[Assessment of trainee urologists' knowledge in urogenital anatomy]. / Évaluation des connaissances en anatomie uro-génitale des urologues en formation.

The purpose of this study was to assess trainee urologists' [interns and assistant heads of university hospitals (CHU)] knowledge of the anatomy of the urogenital system. An examination consisting of 10 timed (16minutes) multiple-choice questions (MCQ) based on urogenital anatomy assessments for students in third year of the general medical science diploma program (DFGSM3) was sent to members of the French Association of Trainee Urologists (AFUF) in May 2018 in order to compare the average scores of these two populations. In addition, a questionnaire consisting of epidemiological data, their opinion on the quality of education in anatomy and the willingness to have more courses on this subject was included in the examination. The same scale based on a score out of 20 was applied to both populations. Of the 501 AFUF members solicited, 144 answered all the questions (28.7%). The mean score for urologists was lower than that of DFGSM3 students (10.56±1.82 vs. 11.4±2.37 respectively) (P=0.0013). Moreover, the desire for further education in anatomy was widespread among urologists (87%). According to our study, urologists have less knowledge of urogenital anatomy than third year medical students. Many means are being implemented or are available to rectify this failing, especially since the majority of trainee urologists consider that there are insufficient anatomy lessons in the curriculum and would like to receive further education in anatomy. LEVEL IF EVIDENCE: 3.

[Acute renal failure of the donor in encephalic death: A real contraindication to kidney transplantation?] / L'insuffisance rénale aiguë du donneur en mort encéphalique : une réelle contre-indication à la transplantation rénale ?

INTRODUCTION: The shortage of kidney transplants encourages the expansion of the limits of eligibility criteria for donation. Many donors who are brain dead display acute renal failure at the time of death; is this a real contraindication to harvesting? The aim of this study was to assess kidney graft survival from donors after brain death with confirmed acute renal failure, with or without anuria previous donation. MATERIALS AND METHODS: All of the transplants performed in two university hospitals between 2010 and 2017 were analyzed retrospectively. All patients who underwent single kidney transplant from a brain-dead donor with acute renal failure (ARF) were included in this study. ARI was defined here by a decrease over 50 % of glomerular filtration rate (GFR) to a threshold below 45mL/min/1.73 m2 at the time of kidney procurement. Kidney graft survival, incidence of delayed graft function (DGF) and the GFR at 12 months were analyzed. Analysis of kidney transplant survival based on pre-implantation biopsies was additionally done. RESULTS: One hundred and sixty four patients were transplanted with a kidney from donor with ARF during the selected period. At the admission in ICU the average GFR was 67,7±19mL/min/1,73m2. At the time of donation, the average age of donors was 56.4±17.7 years, the GFR was 33.7±8.0mL/min/1.73 m2 16 % of donors were anuric. Cold ischemia time (CIT) was 16.8±5.0hours. The average age of recipients was 55.6±14.1 years. 81 % of the cases were primary transplants. Graft function took place within 7.8±9.4 days after transplantation. There were two non-primary functions (PNF). One hundred and fifty two patients (93 %) had a functional graft at 12 months. The mean GFR at 12 months was 46.8±20.1mL/min/1.73 m2 and 122 patients (73 %) had a GFR greater than 30mL/min/1.73 m2. Seventy-one percent of preimplantation biopsies revealed acute tubular necrosis (ATU); no cortical necrosis was observed. Survival of theses grafts was 85 %, comparable to the total population of study (P=0,21) CONCLUSION: The acute renal failure of the brain-dead donor should not alone be systematically a contraindication to harvesting and kidney transplantation.

Pregnancy and Delivery in Women with Lower Urinary Tract Reconstruction: A National Multicenter Retrospective Study from the French-Speaking Neuro-Urology Study Group (GENULF) and the Neuro-Urology Committee of the French Association of Urology.

