PROSPECT guideline for oncological breast surgery: a systematic review and procedure-specific postoperative pain management recommendations.

Analgesic protocols used to treat pain after breast surgery vary significantly. The aim of this systematic review was to evaluate the available literature on this topic and develop recommendations for optimal pain management after oncological breast surgery. A systematic review using preferred reporting items for systematic reviews and meta-analysis guidance with procedure-specific postoperative pain management (PROSPECT) methodology was undertaken. Randomised controlled trials assessing postoperative pain using analgesic, anaesthetic or surgical interventions were identified. Seven hundred and forty-nine studies were found, of which 53 randomised controlled trials and nine meta-analyses met the inclusion criteria and were included in this review. Quantitative analysis suggests that dexamethasone and gabapentin reduced postoperative pain. The use of paravertebral blocks also reduced postoperative pain scores, analgesia consumption and the incidence of postoperative nausea and vomiting. Intra-operative opioid requirements were documented to be lower when a pectoral nerves block was performed, which also reduced postoperative pain scores and opioid consumption. We recommend basic analgesics (i.e. paracetamol and non-steroidal anti-inflammatory drugs) administered pre-operatively or intra-operatively and continued postoperatively. In addition, pre-operative gabapentin and dexamethasone are also recommended. In major breast surgery, a regional anaesthetic technique such as paravertebral block or pectoral nerves block and/or local anaesthetic wound infiltration may be considered for additional pain relief. Paravertebral block may be continued postoperatively using catheter techniques. Opioids should be reserved as rescue analgesics in the postoperative period. Research is needed to evaluate the role of novel regional analgesic techniques such as erector spinae plane or retrolaminar plane blocks combined with basic analgesics in an enhanced recovery setting.

Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program.

BACKGROUND: EGFR mutations cause inconsistent response to EGFR tyrosine-kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR-mutated non-small-cell lung cancer collected in the Biomarkers France database. PATIENTS AND METHODS: Of 17 664 patients, 1837 (11%) with EGFR-mutated non-small-cell lung cancer were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 stage IV patients. RESULTS: EGFR exon 18, 19, 20 and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%) and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7 months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type {exon 19: hazard ratio (HR)=0.51 [95% confidence interval (CI): 0.41-0.64], P < 0.0001; exon 21: HR = 0.76 (95% CI: 0.61-0.95), P = 0.002; exon 20: HR = 1.56 (95% CI: 1.02-2.38), P = 0.004}. EGFR mutation type was prognostic of progression-free survival versus wild-type [exon 19: HR = 0.62 (95% CI: 0.49-0.78), P < 0.0001; exon 20: HR = 1.46 (95% CI: 0.96-2.21), P = 0.07]. First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved progression-free survival versus chemotherapy [HR = 0.67 (95% CI: 0.53-0.85), P = 0.001]. OS was longer for del19 versus L858R, which was associated with better OS compared with other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients. CONCLUSION: EGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.

High-throughput somatic mutation profiling in pulmonary sarcomatoid carcinomas using the LungCarta™ Panel: exploring therapeutic targets.

BACKGROUND: Pulmonary sarcomatoid carcinomas (SC) are tumors characterized by poor prognosis and resistance to conventional platinum-based chemotherapy. This study sought to describe the mutational profile of SC using high-throughput genotyping technology. PATIENTS AND METHODS: We used mass spectrometry to test 114 surgical biopsies from 81 patients with SC for 214 mutations affecting 26 oncogenes and tumor suppressor genes. RESULTS: In total, 75 (92.6%) patients were smokers. Within the total 81 tumors, 67 distinct somatic alterations were identified, with 56 tumors (69.1%) harboring at least one mutation. The most frequent mutations were KRAS (27.2%), EGFR (22.2%), TP53 (22.2%), STK11 (7.4%), NOTCH1 (4.9%), NRAS (4.9%), and PI3KCA (4.9%). The EGFR mutations were almost always rare mutations (89%). In 32 tumors (39.5%), two or more mutations co-existed, with up to four mutations in a single case. In six different cases, comparative genetic analysis of different histological areas from the same tumor (giant, spindle, or epithelial component) revealed a 61% concordance rate for all the mutations with a 10% detection threshold, compared with 91.7% with a 20% detection threshold. CONCLUSION: Our results demonstrated a high mutation rate and frequent co-mutations. Despite SC tumors exhibiting a high histological heterogeneity, some intratumoral molecular homogeneity was found. Now with newly developed targeted therapies, SC patients may be eligible for new target mutations, and can now therefore be screened for clinical trials.

