: The importance of nutritional status]. / Toxicité de la chimiothérapie d'induction par docétaxel, platine, 5-fluorouracile (TPF) pour les cancers des voies aérodigestives supérieures localement évolués en routine clinique : importance du statut nutritionnel.

PURPOSE: The objective of this study was to identify predictive factors of toxicity of docetaxel, platin, 5-fluorouracil (TPF) induction chemotherapy for locally advanced head and neck cancers. PATIENTS AND METHODS: From July 2009 to March 2015, 57 patients treated consecutively with TPF were included retrospectively. There were 47 males (83%), the median age was 56 years [40-71 years]. Thirty-eight patients (67%) were treated for inoperable cancer (highly symptomatic and/or high tumor burden) and 19 (33%) were treated for laryngeal preservation. There were 47% stage IVa, 32% stage III and 21% stage IVb. At diagnosis, there were 53% stable weight, 28% grade 1 weight loss, 17% grade 2 weight loss and 2% grade 3 weight loss. RESULTS: Forty-seven percent of patients were in partial response after TPF, 28% in complete response, 7% stable, 2% progressing and 2% discordant response. The possibility of oral feeding without a feeding tube was predictive of a better response (P=0.02). Thirty-nine percent of patients increased weight during TPF, 35% were stable, 18% in grade 1 weight loss, 6% in grade 2 and 2% in grade 3. Six of the patients (10.5%) died during chemotherapy: four from febrile neutropenia, one from pneumopathy and one of unknown cause. Age 57years and older was associated with a higher risk of grade≥3 anemia and thrombocytopenia. There was a higher risk of grade≥3 infection for weight loss at diagnosis (P=0.04) and feeding tube (P=0.05). There was a higher risk of grade≥3 neutropenia for weight loss during TPF (P=0.03). CONCLUSION: Induction chemotherapy by TPF has an strong anti-tumor efficacy (75.5% objective response) but an important morbidity with 10% toxic deaths in our very symptomatic population with a very important tumor burden. Age and nutritional status are important factors to consider.

Expression of phospholipase PLC Zeta in human spermatozoa: impact of cryopreservation.

BACKGROUND: Cryopreservation is used for infertility treatment and for fertility preservation. The results of the use of frozen spermatozoa for ART (Assisted Reproductive Technology) are lower than those of fresh spermatozoa. The phospholipase C Zeta (PLCζ) protein is involved in oocyte activation. OBJECTIVES: The aim of this study was to compare the percentage of spermatozoa expressing phospholipase C Zeta protein before and after a frozen-thawing cycle. MATERIALS AND METHODS: Samples were provided after at least 2 days of sexual abstinence. A part of the fresh ejaculate (200 µL) was recovered for the study. Fifty microliters was necessary to carry out the technique before freezing. The remaining 150 µl was frozen according to a slow manual freezing technique. The samples were treated based on the procedure described by Yelumalai et al. (Fertil. Steril., 104, 2015, 561-568.e4) and Grasa et al. (Hum. Reprod. Oxf. Engl. 23, 2008, 2513-2522). RESULTS: Freezing was associated with a decrease in the percentage of spermatozoa exhibiting PLCζ (44 ± 22% before vs 31 ± 19% after, p < 0.05). The percentage of spermatozoa exhibiting PLCζ at post-acrosomal position was significantly greater before freezing (8% vs 5%, p < 0.05). There was no significant difference for the percentage of spermatozoa exhibiting PLCζ at equatorial position (15% before freezing versus 12% after thawing, NS). DISCUSSION: The results of the present study show that the presence of PLCζ on spermatozoa is decreased after freezing-thawing procedures. PLCζ is a soluble cytosolic protein (Nomikos et al., ), so it can be lost during cryopreservation. These membrane alterations are probably multifactorial. CONCLUSION: Our results, in agreement with other studies, raise the hypothesis that cryopreservation reduces spermatic PLCζ expression.

Postoperative compensation after neurotomy in Meniere's disease: Retrospective study of 15 cases.