PURPOSE: Management of pregnancy and delivery in women with lower urinary tract reconstruction is challenging and the currently available literature is insufficient to guide clinical practice. We report pregnancy and delivery outcomes in this specific population. MATERIALS AND METHODS: We conducted a national multicenter retrospective study (16 centers) including 68 women with 96 deliveries between 1998 and 2019. These women had at least 1 successful pregnancy and delivery after augmentation enterocystoplasty, catheterizable channel creation and/or artificial urinary sphincter implantation. Maternal and fetal complications during pregnancy and delivery were reported, as well as postpartum functional outcomes, according to the delivery mode. The chi-square test and Student's t-test were used to compare categorical and continuous variables, respectively. RESULTS: Overall 32% of reported pregnancies were complicated by febrile urinary tract infections, 13.5% by renal colic and 14.6% required upper urinary tract diversion. In addition, 10% of patients reported transient self-catheterization difficulties and 13.5% reported de novo or increased urinary incontinence. The preterm delivery rate was 35.3%. Elective C-section was performed in 61% of pregnancies. Twenty complications occurred during delivery (20%), including 19 during elective C-section. Urinary continence at 1 year was unchanged for 93.5% of deliveries. Delivery mode (p=0.293) and multiparity (p=0.572) had no impact on urinary continence. CONCLUSIONS: In this population C-section appeared to be associated with a high risk of complications. In the absence of any obstetric or neurological contraindications, vaginal delivery should be proposed as the first line option to the majority of these women.

Diagnostic delay and outcome in immunocompetent patients with primary central nervous system lymphoma in Spain: a multicentric study.

INTRODUCTION: To assess the management of immunocompetent patients with primary central nervous system lymphomas (PCNSL) in Spain. METHODS: Retrospective analysis of 327 immunocompetent patients with histologically confirmed PCNSL diagnosed between 2005 and 2014 in 27 Spanish hospitals. RESULTS: Median age was 64 years (range: 19-84; 33% ≥ 70 years), 54% were men, and 59% had a performance status (PS) ≥ 2 at diagnosis. Median delay to diagnosis was 47 days (IQR 24-81). Diagnostic delay > 47 days was associated with PS ≥ 2 (OR 1.99; 95% CI 1.13-3.50; p = 0.016) and treatment with corticosteroids (OR 2.47; 95% CI 1.14-5.40; p = 0.023), and it did not improve over the years. Patients treated with corticosteroids (62%) had a higher risk of additional biopsies (11.7% vs 4.0%, p = 0.04) but corticosteroids withdrawal before surgery did not reduce this risk and increased the diagnostic delay (64 vs 40 days, p = 0.04). Median overall survival (OS) was 8.9 months [95% CI 5.9-11.7] for the whole series, including 52 (16%) patients that were not treated, and 14.1 months (95%CI 7.7-20.5) for the 240 (73.4%) patients that received high-dose methotrexate (HD-MTX)-based chemotherapy. Median OS was shorter in patients ≥ 70 years (4.1 vs. 13.4 months; p < 0.0001). Multivariate analysis identified age ≥ 65 years, PS ≥ 2, no treatment, and cognitive/psychiatric symptoms at diagnosis as independent predictors of short survival. CONCLUSIONS: Corticosteroids withdrawal before surgery does not decrease the risk of a negative biopsy but delays diagnosis. In this community-based study, only 73.4% of patients could receive HD-MTX-based chemotherapy and OS remains poor, particularly in elderly patients ≥ 70 years.

Frailty predicts morbidity, complications, and mortality in patients undergoing complex abdominal wall reconstruction.

PURPOSE: Frailty is becoming an increasingly established risk factor for adverse postoperative outcomes. Given the innately high morbidity involved in complex abdominal wall reconstruction (CAWR) and the propensity for co-morbidities among this patient population, we sought to determine the predictive utility of a frailty index in patients undergoing CAWR. METHODS: A retrospective analysis was conducted using the American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP) database. A total of 70,339 patients undergoing CAWR were identified using CPT codes for ventral hernia repair ± components separation, ± placement of mesh. A Modified Frailty Index (mFI) was calculated for each patient. Outcomes included overall morbidity, Clavien-Dindo Grade IV (CDIV) complications, and mortality. RESULTS: Overall, 9931 patients had at least one complication associated with their procedure and an average calculated mFI of 0.12 (± 0.11) which was significantly greater than the average mFI noted in patients with no complications (0.077 ± 0.85, p < 0.001). Similarly, average mFI score (0.16 ± 0.12) in patients with CDIV complications (n = 2541) was once again significantly greater than those without CDIV complications (0.080 ± 0.09; p < 0.001). Multivariable analyses also showed that all individual factors of the mFI were predictive of all-cause and CDIV complications (p < 0.001). Higher pre-operative mFI conferred a 7.77× likelihood of all-cause complications, 35.71× likelihood of CDIV complications, 3.85× likelihood of surgical site complications, and a 62.05× likelihood of death (p < 0.001 for all comparisons). CONCLUSION: We have shown that frailty as measured by mFI is an accurate predictor of morbidity and mortality in patients undergoing CAWR.