A proposed new method for assessing the pathological response to chemotherapy in resected colorectal liver metastases.

BACKGROUND: Pathological response (PR) to preoperative chemotherapy for colorectal liver metastases (CLM) is recognised as a prognostic factor of outcome. However, the optimal system to assess this parameter is still debated. This study focuses on current methods and proposes a possibly better method for assessing PR. METHODS: Among 223 patients resected for CLM between 2004 and 2011, after more than three cycles of chemotherapy, the percentage of tumour cells, necrosis and fibrosis, and the tumour regression grade were assessed for each of 802 nodules. Pathological response was evaluated according to validated methods and their combinations. A new method combined the percentage of tumour cells and the size of all nodules as follows: , where n is each separate nodule, % is the percentage of remaining tumour cells within nodule n (%) and s is the size of nodule n (cm).The prognostic value of each method was calculated. RESULTS: After a median follow-up of 47 months (3-106), the cumulative 5-year overall survival rate after liver resection was 59%. The proposed method categorised as follows: 0 residual tumour; 0.1-6-cm residual tumour; >6-cm residual tumour, and necrosis rate >50% stratified prognosis (P=0.0027; P=0.02), while the other methods did not. At multivariate analysis, our method remained an independent predictor of outcome (P=0.001). CONCLUSIONS: Combining the percentage of tumour cells multiplied by the size of each separate tumour seems to be a better method for assessing PR. External validation is required.

Tauroursodeoxycholic acid affects PPARγ and TLR4 in Steatotic liver transplantation.

Numerous steatotic livers are discarded for transplantation because of their poor tolerance to ischemia-reperfusion (I/R). We examined whether tauroursodeoxycholic acid (TUDCA), a known inhibitor of endoplasmic reticulum (ER) stress, protects steatotic and nonsteatotic liver grafts preserved during 6 h in University of Wisconsin (UW) solution and transplanted. The protective mechanisms of TUDCA were also examined. Neither unfolded protein response (UPR) induction nor ER stress was evidenced in steatotic and nonsteatotic liver grafts after 6 h in UW preservation solution. TUDCA only protected steatotic livers grafts and did so through a mechanism independent of ER stress. It reduced proliferator-activated receptor-γ (PPARγ) and damage. When PPARγ was activated, TUDCA did not reduce damage. TUDCA, which inhibited PPARγ, and the PPARγ antagonist treatment up-regulated toll-like receptor 4 (TLR4), specifically the TIR domain-containing adaptor inducing IFNß (TRIF) pathway. TLR4 agonist treatment reduced damage in steatotic liver grafts. When TLR4 action was inhibited, PPARγ antagonists did not protect steatotic liver grafts. In conclusion, TUDCA reduced PPARγ and this in turn up-regulated the TLR4 pathway, thus protecting steatotic liver grafts. TLR4 activating-based strategies could reduce the inherent risk of steatotic liver failure after transplantation.

From metastability to equilibrium during the sequential growth of Co-Ag supported clusters: a real-time investigation.

Atomic motions and morphological evolution of growing Co-Ag nanoparticles are followed in situ and in real time, by wide and small angle X-ray scattering obtained simultaneously in grazing incidence geometry (GISAXS and GIWAXS), in single or multi-wavelength anomalous modes. The structural analysis of the experimental data is performed with the aid of equilibrium Monte Carlo simulations and of molecular-dynamics simulations of nanoparticle growth. Growth is performed by depositing Co atoms above preformed Ag nanoparticles. This growth procedure is strongly out of equilibrium, because Ag tends to surface segregation, and generates complex growth sequences. The real time analysis of the growth allows to follow the nanoparticle evolution pathways almost atom-by-atom, determining the key mechanisms during Co deposition: starting with the incorporation of Co atoms in sub-surface positions, to the off-center Co domain formation, then by which the nanoparticles finally approach their equilibrium quasi-Janus then core-shell structures.