INTRODUCTION: Vestibular neurotomy is a functional surgery for Meniere's disease in the event of medical treatment failure. The aim of the study was to assess the efficacy and complications of vestibular neurotomy, and to address the question of postoperative compensation. MATERIAL AND METHOD: All patients included in this retrospective study underwent a vestibular neurotomy at our center between 2009 and 2016. A preoperative evaluation was performed including MRI, audiometry, and videonystagmography. The functional level of disability was evaluated by the Dizziness Handicap Inventory (DHI) score. In all patients suboccipital retrosigmoid approach was performed. All patients underwent early postoperative vestibular rehabilitation. One month and two years after surgery, we assessed the effectiveness of treatment on dizziness, disability and imbalance. At the time of this study (2 to 8 years), DHI and patients' satisfaction by patient's global impression of change (PGIC) scale were evaluated. RESULTS: Fifteen patients aged between 42 and 74 years of age were included in our study. Postoperative complications occurred in two patients (meningitis and a wound infection). At one month, all patients had a dramatic clinical improvement with decreased vertigo. Two years after surgery, 85% of the patients were cured and had no dizziness or balance disorder. Only one patient experienced bilateralization and only one had a persistent poor compensation. CONCLUSION: Vestibular neurotomy is a very effective treatment in the case of Meniere's disease resistant to medical treatment, with very good functional results and an extremely low failure rate.

Cryptococcal meningitis in an immunocompetent patient with obstructive hydrocephalus: A case report.

BACKGROUND: Cryptococcal infections of the central nervous system are very rare in immunocompetent patients. They usually present as meningitis or as fungal cysts with or without hydrocephalus. Rapid diagnosis and treatment is crucial to the prognosis. CASE REPORT: We report the case of an immunocompetent 40-year-old male patient with no medical or surgical history and no recent travel, who was hospitalized in our neurosurgery department because of a rapidly worsening headache. The neurological examination revealed no focal deficit but worrying signs of increased intracranial pressure. Magnetic resonance imaging (MRI) with contrast showed thick and large-scale cortico-pial cerebellar enhancements, associated with severe obstructive hydrocephalus. This required emergency endoscopic ventriculocisternostomy during which we observed cottony tissues along the ventricular walls. Biopsied tissues and cerebrospinal fluid samples (CSF) were not contributive. A CT scan of the chest and abdomen and blood markers of common primary tumors were all negative. No evidence of HIV infection or any cause of immunosuppression was identified. Symptoms and a second MRI slightly improved with intravenous corticosteroid therapy. The hypothesis of a lymphoma or granulomatous disease was made initially for which direct surgical biopsies were scheduled. The diagnosis of cryptococcal meningitis was obtained later on by simultaneous plasma and CSF Cryptococcus antigen detection. Cryptococcus neoformans (formerly C. neoformans var. grubii [serotype A]) was then identified by PCR. Clinical improvement was obtained with antifungal therapy. CONCLUSION: Cryptococcal meningitis is a well-known condition in immunocompromised patients, often causing hydrocephalus requiring neurosurgical management. The diagnosis is more difficult in patients with no history of HIV or organ transplant. Neurologists and neurosurgeons must consider this possibility in case of diffuse, thick leptomeningeal enhancement on MRI.

Prostate-specific antigen bounce in patients treated before 60 years old by iodine 125 brachytherapy for prostate cancer is frequent and not a prognostic factor.

PURPOSE: The only prognostic factor of prostate-specific antigen (PSA) bounce in prostate cancer found in several studies is young age but has never been specifically studied in this subset of patients for long-term results. Bounce characteristics, histological, clinical, and dosimetric data in young patients were analyzed, as well as their impact on toxicity and survival. MATERIAL AND METHODS: This retrospective study included patients aged ≤60 years treated with exclusive iodine 125 brachytherapy with low or intermediary prostate adenocarcinoma during 1999-2014. Exclusion criteria were a follow-up of ≤24 months. PSA bounce was defined as a ≥0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. RESULTS: This study analyzed 179 patients. Median age was 56 years (46-59 years). The median follow-up was 79 months (54; 123). The bounce incidence was 56.8% (49.6%; 64.2%) at 5 years, inversely proportional to positive/total biopsies ratio (HR 0.98, 95% CI [0.97, 0.99]). Incidence of biochemical failure was 1.2%, 95% CI (0.3%; 4.7%), at 5 years with no difference between the bounce and no-bounce group (HR 0.96, 95% CI [0.25; 3.58]). Bounce is an unfavorable prognostic factor for grade two and three urinary toxicities 6.67 (4.14; 10.76) (p < 0.001). CONCLUSIONS: PSA bounce is common in young people after brachytherapy. It should be monitored without starting an inadequate and sometimes invasive relapse checkup or a relapse treatment.

