Association of Circulating Tumor Cells and Tumor Molecular Profile With Clinical Outcomes in Patients With Previously Untreated Metastatic Colorectal Cancer: A Pooled Analysis of the Phase III VISNÚ-1 and Phase II VISNÚ-2 Randomized Trials.

BACKGROUND: The bCTC count is a well-established prognostic biomarker in mCRC, as well as in other tumor types. The aim of this analysis was to evaluate the prognostic/predictive role of the bCTC count (≥3 vs. <3) in previously untreated mCRC. PATIENTS AND METHODS: The study involved 589 untreated mCRC patients included in the intention-to-treat population of 2 randomized clinical trials (phase III VISNU-1 [NCT01640405] and phase II VISNU-2 [NCT01640444] studies). RESULTS: Of the 589 patients, 349 (59.2%) had bCTC≥3 and 240 (40.7%) had bCTC<3. Multivariate analysis showed that the bCTC count is an independent prognostic factor for overall survival (OS) (HR 0.59, 95% CI 0.48-0.72; P = 0.000) and potential for progression-free survival (PFS) (P = 0.0549). Median OS was 32.9 and 19.5 months in patients with bCTC<3 and bCTC≥3 (P <0.001), respectively. This effect was also observed comparing OS in RASwt patients from both studies. Other prognostic factors were: ECOG-PS, primary tumor site, number of metastatic sites and surgery of the primary tumor. Median OS was lower for patients treated with anti-VEGF versus anti-EGFR (22.3 vs. 33.3 months, P <0.0001) while there were no significant differences in PFS according to the targeted treatment received. CONCLUSION: This post-hoc analysis of 2 randomized studies confirms the poor prognosis of patients with bCTC≥3 but this is not associated with other adverse independent prognostic factors such as RAS/BRAF mutations.

Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study.

BACKGROUND: We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. RESULTS: Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. CONCLUSIONS: BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.

[How to treat palmar burn sequelae in children, about 49 cases]. / Prise en charge des séquelles de brûlure palmaire chez l'enfant, à propos de 49 cas.

INTRODUCTION: Even if they represent only 2.5 % of the total body surface area, the hands are burnt in 50 % of hospitalized patients. The risk of sequelae is significant, especially in children, human being in full growth, and a source of aesthetic and functional handicap. The aim of this study is to research the predictive factors of sequelae, to study their treatment of and their evolution. MATERIAL AND METHODS: We included children under six years of age with deep palmar burns of the hand between 1998 and 2008. Demographics, characteristics of the initial burn and its treatment were noted. Then, we studied the types of hand burn sequelae and their treatment. Finally, we observed their evolution over time with an aesthetic and functional evaluation and their impact on quality of life. RESULTS: Forty-nine children, representing 70 hands, were included in the study. The mean age at the time of the initial burn was 16.2 months (6; 60). The initial treatment was directed healing in 39 % of cases and thin skin excision-grafting in 61 % of cases. The type of sequelae most represented was bridle in 73 % of cases. Treatment consisted of rehabilitation measures (13 %) or surgery (69 %). The mean age at the time of surgery was 10.1 years (4; 19). These were plasties (62 %), total skin grafts (15 %) or a combination of both (23 %). The current follow-up is 16.2 years. The aesthetic result is considered good in 52 % of cases, the functional result is good in 78 % of cases. The impact on the quality of life is low and the parents are satisfied with the initial care. CONCLUSION: The treatment of the sequelae of burnt hands gives good results but involves well-conducted rehabilitation and regular monitoring. The treatment period must be adapted and the surgery simple, effective and specific to the type of sequelae.

[Tissue expansion in child's burn reconstruction. Management principles and eleven years retrospective study of 42 patients]. / Expansion cutanée pour séquelles de brûlure de l'enfant. Principes de prise en charge et étude rétrospective de 42 patients sur 11 ans.