PTEN, ATM, IDH1 mutations and MAPK pathway activation as modulators of PFS and OS in patients treated by first line EGFR TKI, an ancillary study of the French Cooperative Thoracic Intergroup (IFCT) Biomarkers France project.

OBJECTIVES: Tumor mutation screening is standard of care for patients with stage IV NSCLC. Since a couple of years, widespread NGS approaches used in routine diagnostics to detect driver mutations such as EGFR, KRAS, BRAF or MET allows the identification of other alterations that could modulated the intensity or duration of response to targeted therapies. The prevalence of co-occurring alterations that could affect response or prognosis as not been largely analyzed in clinical settings and large cohorts of patients. Thanks to the IFCT program "Biomarkers France", a collection of samples and data at a nation-wide level was available to test the impact of co-mutations on first line EGFR TKI in patients with EGFR mutated cancers. MATERIALS AND METHODS: Targeted NGS was assessed on available (n = 208) samples using the Ion AmpliSeq™ Cancer Hotspot Panel v2 to screen for mutations in 50 different cancer genes. RESULTS: This study showed that PTEN inactivating mutations, ATM alterations, IDH1 mutations and complex EGFR mutations were predictors of short PFS in patients with a stage 4 lung adenocarcinoma receiving first line EGFR TKI and that PTEN, ATM, IDH1 and KRAS mutations as well as alterations in the MAPK pathway were related to shorter OS. CONCLUSION: These findings may lead to new treatment options in patients with unfavorable genotypes to optimize first line responses.

Progression of alphafetoprotein before liver transplantation for hepatocellular carcinoma in cirrhotic patients: a critical factor.

Liver transplantation (LT) for cirrhotic/Hepatocellular carcinoma (HCC) is associated with reduced survival in patients with poor histological features. Preoperative levels of alphafetoprotein (AFP) could predict negative biological features. AFP progression could be more relevant than static AFP levels in predicting LT outcomes. A total of 252 cirrhotic/HCC patients transplanted between 1985 and 2005 were reviewed. One hundred fifty-three patients were analyzed, 99 excluded (for nonsecreting tumors and/or salvage transplantation). Using receiver operating characteristics analysis for recurrence after LT, 'progression' of AFP was defined by >15 microg/L per month before LT. A total of 127 (83%) were transplanted under and 26 (16%) over this threshold. After 45 months of follow-up (median), 5-year overall survival (OS) and recurrence free-survival (RFS) were 72% and 69%, respectively. Five-year survival in the progression group was lower than the nonprogression group (OS 54% vs. 77%; RFS 47% vs. 74%). Multivariate analysis showed progression of AFP>15 microg/L per month and preoperative nodules>3 were associated with decreased OS. Progression group and age>60 years were associated with decreased RFS. Male gender, progression of AFP and size of tumor>30 mm were associated with satellite nodules and/or vascular invasion. In conclusion, increasing AFP>15 microg/L/month while waiting for LT is the most relevant preoperative prognostic factor for low OS/DFS. AFP progression could be a pathological preoperative marker of tumor aggressiveness.

Childhood anemia and iron deficiency in sub-Saharan Africa - risk factors and prevention: A review.

Iron deficiency and iron deficiency anemia are public health issues recognised by the World Health Organisation, especially in sub-Saharan Africa. In some countries on this continent, the prevalence of anemia exceeds 60% in the pediatric population. Iron supplementation could prevent around one third of anemia cases in children in Africa and could decrease morbidity and mortality. A number of factors are behind this anemia, including iron deficiency caused by an inadequate diet, pica and geophagia, as well as chronic inflammation (malaria, digestive and urinary parasites, etc.). Ferritin is a good indicator of the body's iron stores, but it is not a specific reflection, with both inflammation and infection causing an increase. Ferritin could be interpreted according to C-reactive protein (CRP) or alpha-1 glycoprotein (AGP), or by adjusting the ferritin threshold to 30µg/L. The treatment of malaria and digestive or urinary worms, the correction of factors that stimulate inflammation, the fight against geophagia, as well as more hygienic living conditions, are all prerequisites for overcoming iron deficiency. A number of campaigns using iron supplements have proven to be effective, especially in schools, to fight against iron deficiency and malnutrition. Biofortification is an innovative and promising cultivation technique that increases the content of bioavailable iron in local produce such as beans. It will become a lever in the fight against iron deficiency.