[Long-term outcomes of prostate cancer patients with lymph nodes metastasis after radical prostatectomy and pelvic lymph node dissection]. / Résultats oncologiques à long terme des patients ayant un cancer de la prostate traité par prostatectomie totale et curage ganglionnaire avec atteinte métastatique ganglionnaire infraclinique.

INTRODUCTION: The aim of this study was to evaluate biochemical recurrence-free survival (RFS) and to identify useful predictors of such survival in localized prostate cancer patients (cN0) and pelvic lymph node metastasis (pN+) treated with radical prostatectomy and pelvic lymph node dissection. PATIENTS AND METHODS: This multicenter and retrospective study, assessed overall survival (OS), cancer specific survival (CSS) and biochemical recurrence-free survival (RFS), between January 2005 until December 2010 with 5 years of distance. We evaluated factors predicting long-term RFS in node positive prostate cancer patients. RESULTS: Thus, 30 patients were included. Median follow-up was 89.9±27.4 months. After surgery, patients were treated with surveillance (n=4, 13.5%), adjuvant hormone therapy (n=22, 73%) or combination of radio and hormone therapy, (n=4, 13.5%). During the follow-up, 50% of patients had biochemical recurrence, with a mean time period of 38±30 months. Five and 10-year RFS were 57% and 41% respectively. Extra lymph nodes extension (P=0.00021) and pathological margin status (P=0.0065) were independent predictors of 5-year RFS. CONCLUSION: Biochemical RFS of patients treated with radical prostatectomy and subclinical lymph node metastatic disease is adequate and multifactorial. However, this study identifies pathological margin status and extra lymph node extension as independent factors of b RFS. LEVEL OF EVIDENCE: 4.

Long-term outcomes of I-Stop TOMS™ male sling implantation for post-prostatectomy incontinence management.

OBJECTIVES: To report long-term outcomes after I-Stop TOMS™ implantation for PPI. PATIENTS AND METHODS: A retrospective evaluation was conducted in three tertiary reference centers. All consecutive patients implanted with an I-Stop TOMS™ sling between 2007 and 2012 for mild to moderate PPI (24-hour Pad test<400g) without history of pelvic radiation therapy were included. Evaluation had been conducted preoperatively, at one and six months postoperative and yearly thereafter. The main outcome criterion was the number of pads per day. Secondary criteria were International Consultation on Incontinence Questionnaire (ICIQ), SF-36 questionnaire, and complications. RESULTS: A hundred patients were evaluated with a median follow-up of 58months [19-78]. Pad use was significantly reduced and quality of life improved at last follow-up (P<0.0001). The percentage of patients dry and socially continent (0 or 1 pad) were 40% and 77% at 1 year, then dropped to 15% and 22%, respectively after 5years. Twelve patients were treated by artificial urinary sphincter implantation, five by ProACT™ balloons and one by a re-do I-Stop TOMS™. No severe complications were recorded at last follow-up. CONCLUSIONS: I-Stop TOMS™ implantation is a safe and effective option in the short-term for mild to moderate PPI management. However, a significant trend to recurrence of leakage has been established after long-term follow-up. If confirmed by further studies, these results may substantially impact patient information before male sling implantation. LEVEL OF EVIDENCE: 4.

Sequential treatment with ProACT™ device implantation after male sling failure for male urinary incontinence.