PURPOSE: With constraints and a risk of complication, tissue expansion in child's burn sequelae need a controlled surgical procedure, and a therapeutic plan appropriate to the specific pediatric healing, growth, and development. MATERIAL AND METHODS: Our principles of management and technical points are described. A retrospective study of tissue expansion in child's burn sequelae between 2005 and 2016 is submitted. RESULTS: There are 185 expanders, 98 protocols in 41 children, over half of sequelae concerning scalp, neck and chest. Mean age at the first expansion was 10.3 years old (5.8 years after burn). There are in average 2,4 (1-8) protocols by patient, with 1.9 (1-4) expanders by procedure. Surgical repair was a flap (78.8%), a full-thickness skin graft (13.3%) or both. Fifteen patients (30 expanders (14.6%) and 22 protocols (22.4%)), had expansion's complications, mostly infections and expositions. Eight patients (14 expanders (7.6%) and 10 protocols (10.2%)) had reconstructive's complications. An increase of burn area was a risk factor of complication (significant). Complicated expanders rate by location was 7.9% (scalp), 12.5% (neck), 9.8% (supraclavicular), 10.5% (chest), 19.4% (abdomen), 30% (buttock), 29.4% (lower limb), 1/2 (face). CONCLUSION: Tissue expansion in child's burn sequelae is ideal in scalp, good in neck, chest and proximal upper limb, and to do carefully in lower limb and face.

Is there any place for spontaneous healing in deep palmar burn of the child?

Child palm burns arise by contact and are often deep. The singular difficulty of such a disease comes from the necessity of the child growth and from the potential occurrence of constricted scars. In order to avoid sequelae, the actual gold standard is to practice an early excision of the burn, followed by a skin graft. The aim of this study is to evaluate the results of spontaneous healing combined with rehabilitation versus early skin grafting and rehabilitation concerning the apparition of sequelae. We performed a retrospective study in two burn centers and one rehabilitation hospital between 1995 and 2010. Eighty-seven hands have been included in two groups: one group for spontaneous healing and the other group for excision and skin grafting. Every child benefited from a specific rehabilitation protocol. The two main evaluation criteria were the duration of permanent splint wearing and the number of reconstructive surgery for each child. The median follow-up duration is about four years. The two groups were comparable. For the early skin grafting group, the splint wearing duration was 1/3 longer than for the spontaneous healing group. Concerning the reconstructive surgery, half of the grafted hands needed at least one procedure versus 1/5 of spontaneous healing hands. Our results show the interest of spontaneous healing in palmar burn in child, this observation requires a specific and intense rehabilitation protocol.

A novel allele HLA-C*07:445 identified in a French hematopoietic stem cell donor.

The novel allele HLA-C*07:445 has 1 nucleotide change from HLA-C*07:01 at nucleotide 277 C>A in exon 2.

[Chronic cough in the elderly is associated with expiratory flow limitation]. / La toux chronique du sujet âgé est associée à une limitation expiratoire des débits.

As chronic respiratory symptoms and the presence of expiratory flow limitation (EFL) are commonly reported in the elderly, we investigated whether they were associated in a population of 75 years old volunteers. We analyzed the results of a prevalence survey of chronic respiratory symptoms and respiratory infections, and performed spirometry and measured EFL after application of a negative expiratory pressure at the mouth (NEP). EFL was present in 170 (46%) subjects, a chronic cough in 49 (13%), chronic sputum in 58 (29%) and a history of respiratory infection in 62 (17%). Chronic cough and the composite outcome "chronic cough or sputum" were significantly associated with the presence of EFL (respectively 60% vs. 43%, OR=2.04 [1.09 to 3.78], P=0.023, and 56% vs. 43%, OR=1.74 [1.05 to 2.87], P=0.04), after controlling for smoking or airway obstruction. History of respiratory infections were not associated with an increased prevalence of EFL. We concluded that the presence of a LED could be an interesting indicator of respiratory aging. Its detection could be advocated in elderly subjects presenting with respiratory symptoms.

Pain induced by a minor medical procedure (bone marrow aspiration) in dogs: comparison of pain scales in a pilot study.

BACKGROUND: Bone marrow aspiration (BMA) is a clinical procedure frequently performed in dogs. OBJECTIVE: To compare levels of pain intensity induced by 3 different BMA procedures using several pain scoring instruments. ANIMALS: Sixteen healthy Beagles. METHODS: A prospective experimental pilot study was conducted using blinded observers. Dogs were randomized into 3 groups: iliac BMA under sedation (Iliac-Sed, n = 4), sternum BMA under sedation (Stern-Sed, n = 4), and sternum BMA on conscious dogs without sedation (Stern-No-Sed, n = 8). RESULTS: Using the SF-Glasgow pain scale, the overall pain score in the Stern-No-Sed group was lower than that in the Stern-Sed group (P = 0.04). Using the 4A-VET pain scale, the effects of procedures over time on pain scores did not differ between and within groups. An inactivity index indicated that the overall score for the Stern-No-Sed group was significantly lower than the scores for the Stern-Sed and Iliac-Sed groups (P ≤ 0.01). There was a significant association in pain assessment using the SF-Glasgow and 4A-VET pain scales (P = 0.0004). When comparing the SF-Glasgowscale to the 4A-VET pain scale, the scores for the Stern-No-Sed group were lower compared to those of the Stern-Sed scores (P = 0.03). Based on telemetered motor activity, the Iliac-Sed group may have experienced more discomfort during the post-procedural period. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs may experience mild to moderate pain after BMA procedures, and the sternal site should be preferred. The SF-Glasgow pain scale showed better interobserver reliability, but the 4A-VET scale was less biased by sedation.