Adverse reactions to food additives in children: A retrospective study and a prospective survey.

BACKGROUND: Allergic reactions to food additives are often suspected by families. The aim of this study was to describe oral food challenge (OFC) outcomes in a pediatric cohort with a suspected diagnosis of allergy to food additives (food dyes or sodium benzoate). METHODS: All patients who underwent an open OFC to carmine red, cochineal red, erythrosine, patent blue V, tartrazine, yellow sunset S, and/or sodium benzoate were included. A survey was sent to families after testing to evaluate whether the OFC results had altered feeding behaviors with food additives. RESULTS: Twenty-three patients were included. The main suspected food was candy (n=11/23; 48%). Only one OFC out of 45 was formally positive for the carmine and cochineal red. Subsequently, most OFCs were negative (44/45; 97.8%). Despite the negativity of the challenge, four families out of 14 reported occurrences of supposed allergic reactions to food additives and six out of 15 continued to completely avoid the additive of concern in their children's diet. CONCLUSIONS: Allergies to food additives remain rare. Even if an IgE-mediated allergy was excluded with a negative OFC, families remained suspicious about ready-made products. Health professionals and parents should be reassured about the low risk of food dye intolerance or allergies.

Case report of nutritional rickets in an infant following a vegan diet.

We report the case of a 13-month-old infant who was referred to the pediatric emergency department because of psychomotor regression with four bone fractures due to nutritional rickets. The reason was prolonged breastfeeding from a vegetarian mother followed by a vegan diet for the infant after weaning. Rickets is one of the many nutritional deficiencies that could affect infants fed vegan or vegetarian diets. These diets are a public health concern requiring adapted information that suggests alternative formulas made from rice or soy proteins and adapted supplementation after weaning.

The cis-regulatory sequences required for expression of the Drosophila melanogaster adult cuticle gene ACP65A.

Post-embryonic development in insects requires successive molts. Molts are triggered by ecdysteroids, and the nature of the molt (larval, pupal or adult) is determined by juvenile hormones. The genes encoding cuticle proteins are targets of both classes of hormones, and therefore are interesting models to study hormone action at the molecular level. The Drosophila ACP65A cuticle gene is expressed exclusively during the synthesis of the adult exoskeleton, in epidermal domains synthesising flexible cuticle. We have examined the cis-regulatory sequences of ACP65A using phylogenetic comparisons and functional analysis, and find that only about 180 bp are essential, including an 81 bp intron. The restriction of ACP65A expression appears to depend on a strong repression mechanism.

[Perioperative care of epithelial ovarian cancer: Article drafted from the French Guidelines in oncology entitled "Initial management of patients with epithelial ovarian cancer" developed by FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY under the aegis of CNGOF and endorsed by INCa]. / Soins périopératoires dans le cancer de l'ovaire. Article rédigé sur la base de la recommandation nationale de bonnes pratiques cliniques en cancérologie intitulée « Conduites à tenir initiales devant des patientes atteintes d'un cancer épithélial de l'ovaire ¼ élaborée par FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY sous l'égide du CNGOF et labellisée par l'INCa.

