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.

New evidence in severe pneumonia: meropenem-vaborbactam.

The appearance and spread of new mechanisms of bacterial resistance to antibiotics is a serious health problem. One of the most difficult resistance mechanisms to treat is the production of carbapenemases. Carbapenemase KPC is one of those mechanisms with few therapeutic options. Meropenem-vaborbactam has shown great efficacy against this type of microorganism, both from a clinical and microbiological point of view. Its good pharmacokinetics, including in the lung, and its safety profile make meropenem-vaborbactam an excellent therapeutic option. Finally, the absence of resistance genesis during treatment seems to indicate that its efficacy will be long-lasting.

Large artery intracranial stenosis in young adults with ischaemic stroke.

Large artery intracranial stenosis (ICS) is a common finding in stroke patients, but is much less prevalent in Western countries than in Asia and in young adults than in the elderly. We investigated the prevalence and causes of ICS among French young adults with ischaemic stroke. Clinical and radiological data of patients aged 18-54 years treated consecutively for acute ischaemic stroke in the anterior circulation at a tertiary stroke centre were analysed retrospectively. Patients with>50% ICS were identified. ICS was evaluated using TOF-MRA, vessel wall-MRI, digital subtraction angiography and CT-angiography. A total of 316 patients were included. ICS was diagnosed in 29 patients, resulting in a prevalence of 9.2% (95% CI, 6.2 to 13.3). The leading cause of ICS was atherosclerosis (n=13), ahead of moyamoya disease (n=4), dissection (n=2), vasculitis (n=2), and reversible cerebral vasoconstriction syndrome (n=1). The cause of ICAS could not be determined in 7 patients. ICS was found in nearly one in 10 ischaemic strokes among French young adults. Atherosclerosis was the leading cause of ICS. The cause of ICS could not be determined in almost a quarter of the patients.

Laboratory safety evaluation of bedinvetmab, a canine anti-nerve growth factor monoclonal antibody, in dogs.

Nerve growth factor (NGF), a critical mediator of nociception, is a novel analgesic therapeutic target. Bedinvetmab, a canine monoclonal antibody (mAb), binds NGF and inhibits its interaction with tropomyosin receptor kinase A (trkA) and p75 neurotrophin receptor (p75NTR) receptors. The objective of three integrated laboratory studies was to demonstrate the safety of bedinvetmab in adult laboratory Beagle dogs. Daily health, veterinary, clinical pathology, systemic exposure, and anti-drug antibody evaluations were performed. Study 1 additionally included electrocardiography, neurologic, and ophthalmic assessments, and radiographic monitoring of joints of the appendicular skeleton. Study 2 evaluated T-lymphocyte-dependent immune function. Study 3 evaluated the safety of short-term concurrent administration of carprofen, a nonsteroidal anti-inflammatory drug (NSAID), with bedinvetmab. Studies 1 and 3 included terminal pathology and histopathology evaluations. Study designs and procedures included directed complementary morphologic and functional evaluations of a literature- and in vitro-based list of potential safety issues related to the NGF signaling pathway and characteristics engineered into this mAb. Screening-level general procedures evaluated effects associated with mAbs that target and inhibit soluble agonist cytokines. There were no treatment-related adverse changes in clinical evaluations, clinical neurological and ophthalmic examinations, joints, immune morphology or function, and no effects of short-term concurrent NSAID usage. Treatment-emergent immunogenicity was not observed. Bedinvetmab (1 mg/kg SC monthly; 3× and 10× dose multiples) was well tolerated in normal laboratory Beagle dogs for 6 months and with 2 weeks' concurrent NSAID administration.

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.

Serotonin Selective Reuptake Inhibitors (SSRIs) and Stroke.

PURPOSE OF REVIEW: The interest in SSRIs after stroke has increased in the past few years, with better knowledge of post-stroke depression and with the demonstrated capacity of some SSRIs to act on the functional recovery of non-depressed subjects. RECENT FINDINGS: Arguments for the action of SSRIs in favour of post-stroke neurological function recovery have improved through new elements: basic science and preclinical data, positive clinical trials and repeated series of stroke patient meta-analysis, and confirmation of favourable safety conditions in post-stroke patients. Global coherence is appearing, showing that SSRIs improve stroke recovery in non-depressed patients when given for 3 months after the stroke, with highly favourable safety conditions and a favourable benefit/risk ratio. Large series are still needed.