RNA interference validation of detoxification genes involved in ivermectin tolerance in Drosophila melanogaster.

Previously, we observed increased transcription levels of specific cytochrome P450 monooxygenase (P450) and adenosine triphosphate binding cassette (ABC) transporter genes in human body lice, Pediculus humanus humanus, following exposure to ivermectin using the non-invasive induction assay, which resulted in tolerance. To confirm the roles of these genes in induction and tolerance, the robust genetic model insect Drosophila melanogaster was chosen. Orthologous genes corresponding to the body louse P450 (Cyp9f2, Cyp6g2 and Cyp9h1) and ABC transporter (Mrp1, GC1824 as an ABCB type and CG3327 as an ABCG type) genes were selected for in vivo bioassay. Following a brief treatment with a sublethal dose of ivermectin, the mortality response was significantly slower, indicating the presence of tolerance. Concurrently, the transcription levels of Cyp9f2 and Mrp1 at 3 h and those of Cyp6g2, Cyp9h1, Mrp1, CG1824 and CG3327 at 6 h post-treatment were upregulated, indicating gene induction. In behavioural bioassay using GAL4/UAS-RNA interference transgenic fly lines, increased susceptibility to ivermectin was observed following heat shock in the Cyp9f2 , Cyp6g2 , Cyp9h1 , Mrp1 or CG3327-knockdown flies. Considering that these five genes are orthologous to those which had the largest over-expression level following ivermectin-induced tolerance in the body louse, the current results suggest that they are also associated with ivermectin detoxification in D. melanogaster and that body lice and D. melanogaster are likely to share, in part, similar mechanisms of tolerance to ivermectin.

Long-term outcome of patients with steroid-refractory acute severe UC treated with ciclosporin or infliximab.

OBJECTIVE: Ciclosporin and infliximab have demonstrated short-term similar efficacy as second-line therapies in patients with acute severe UC (ASUC) refractory to intravenous steroids. The aim of this study was to assess long-term outcome of patients included in a randomised trial comparing ciclosporin and infliximab. DESIGN: Between 2007 and 2010, 115 patients with steroid-refractory ASUC were randomised in 29 European centres to receive ciclosporin or infliximab in association with azathioprine. Patients were followed until death or last news up to January 2015. Colectomy-free survival rates at 1 and 5 years and changes in therapy were estimated through Kaplan-Meier method and compared between initial treatment groups through log-rank test. RESULTS: After a median follow-up of 5.4 years, colectomy-free survival rates (95% CI) at 1 and 5 years were, respectively, 70.9% (59.2% to 82.6%) and 61.5% (48.7% to 74.2%) in patients who received ciclosporin and 69.1% (56.9% to 81.3%) and 65.1% (52.4% to 77.8%) in those who received infliximab (p=0.97). Cumulative incidence of first infliximab use at 1 and 5 years in patients initially treated with ciclosporin was, respectively, 45.7% (32.6% to 57.9%) and 57.1% (43.0% to 69.0%). Only four patients from the infliximab group were subsequently switched to ciclosporin. Three patients died during the follow-up, none directly related to UC or its treatment. CONCLUSIONS: In this cohort of patients with steroid-refractory ASUC initially treated by ciclosporin or infliximab, long-term colectomy-free survival was independent from initial treatment. These long-term results further confirm a similar efficacy and good safety profiles of both drugs and do not favour one drug over the other. TRIAL REGISTRATION NUMBER: EudraCT: 2006-005299-42; ClinicalTrials.gouv number: NCT00542152; post-results.