Influence of preoperative cognitive status on propofol requirement to maintain hypnosis in the elderly.

BACKGROUND: The loss of cholinergic neurones in the basal forebrain has been shown to correlate to the extent of cognitive dysfunction during ageing in humans and to the hypnotic potency of propofol in animal models. We examined how the preoperative cognitive status, as assessed by mini-mental state examination (MMSE), may interact with propofol consumption during anaesthesia in the elderly. METHODS: In a prospective study, we recruited 41 patients (65-99 yr) undergoing surgery for hip fracture. Femoral nerve block was performed for analgesia. Target-controlled infusion of propofol (Schnider's model) was adjusted to the bispectral index within the range 40-60. Multiple linear regression analysis determined whether age, BMI, gender, duration of anaesthesia, and preoperative MMSE score affected the propofol consumption (general linear model, Systat 8.0). RESULTS: BMI and MMSE score significantly affected the mean value of propofol consumption. A low MMSE score (below 19) was associated with an observed decrease in propofol requirement in patients >65 yr of age. No significant effect of age, gender, and duration of anaesthesia on the propofol consumption was observed. CONCLUSIONS: Propofol requirement to maintain hypnosis during general anaesthesia appears to decrease with deterioration in the cognitive status in the elderly. We suggest that a cognitive dysfunction linked to a cerebral cholinergic dysfunction may influence the brain sensitivity for propofol in aged patients.

Inferior turbinate hypertrophy radiofrequency management for children with cystic fibrosis.

OBJECTIVE: To evaluate, using radiofrequency techniques, the relevance and effectiveness of treatment of inferior turbinate hypertrophy in children with cystic fibrosis. MATERIALS AND METHODS: A study of patients with cystic fibrosis with hypertrophy of inferior turbinate who were being treated at Lisieux Hospital In-Patient Paediatric and ENT- Head and Neck Surgery Department. 41 patients were included in the study and followed over 2 years. We analyzed the postoperative phase and the effectiveness of treatment, through clinical and radiological examination. RESULTS: A clinical improvement of symptoms is observable from the third month after surgery in 100% of cases. However, we noted a loss in the effectiveness of radiofrequency on the turbinate tissue one year following operation, which worsens with time. However, the postoperative results remain satisfactory at 1 year and 2 years. CONCLUSION: Radiofrequency is, in our opinion, the treatment of choice for inferior turbinate hypertrophy in children with cystic fibrosis. It combines a simple and low-risk effect with effective preservative treatment. However, the benefits of radiofrequency fade with time. Nonetheless, this technique yields postoperative results that remain satisfactory beyond 2 years. It is often useful to consider a new session after this date.

[Recommendations for the management of bone demineralization in cystic fibrosis]. / Recommandations pour la prise en charge de la déminéralisation osseuse dans la mucoviscidose.

A high prevalence of low bone mineralization is documented in adult patients with cystic fibrosis (CF). Osteopenia is present in as much as 85% of adult patients and osteoporosis in 13 to 57% of them. In children, studies are discordant probably because of different control database. Denutrition, inflammation, vitamin D and vitamin K deficiency, altered sex hormone production, glucocorticoid therapy, and physical inactivity are well known risk factors for poor bone health. Puberty is a critical period and requires a careful follow-up for an optimal bone peak mass. This review is a consensus statement established by the national working group of the French Federation of CF Centers to develop practice guidelines for optimizing bone health in patients with CF. Recommendations for screening and for calcium, vitamin D and K supplementation are given. Further work is needed to define indications for treatment with biphosphonates and anabolic agents.

[Hand allografts: experience from Lyon team]. / Allogreffe de mains: expérience lyonnaise.