OBJECTIVES: There is no strong evidence for second line therapy after male sling failure for post-prostatectomy urinary incontinence (PPUI). We report the outcomes after periurethral balloons implantation for persistence or recurrence of mild PPI symptoms after male sling implantation. METHODS: All patients implanted of a ProACT™ device (Uromedica, Inc., MN, USA) following I-STOP transobturator male sling (TOMS) failure, in a tertiary reference center between 2009 and 2016, were included. Patients were evaluated by 24-hour pad-test before and after implantation, and after each balloon repressurizing procedure. PGI-I and Likert scale patient satisfaction were estimated during a telephone interview conducted in 2016. Objective and subjective cure of urinary incontinence were defined by a 24-hour pad-test<8g and the use of zero or one pad per day, respectively. RESULTS: Fourteen patients were included. Median follow-up was 34months [4-89]. Objective and subjective cure were 29% (n=4) and 57% (n=8), respectively. Median pad-test decreased from 95g [IQR: 130] to 34g [IQR: 83] (P=0.022). ProACT™ significantly decreased median pad-test by a factor 2.73 [1.19-6.29]. Eighty-eight percent patients were feeling a little better, much better or very much better and 77% were satisfied or very satisfied at the end of follow-up. Reoperation rate was 28% (n=4): 3 balloons were changed for caudally migration (n=2) or deflation (n=1) and 1 had a urinary sphincter implanted for severe UI. CONCLUSIONS: ProACT™ is a safe and efficient treatment that can be used in second line therapy after TOMS failure for PPUI. LEVEL OF EVIDENCE: 4.

[Evaluation of practices and costs of vasectomy. French monocentric experience]. / Évaluation des pratiques et des coûts de la vasectomie. Expérience monocentrique française.

INTRODUCTION: Since the law of 4 July 2001, vasectomy has been recognized as a method of male contraception. We report the experience of vasectomy practice in a hospital-university center. METHODS: A monocentric retrospective cohort study of 45 patients who benefited from a contraceptive vasectomy between July 2001 and May 2016. For each patient were studied: modalities of implementation, compliance with the recommendations of the 2001 law, costs and benefits generated by the intervention, the effectiveness of the gesture on the control spermograms, the satisfaction of the patients by a telephone questionnaire. RESULTS: The mean age was 41.3 years. The second consultation was carried out in 91 % of the cases but the reflection period was not respected in 24 % of the cases. Written consent was signed in 89 % of cases. Vasectomy was performed on an outpatient basis in 73 % of cases, under local anaesthesia in 6.7 % of cases. The average cost per patient was 660.63 euros for an average gain of 524.50 euros, a loss of 136.13 euros. On the control spermogram, 54.3 % were azoosperms but the 3-month delay was not observed in 23 % of them. No patients expressed regret after surgery. CONCLUSION: The recommendations of the 2001 law were not systematically followed. This lack of standardization of practices, potential reflection of a lack of interest, is to be highlighted with the extra cost generated. The revaluation of the act should be integrated into the reflection of improvement of male sterilization practices. LEVEL OF PROOF: 4.

Pelvic fracture in multiple trauma: A 67-case series.

INTRODUCTION: Severe pelvic trauma remains associated with elevated mortality, largely due to hemorrhagic shock. OBJECTIVE: The main study objective was to test for correlation between fracture type and mortality. The secondary objective was to assess the efficacy in terms of mortality of multidisciplinary management following a decision-tree in multiple trauma victims admitted to a level 1 trauma center. MATERIAL AND METHODS: Between July 2011 and July 2013, 534 severe trauma patients were included in a single-center continuous prospective observational study. All patients with hemorrhagic shock received early treatment by pelvic binder. Patients with active bleeding on full-body CT or persisting hemorrhagic shock underwent arteriography with or without embolization. Pelvic trauma was graded on the Tile classification. The principle end-point was mortality. RESULTS: Median age was 40 years (range, 26-48 years), with a 79% male/female sex ratio. Thirty-two of the 67 patients with pelvic trauma (48%) were in hemorrhagic shock at admission. Median injury severity score (ISS) was 36 (range, 24-43). On the Tile classification, 22 patients (33%) were grade A, 33 (49%) grade B and 12 (18%) grade C. Overall mortality was 19%, and 42% in case of hemorrhagic shock. Mortality was significantly higher with Tile C than A or B (58% vs. 9.1% and 12.1%, respectively; P=0.001). CONCLUSION: Vertical shear fracture (Tile C) was associated with greater mortality from hemorrhagic shock. LEVEL OF EVIDENCE: IV, case series.

[HoLEP learning curve: Toward a standardised formation and a team strategy]. / Apprentissage de l'HoLEP : vers une formation standardisée et une stratégie d'équipe.