The following recommendations cover the perioperative management of ovarian, Fallopian tube and primary peritoneal cancers. Five questions related to pre-habilitation and enhanced recovery after surgery were evaluated. The conclusions and recommendations are based on an analysis of the level of evidence available in the literature. These recommendations are part of the overall recommendations for improving the management of ovarian, fallopian or primary peritoneal cancer, made with the support of INCa (Institut National du Cancer). The main preoperative measures are screening for nutritional deficiencies (Grade B) and for anaemia (GradeC) in patients with ovarian cancer. It is not possible to make recommendations on the correction of malnutrition and/or anemia or on the contribution of pre-operative immuno-nutrition due to the absence of data in ovarian cancer, tube cancer or primary peritoneum cancer. For the same reasons, no recommendation can be made on the value of preoperative digestive preparation in ovarian, fallopian tube or primary peritoneum cancer. During surgery, goal-directed fluid therapy for patients with advanced ovarian cancer is recommended (Grade B). A single dose infusion of tranexamic acid is recommended for patients with ovarian, fallopian tube or primary peritoneal cancer (GradeC). For postoperative analgesia, epidural analgesia is recommended for patients undergoing cyto-reduction surgery by laparotomy (Grade B). In the absence of epidural analgesia, patient controlled analgesia with morphine without continuous infusion (Grade B) is recommended. No recommendation can be given regarding intravenous administration of lidocaine and/or ketamine during surgery, or, regarding peri-operatively prescription of gabapentin or pregabalin. In the absence of studies on the impact of different non-opiate analgesic combinations for ovarian cancer surgery, no recommendations can be made. Early oral feeding is recommended, including in cases of digestive resection (Grade B). The implementation of enhanced recovery programs, including early mobilization, is recommended (GradeC).

Ingestion of neodymium magnet spheres: Three case studies.

We report three pediatric cases of two, five, and 12 neodymium magnet spheres ingested simultaneously. In two cases, endoscopic extraction failed because of the strength of the magnetic attraction and a gastrotomy was performed to remove all magnets. In the third case, the magnets were not accessible endoscopically and were removed by laparotomy. We wish to warn consumer groups and pediatricians about the danger of neodymium magnets.

Management of epithelial cancer of the ovary, fallopian tube, primary peritoneum. Long text of the joint French clinical practice guidelines issued by FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY, endorsed by INCa. (Part 2: systemic, intraperitoneal treatment, elderly patients, fertility preservation, follow-up).

Adjuvant chemotherapy by carboplatin and paclitaxel is recommended for all high-grade ovarian and tubal cancers (FIGO stages I-IIA) (grade A). After primary surgery is complete, 6 cycles of intravenous chemotherapy (grade A) are recommended, or a discussion with the patient about intraperitoneal chemotherapy, according to her risk-benefit ratio. After complete interval surgery for FIGO stage III, hyperthermic intraperitoneal chemotherapy (HIPEC) can be proposed, in accordance with the modalities of the OV-HIPEC trial (grade B). In cases of postoperative tumor residue or in FIGO stage IV tumors, chemotherapy associated with bevacizumab is recommended (grade A).

Management of epithelial cancer of the ovary, fallopian tube, and primary peritoneum. Long text of the Joint French Clinical Practice Guidelines issued by FRANCOGYN, CNGOF, SFOG, and GINECO-ARCAGY, and endorsed by INCa. Part 1: Diagnostic exploration and staging, surgery, perioperative care, and pathology.

An MRI is recommended for an ovarian mass that is indeterminate on ultrasound. The ROMA score (combining CA125 and HE4) can also be calculated (grade A). In presumed early-stage ovarian or tubal cancers, the following procedures should be performed: an omentectomy (at a minimum, infracolic), an appendectomy, multiple peritoneal biopsies, peritoneal cytology (grade C), and pelvic and para-aortic lymphadenectomies (grade B) for all histologic types, except the expansile mucinous subtypes, for which lymphadenectomies can be omitted (grade C). Minimally invasive surgery is recommended for early-stage ovarian cancer, when there is no risk of tumor rupture (grade B). For FIGO stages III or IV ovarian, tubal, and primary peritoneal cancers, a contrast-enhanced computed tomography (CT) scan of the thorax/abdomen/pelvis is recommended (grade B), as well as laparoscopic exploration to take multiple biopsies (grade A) and a carcinomatosis score (Fagotti score at a minimum) (grade C) to assess the possibility of complete surgery (i.e., leaving no macroscopic tumor residue). Complete surgery by a midline laparotomy is recommended for advanced ovarian, tubal, or primary peritoneal cancer (grade B). For advanced cancers, para-aortic and pelvic lymphadenectomies are recommended when metastatic adenopathy is clinically or radiologically suspected (grade B). When adenopathy is not suspected and when complete peritoneal surgery is performed as the initial surgery for advanced cancer, the lymphadenectomies can be omitted because they do not modify either the medical treatment or overall survival (grade B). Primary surgery (before other treatment) is recommended whenever it appears possible to leave no tumor residue (grade B).