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.

Characterization of osteoarthritis in cats and meloxicam efficacy using objective chronic pain evaluation tools.

This study aimed to characterize osteoarthritis (OA)-related chronic pain and disability in experimental cats with naturally occurring OA. Peak vertical ground reaction force (PVF), accelerometer-based motor activity (MA) and the von Frey anesthesiometer-induced paw withdrawal threshold were used to define OA and to test the efficacy of meloxicam. A diagnosis of OA was based on radiographic and orthopedic examinations. Cats with OA (n=39) and classified as non-OA (n=6) were used to assess the reliability and sensitivity of the parameters to assess OA over 3weeks while being administered placebo medication. A randomised parallel design study was then used to investigate the effects on OA of daily oral meloxicam treatment for 4weeks at different dose rates (0.025mg/kg, n=10mg/kg; 0.04mg/kg, n=10; 0.05mg/kg, n=9), compared to cats administered a placebo (n=10). The test-retest repeatability for each tool was good (intra-class correlation coefficient ⩾0.6). The PVF and the von Frey anesthesiometer-induced paw withdrawal threshold discriminated OA (P<0.05). Meloxicam did not add to the PVF improvement observed in placebo-treated cats during the treatment period (adj-P⩽0.01). The 0.025 and the 0.05mg/kg meloxicam-treated cats experienced a higher night-time (17:00-06:58h) MA intensity during the treatment period compared to the placebo period (adj-P=0.04, and 0.02, respectively) and this effect was not observed in the placebo group. The high allodynia rate observed in the 0.04mg/kg meloxicam-treated group may explain the lower responsiveness to the drug. The von Frey anesthesiometer-induced paw withdrawal threshold demonstrated no responsiveness to meloxicam. The results from this study indicated that daily oral meloxicam administration for 4weeks provided pain relief according to night-time MA.

The upper airway resistance syndrome.

Obstructive sleep apnea syndrome has been recognized as a major public health problem. Both its cardiovascular and metabolic comorbidities and symptoms motivate for an accurate diagnosis and appropriate treatment. The main stimulus associated with obstructive sleep apnea (OSA) and explaining deleterious consequences is intermittent hypoxia. The upper airway resistance syndrome (UARS) has been described based on the hypothesis that snoring and repetitive occurrence of respiratory effort-related arousals (RERAs) but not oxygen desaturation might produce a significant disease with symptoms, altered quality of life and cardiovascular morbidity. Diurnal sleepiness remains the main diagnostic criteria, which is often confounded with tiredness in women. UARS patients may also report insomnia and symptoms that closely resemble those of the functional somatic syndromes. Currently, the International Classification of Sleep Disorders does not individualize UARS as a specific entity and reports UARS patients as a subgroup of OSA. However, RERAs are described as unambiguous abnormal respiratory events occurring during sleep and requiring a specific scoring. In this review, the authors attempt to describe the specific characteristics of UARS that are relevant for both clinicians and researchers.

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.

Patlak plot analysis CT-GFR for the determination of renal function: comparison of normal dogs with autologous kidney transplant dogs.

Glomerular filtration rate (GFR) can be determined using Patlak plot analysis with single-slice dynamic computed tomography (CT). Acute autologous graft failure has several causes, all of which induce a measurable decrease in glomerular filtration rate. This study demonstrated in an experimental model of canine autologous renal transplant that CT-derived renal plasma clearance was significantly lower (p = 0.002) in dogs having undergone transplant (0.077 +/- 0.058 ml min(-1) ml renal tissue(-1)) compared with control dogs (0.396 +/- 0.139 ml min(-1) ml renal tissue(-1)). A significant negative curvilinear relationship was seen between serum creatinine and total renal plasma clearance (R(2) = 0.84, p = 0.0001). Alterations in renal time attenuation curve shape in dogs having undergone transplant may have been related to increased renal vascular resistance related to tubular necrosis. CT-GFR may be a useful experimental tool in the evaluation of renal dysfunction in transplant models.