AIM: Holmium laser enucleation of prostate (HoLEP) is renowned for the difficulty of its learning curve. Our aim was to evaluate the interest of a three-step tutorial in the HoLEP learning curve, in a university center. METHODS: It is a retrospective, monocentric study of the 82 first procedures done consecutively by the same operator with a proctoring in early experience and after 40 procedures. For all patients were noted: enucleation efficiency (g/min), morcellation efficiency (g/min), percentage of enucleated tissue (enucleated tissue/adenome weigth evaluated by ultrasonography. g/g), perioperative morbidity (Clavien), length of hospital stay, length of urinary drainage, functional outcomes at short and middle term (Qmax, post-void residual volume [PVR], QOL scores and IPSS at 3 and 6months). RESULTS: Enucleation and morcellation efficiency were significantly higher after the second proctoring (0.87 vs 0.44g/min; P<0.0001 and 4.2 vs 3.37g/min, P=0.038, respectively) so as the prostatic volume (43.5 vs 68.1mL, P=0.0001). Percentage of enucleated tissue was higher in the second group, however, the difference was not significant (69.5% vs 80.4%, P=0.03). Per- and postoperative complications, hospital length of stay, urinary drainage length and functional results at 3 and 6months were not significantly different. CONCLUSION: The learning curve did not interfere with functional results. The second proctoring was essential to us in order to grasp the technique. These data underlined the necessity of a pedagogic reflexion in order to built a standardized formation technique to the HoLEP. LEVEL OF EVIDENCE: 4.

Early thromboelastometry variables predict maximum clot firmness in children undergoing cardiac and non-cardiac surgery.

BACKGROUND: Early clot amplitudes measured on thromboelastometry (ROTEM®) predict maximum clot firmness (MCF) in adults. In this multicentre, retrospective study, we aimed to confirm the suspected relationship between early ROTEM® variables and MCF, in children undergoing cardiac or non-cardiac surgery. METHODS: 4762 ROTEM® tests (e.g. EXTEM, INTEM, FIBTEM, APTEM, and HEPTEM) performed in children undergoing cardiac or non-cardiac surgery at three University hospitals between January 2011 and June 2014 were reviewed. To assess the correlation between clot amplitudes measured after 5, 10 and 15 min and MCF, each variable was compared with the corresponding MCF by calculating Spearman's correlation coefficient. RESULTS: For the EXTEM® test, we observed that amplitude measured after 5 min (A5: r=0.91, P<0.001), 10 min (A10: r=0.95, P<0.001) and 15 min (A15: r=0.96, P<0.001) were strongly correlated to MCF. The same correlations were observed for INTEM® test (A5: r=0.93, P<0.001; A10: r=0.97, P<0.001; A15: r=0.97, P<0.001), and FIBTEM® test (A5: r=0.93, P<0.001; A10: r=0.94, P<0.001; A15: r=0.96, P<0.001). In addition, the amplitudes measured after five, 10 and 15 min were also strongly correlated with MCF in the APTEM® and the HEPTEM® tests. Receiver operating characteristics (ROC) analysis confirmed that A5, A10, A15 strongly predicted decreased MCF on all ROTEM® tests. CONCLUSIONS: This study confirmed that early values of clot amplitudes measured as soon as five, 10 or 15 min after clotting time could be used to predict maximum clot firmness in all ROTEM® tests.

[Mnesic disorders caused by left temporal gliomas]. / Les troubles mnésiques dans les gliomes temporaux gauches.

Episodic memory disorders are frequent in patients with temporal lesion. Verbal or visuo-spatial memory disorders depend on the location and the lateralization of the lesion. These disorders are well described in temporal epilepsy but rarely in population with cerebral tumor and especially not specifically focus on temporal glioma. The purpose of this study was to describe neuropsychological examination in patient with temporal glioma in the database of the regional memory centre of Besançon. Four patients were identified (all right-handed and with a left temporal glioma). Verbal episodic memory impairment and auditory-verbal short-term memory impairment were observed. One patient had also visual memory disorders. Therefore, further investigations showed an associated Alzheimer's disease. This finding modified the clinical management of this patient. Extensive neuropsychological assessment should be systematic initially to seek an associated pathology, especially in elderly patients, if the cognitive profile is unusual, during the follow-up to better understand cognitive evolution and the effect of therapies on cognition.