Hand allograft is a method in the stage of clinical experimentation, which is reserved in France for the treatment of bilateral traumatic amputees. This study reports the Lyon team experience, which is pioneer in this domain. Four patients (3 males and 1 female) underwent seven (one unilateral and three bilateral) hand transplantations from September 1998 to February 2007. The level of amputation was at the wrist or at the mid-forearm. Delay since hand loss ranged from 2.5 to 9 years. The surgical protocol was elaborated and planned case by case. All recipients received the same immunosuppressive treatment. Episodes of acute rejection were observed in the first 3 months after transplantation, which were easily managed after a few days increasing oral prednisone doses and applying topical immunosuppressants. Currently the patients receive the doses of immunosuppressants comparable to those in kidney-grafted patients. We have not registered any severe complication of immunosuppressive treatment up till now (7 years follow-up for the earliest graft). We performed analytical and functional clinical, as well as questionnaire evaluation of patients. The first case (unilateral graft) resulted in graft failure at 2 years due to non-compliance of the patient. The three bilateral graftees demonstrate a favorable evolution despite some immunological (hyperglycemia, serum sickness) and surgical (thrombosis, osteomyelitis, skin loss) complications, which could be managed. The middle and long-term follow-up evaluation revealed good to excellent sensorimotor recovery of 4 hands in both male recipients (4 and 7 years) with satisfactory social adaptation, higher or equal to those expected after post-traumatic replantations at the equivalent level and higher to those obtained with currently available myoelectric prosthesis. The last patient, a young female who has been grafted in February 2007, receives ongoing reeducation course and shows normal progress of functional restoration of both hands. The encouraging results of this clinical experimentation make us currently consider hand allografting as reasonable and useful both for the patients and for evolution of research in composite tissues allotransplantation (CTA). Further long-term careful research and worldwide monitoring of all patients with hand allografts is required to, on the one part, state on the authorization of this surgery, and, on the other part, to better elucidate the mechanisms of successful CTA.

[Macrolides, Pseudomonas aeruginosa and cystic fibrosis]. / Macrolides, Pseudomonas aeruginosa et mucoviscidose: concepts actuels.

Long-term low dose azithromycin treatment in cystic fibrosis patients with chronic Pseudomonas aeruginosa infection is safe and reduces the decline in lung function, the number of acute exacerbations and improves nutritional status; underlying efficacy mechanisms are multiple and synergistic.

Use of an artificial dermis (Integra) for the reconstruction of extensive burn scars in children. About 22 grafts.

We used an artificial dermis (Integra) for the reconstruction of extensive burn scars in children. Integra was initially developed for the primary coverage of acute burns, but several authors report good experiences with Integra for reconstructive surgery. We present a group of 10 children who underwent Integra grafting at 22 different operational sites. Five children received several grafts with Integra. On average, 260 cm(2) per session were grafted. We compared the surface of Integra on the day of grafting and then again on the evaluation day to measure the secondary retraction of the grafts. Complications (infection of Integra, failure of the epidermal graft) were observed in 5 cases. At the final evaluation, 20 grafts were visible. The surface of the Integra graft represented less than 50% of the initial surface in 7 cases, 51-75% in 5 cases and more than 76% in 8 cases. The disadvantages of Integra in reconstructive surgery are that two operative procedures are necessary and the recurrence of contraction seems to be more significant than with full thickness auto grafts. However, Integra has many advantages: the immediate availability of large quantities, the simplicity and reliability of the technique, the pliability and the cosmetic aspect of the resulting coverage. In light of these preliminary results, Integra appears to offer a new alternative for the reconstruction of extensive burn scars in children.

[Aspergillosis in cystic fibrosis patients]. / Aspergillose et mucoviscidose.

Allergic bronchopulmonary aspergillosis (ABPA) should be suspected in any CF patient whose pulmonary disease deteriorates precipitously, suddenly or unexpectedly, and has to be correlated to fungal hypersensitivity biological tests. The standard therapeutic approach is based upon systemic corticosteroids. Invasive pulmonary aspergillosis (IPA) may occur mainly but not exclusively in immunosuppressed patients undergoing lung transplantation. New antifungal compounds (Triazoles, Itraconazole, Voriconazole), Echinochandins (Caspofungin) are effective, synergistic, well tolerated, should their contraindications and side effects be carefully respected and monitored.

Phase I study of weekly CPT-11 (irinotecan)/docetaxel in patients with advanced solid tumors.