Dugbe virus ovarian tumour domain interferes with ubiquitin/ISG15-regulated innate immune cell signalling.

The ovarian tumour (OTU) domain of the nairovirus L protein has been shown to remove ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host cell proteins, which is expected to have multiple effects on cell signalling pathways. We have confirmed that the OTU domain from the L protein of the apathogenic nairovirus Dugbe virus has deubiquitinating and deISGylating activity and shown that, when expressed in cells, it is highly effective at blocking the TNF-α/NF-κB and interferon/JAK/STAT signalling pathways even at low doses. Point mutations of the catalytic site of the OTU [C40A, H151A and a double mutant] both abolished the ability of the OTU domain to deubiquitinate and deISGylate proteins and greatly reduced its effect on cell signalling pathways, confirming that it is this enzymic activity that is responsible for blocking the two signalling pathways. Expression of the inactive mutants at high levels could still block signalling, suggesting that the viral OTU can still bind to its substrate even when mutated at its catalytic site. The nairovirus L protein is a very large protein that is normally confined to the cytoplasm, where the virus replicates. When the OTU domain was prevented from entering the nucleus by expressing it as part of the N-terminal 205 kDa of the viral L protein, it continued to block type I interferon signalling, but no longer blocked the TNF-α-induced activation of NF-κB.

[Retrospective descriptive study about the use of levosimendan in children undergoing surgical correction for congenital heart disease]. / Estudio descriptivo retrospectivo sobre la utilización de levosimendán en niños sometidos a corrección quirúrgica de cardiopatía congénita.

OBJECTIVES: To describe the use of levosimendan for compassionate use in children undergoing surgery for congenital heart disease, as well as survival rates, and the variations in the haemodynamic and analytical variables studied. MATERIAL AND METHODS: An observational retrospective descriptive study was performed, using a review of clinical histories, from May 2005 to January 2010. Haemodynamic and analytical variables pre- and post- levosimendan administration, drugs used, and their dosages, and any adverse reactions were recorded. RESULTS: Forty two children, 38 of them undergoing surgical correction, between the ages of four days and 5.75 years (median 92 days) were included. The drug was infused on 46 occasions. Four children received two doses. The infusion rate was among 0.1 to 0.6 µg × kg⁻¹ × min⁻¹. Only one patient received a loading dose. In 15 administrations (32.6%), the same dose was maintained throughout the infusion period. In 19 cases (41.3%), the dose was increased or decreased according to the need for vasoactive support. In surgical patients, overall survival after 30 days of the administration, calculated using the Kaplan-Meier method, was 80%. Blood lactate levels were statistically associated with mortality (P<.001). CONCLUSIONS: There were no uniform criteria for using levosimendan, and it was only used as a rescue drug. Overall survival was similar to that reported in adult clinical trials. Clinical trials also need to be carried out in paediatric patients to determine the role of levosimendan in surgical practice, in order to develop and establish a clinical protocol for its use in children.

Analysis of the antioxidant response of Nicotiana benthamiana to infection with two strains of Pepper mild mottle virus.

The present study was carried out to investigate the role of reactive oxygen species (ROS) metabolism in symptom development and pathogenesis in Nicotiana benthamiana plants upon infection with two strains of Pepper mild mottle virus, the Italian (PMMoV-I) and the Spanish (PMMoV-S) strains. In this host, it has been shown that PMMoV-I is less virulent and plants show the capability to recover 21 d after inoculation. Analyses of oxidative stress biomarkers, ROS-scavenging enzyme activities, and antioxidant compounds were conducted in plants at different post-infection times. Only PMMoV-I stimulated a defence response through: (i) up-regulation of different superoxide dismutase isozymes; (ii) maintenance of adequate levels of three peroxiredoxins (2-Cys Prx, Prx IIC, and Prx IIF); and (iii) adjustments in the glutathione pool to maintain the total glutathione content. Moreover, there was an increase in the level of oxidized glutathione and ascorbate in the recovery phase of PMMoV-I-infected plants. The antioxidant response and the extent of oxidative stress in N. benthamiana plants correlates to: (i) the severity of the symptoms elicited by either strain of PMMoV; and (ii) the high capacity of PMMoV-I-infected plants for symptom recovery and delayed senescence, compared with PMMoV-S-infected plants.

Analysis of the concordance in the EGFR pathway status between primary tumors and related metastases of colorectal cancer patients:implications for cancer therapy.

Patients with metastatic Colorectal Cancer (mCRC), in which primary tumors are KRAS mutated, have no response to anti-EGFR therapy. However, less than half of mCRC patients with KRAS wild-type primary tumors respond to anti-EGFR therapy. Other downstream effectors of the EGFR pathway are being analyzed to fine-tune KRAS predictive value. However, as the primary tumor is the tissue of analysis that determines the use of anti-EGFR therapy in advanced disease, a high concordance in the status of these effectors between primary tumors and related metastases is required. We analyzed the concordances of downstream EGFR effectors in tumoral pairs of primaries and related metastases in a series of KRAS wild-type patients. One hundred seventeen tumoral pairs from patients with CRC were tested for KRAS mutational status. The level of concordance in the presence of KRAS mutations was 91% between the primary tumor and related metastases. The 70 pairs with KRAS wild-type primary tumors were further analyzed for BRAF and PIK3CA mutational status and for EGFR, PTEN and pAKT expression, and the number of concordant pairs was 70 (100%), 66 (94%), 43 (61%), 46 (66%) and 36 (54%), respectively. Our findings suggest that the mutational status of KRAS, BRAF and PIK3CA in the primary tumor is an adequate surrogate marker of the status in the metastatic disease. On the other hand, the immunohistochemical analysis of EGFR, PTEN and pAKT showed a much higher degree of discordance between primaries and related metastases.

Peste des petits ruminants: a suitable candidate for eradication?

This year will see the final announcement, accompanied by much justifiable celebration, of the eradication from the wild of rinderpest, the 'cattle plague' that has been with us for so many centuries. The only known rinderpest virus (RPV) remaining is in a relatively small number of laboratories around the world, and in the stockpiles of vaccine held on a precautionary basis. As we mark this achievement, only the second virus ever eradicated through human intervention, it seems a good time to look at rinderpest's less famous cousin, peste des petits ruminants ('the plague of small ruminants') and assess if it should, and could, also be targeted for global eradication.

Cytosolic phospholipase A2α gene silencing in the myeloid lineage alters development of Th1 responses and reduces disease severity in collagen-induced arthritis.

OBJECTIVE: Several lines of evidence implicate cytosolic phospholipase A(2)α (cPLA(2)α) as a critical enzyme in inflammatory disorders, including rheumatoid arthritis. Since cells from the myeloid compartment regulate local and systemic disease pathogenesis, the present study was undertaken to examine the effect of cPLA(2)α inhibition in experimental arthritis, using a delivery system tailored to target monocyte functions by RNA interference (RNAi). METHODS: Mice with collagen-induced arthritis (CIA) were injected intravenously with an anti-cPLA(2)α small interfering RNA (siRNA) sequence (siPLA2) formulated as lipoplexes with the RPR209120/DOPE cationic liposome and a carrier DNA. The clinical course of joint inflammation was assessed, and the immunologic balance was analyzed by measuring T helper cell frequencies and cytokine expression. Biodistribution studies of siRNA were also performed. RESULTS: Weekly systemic injection of siPLA2 lipoplexes significantly reduced the incidence and severity of CIA, in both preventive and curative settings, as compared with findings in control animals. Histologic scores for inflammation and cartilage damage were reduced. The clinical effect was associated with local inhibition of tumor necrosis factor α secretion and lower cPLA(2)α expression and activity. The siPLA2 lipoplexes enabled triggering of in vivo RNAi-mediated gene silencing of cPLA(2)α in CD11b+ cells recovered from the spleen. While the treatment had no effect on anti-type II collagen (anti-CII) antibodies, CII-specific T helper cells producing interferon-γ, but not interleukin-17, in draining lymph node cells were decreased. CONCLUSION: Our findings indicate that systemic RNAi-mediated cPLA(2)α gene silencing in CD11b+ cells is effective in the treatment of CIA, and Th1 suppression is one of the potential underlying mechanisms, whereas Th17 suppression is not.