Based on the synergistic cytotoxicity demonstrated in vitro by topoisomerase I inhibitors followed by docetaxel and the feasibility of giving both drugs on a weekly schedule avoiding overlapping toxicities, we designed a phase I trial of weekly CPT-11 (irinotecan)/docetaxel to determine the dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) of this combination. Eighteen patients with advanced solid tumors treated with at least one prior chemotherapy regimen were included in this trial. CPT-11 was administered as a 90-min (intravenous) IV infusion followed immediately by docetaxel as a 30-min IV infusion. Both drugs were given on days 1, 8 and 15 in 4-week cycles. Four escalating dose levels of CPT-11/docetaxel (level I: 60/20 mg/m(2), level II: 60/25 mg/m(2), level III: 70/25 mg/m(2), and level IV: 70/30 mg/m(2)) were studied. Forty-seven cycles were administered (range, 1-5 courses) with a median number of 2.6 cycles per patient. Grade 4 leukopenia was the DLT reached at dose-level IV (CPT-11/docetaxel 70/30 mg/m(2)). Four patients had grade 3 anemia at dose levels III (two patients) and IV (two patients), while grade 3/4 thrombocytopenia was not seen. Grade 3/4 non-hematologic toxicities included grade 3 diarrhea in two patients (dose levels II and IV), grade 3 asthenia in one patient (dose level II) and grade 3 stomatitis in one patient (dose level I). The recommended dose of this weekly schedule is CPT-11 70 mg/m(2) and docetaxel 25 mg/m(2). DLT of this regimen is leukopenia, although toxicity is manageable at the recommended dose level. The activity of this regimen is being evaluated in a phase II study in previously treated patients with advanced non-small cell lung cancer.

[Home environment and acute propylene glycol intoxication in a two-year old. An unusual case report]. / Environnement domestique et intoxication aiguë au propylène glycol chez un nourrisson de deux ans. A propos d'une observation inhabituelle.

BACKGROUND: Acute propylene glycol intoxication in a two-year-old toddler underlines the potentially serious toxicity in children of this chemical agent present as a diluent in many drugs and environmental products such as cosmetics, diapers, cleansing towels, despite a common consideration of safety and lack of toxicity. CASE REPORT: A two-years-old boy previously healthy was found in the morning by his parents in his cradle, lethargic, responsive only to sharp pain. On admission, vital signs were: temperature 38.5 degrees C, lethargy, polypnea; propylene glycol intoxication through disposable cleansing towels chewing was ascertained by anamnesis and blood urine analyses which revealed metabolic acidosis and serum propylene glycol peak. CONCLUSION: Environmental acute propylene glycol intoxication must be considered and searched for in front of a metabolic acidosis case of unknown origin in children.

[Evaluation of diagnosis and follow-up in screened children with cystic fibrosis in Normandy]. / Evaluation du diagnostic et du suivi de la cohorte normande d'enfants dépistés atteints de mucoviscidose.

The neonatal screening programme in Normandy (France) allowed the formation of a homogenous cystic fibrosis (CF) cohort of 150 children diagnosed between 1980 and 1997. At the time of this retrospective study, 11 were deceased, out of which nine had meconium ileus (eight deaths after surgery, one at 5 years of age). Sixty children born between 1980 and 1993 in the Basse-Normandie region were followed up during a mean 80 months following similar protocols. The mean age at diagnosis was 41 days (SD = 27 d) for infants without meconium ileus. The occurrence of Pseudomonas aeruginosa (P. aeruginosa) infection and chronic colonization was studied using a monovariate followed by a multivariate analysis including the following variables: sex; meconium ileus; anthropometric data at birth and at diagnosis; pancreatic insufficiency; radiological data (Brasfield score); microbiology data at diagnosis; and genetic data. P. aeruginosa infection appeared earlier in children with pancreatic insufficiency (OR = 2.2; p < 0.05) or with radiological abnormalities (Brasfield score < 21) at diagnosis (OR = 3.9; p < 0.05). Meconium ileus (OR = 5.3; p < 0.01), pancreatic insufficiency (OR = 3.8; p < 0.01) and Brasfield score < 21 at diagnosis (OR = 5.6; p < 0.001) were prognosis factors for early chronic P. aeruginosa colonization. In CF children without meconium ileus, the major risk factor found through multivariate analysis for earlier infection and for earlier chronic colonization by P. aeruginosa was a diagnosis delay > 40 days (respectively OR = 4.6; p < 0.001 and OR = 10.4; p < 0.005). These results must be compared with the lower Brasfield score at diagnosis in infants diagnosed after 40 days of life (p < 0.01).