A combination of extracellular matrix‐ and interferon‐associated signatures identifies high‐grade breast cancers with poor prognosis

Breast cancer (BC) is a heterogeneous disease in which the tumor microenvironment (TME) seems to impact the clinical outcome. Here, we investigated whether a combination of gene expression signatures relating to both the structural and immune TME aspects can help predict prognosis in women with high‐grade BC (HGBC). Thus, we focused on a combined molecular biomarker variable that involved extracellular matrix (ECM)‐associated gene expression (ECM3 signature) and interferon (IFN)‐associated metagene (IFN metagene) expression. In 97 chemo‐naive HGBCs from the METABRIC dataset, the dichotomous ECM3/IFN (dECIF) variable identified a group of high‐risk patients (ECM3⁺/IFN⁻ vs other; hazard ratio = 3.2, 95% confidence interval: 1.5–6.7). Notably, ECM3⁺/IFN⁻ tumors showed low tumor‐infiltrating lymphocytes, high levels of CD33‐positive cells, absence of PD‐1 expression, or low expression of PD‐L1, as suggested by immune profiles and immune‐histochemical analysis on an independent cohort of 131 HGBCs. To make our results transferable to clinical use, we refined the dECIF biomarker using reduced ECM3 and IFN signatures; notably, the prognostic value of this reduced dECIF was comparable to that of the original dECIF. After validation in a new BC cohort, reduced dECIF was translated into a robust qPCR classifier for real‐world clinical use.     

Ropivacaine 2 mg/mL vs. bupivacaine 1.25 mg/mL with sufentanil using patient-controlled epidural analgesia in labour

BACKGROUND: In recent studies, minimum local analgesic concentrations have been defined as 0.93 mg/mL for bupivacaine and 1.56 mg/mL for ropivacaine for epidural analgesia for the first stage of labour, resulting in an analgesic potency ratio of 1 : 0.6. In the current study we compared ropivacaine and bupivacaine in a PCEA system (combined with sufentanil) taking this potency ratio into account but administering drug doses providing sufficient analgesia for all stages of labour. METHODS: In a prospective, double-blinded study 114 parturients were randomised to receive either ropivacaine 2 mg/mL with sufentanil 0.75 microg/mL or bupivacaine 1.25 mg/with sufentanil 0.75 microg/mL. After epidural catheter placement, PCEA was available with boluses of 4 mL, a lock-out time of 20 min and no basal infusion rate. We evaluated pain intensity during contractions, sensory and motor function, duration of labour, mode of delivery and neonatal outcome. Consumption of local anaesthetic and opioid drugs and PCEA system variables were recorded. RESULTS: Mean total consumption as well as mean hourly drug consumption was significantly increased in the ropivacaine-sufentanil group. No differences in analgesic quality, sensory or motor blocking potencies or neonatal outcome variables between groups were detected. Frequency of instrumental deliveries was significantly increased in the ropivacaine-sufentanil group. CONCLUSIONS: The results support the findings of previously published studies postulating ropivacaine to be 40-50% less potent for labour epidural analgesia compared to bupivacaine. However, we observed an increased frequency of instrumental deliveries with ropivacaine. To evaluate the clinical relevance of these findings, further investigations are warranted.     

Association between DRD4 gene and performance of children with ADHD in a test of sustained attention.

BACKGROUND: The adoption of neuropsychological tests as endophenotypic measures can provide an increased sensitivity to specific dimensions of attention-deficit/hyperactivity disorder (ADHD). METHODS: The association between a variable number of tandem repeats polymorphism at the dopamine D4 receptor gene (DRD4) and the performance of children and adolescents with ADHD in a continuous performance test (CPT) was evaluated. The sample comprised 90 clinically referred children and adolescents with ADHD. Errors of omission and commission in the CPT were computed and the number of 48-base pairs tandem repeats in the exon III of DRD4 was assessed. RESULTS: The presence of a 7-repeat allele was associated with more errors of commission and the homozygosity of the 4-repeat allele was related to fewer errors of commission and omission even after adjusting for age. CONCLUSIONS: These findings bring further evidence on the role of DRD4 polymorphisms on the performance in sustained attention tasks among children and adolescents with ADHD diagnosis.     

Myocardial damage prevented by volatile anesthetics: a multicenter randomized controlled study

OBJECTIVE: The purpose of this study was to evaluate the effects of volatile anesthesia versus total intravenous anesthesia on cardiac troponin release in off-pump coronary artery bypass grafting (OPCAB). DESIGN: The authors performed a multicenter randomized controlled study to compare cardiac troponin release in patients receiving either volatile anesthetics or total intravenous anesthesia for cardiac surgery on the beating heart, which is an excellent model of human myocardial ischemia. SETTING: Three university hospitals. PARTICIPANTS: The authors randomly assigned 57 patients to desflurane (volatile anesthetic) and 55 patients to propofol (intravenous anesthetic) in addition to an opiate-based anesthesia for OPCAB. INTERVENTIONS: The 2 groups of patients received either desflurane (volatile anesthetic) or propofol in addition to an opiate-based anesthesia for OPCAB. Peak postoperative troponin I release was measured as a marker of myocardial necrosis. Prolonged hospitalization was considered as a secondary outcome. MEASUREMENTS AND MAIN RESULTS: Patient mean age was 69 years, and 82% were men. There was a significant (p < 0.001) reduction in postoperative median (25th-75th percentiles) peak of troponin I in patients receiving volatile anesthetics, 1.2 (0.9-1.9) ng/dL, compared with patients receiving total intravenous anesthesia, 2.7 (2.1-4.0) ng/dL. This myocardial protection resulted in a reduced (p = 0.04) number (percentage) of patients requiring postoperative inotropes, 20 (35%) versus 31 (56%), and a reduced number (percentage) of patients submitted to prolonged hospitalization (> or =7 days), 7 (12%) versus 20 (36%) in the 2 groups (p = 0.005). One patient receiving total intravenous anesthesia died within 30 days of surgery. CONCLUSIONS: Myocardial damage measured by cardiac troponin release could be reduced by volatile anesthetics during OPCAB. Because patients underwent cardiac surgery on the beating heart, these results could have implications for cardiac patients undergoing noncardiac surgery.     

Water, sanitation and hygiene for the health of developing nations

The water and sanitation needs of the poor in developing countries are huge. To meet the target of water and sanitation for all by the end of 2025, some 2.9 billion people will have to receive improved water supplies, and 4.2 billion improved sanitation. The technologies used must be appropriate and, in particular, simple, affordable and sustainable.     

Chicken serum albumin (Gal d 5*) is a partially heat-labile inhalant and food allergen implicated in the bird-egg syndrome

BACKGROUND: Chicken serum albumin (alpha-livetin) has been implicated as the causative allergen of the bird-egg syndrome. However, the clinical relevance of sensitization to this allergen has not been confirmed by specific challenge tests and environmental sampling. We investigated whether chicken albumin can be detected in air samples collected in a home with birds, and whether sensitization to this protein may cause respiratory and food allergy symptoms. The heat resistance of chicken albumin and the possible cross-reactivity with conalbumin were also investigated. METHODS: We studied eight patients with food allergy to egg yolk who also suffered from respiratory symptoms (rhinitis and/or asthma) caused by exposure to birds. Sensitization to egg yolk and bird antigens was investigated by skin and serologic tests. Hypersensitivity to chicken albumin was confirmed by specific bronchial, conjunctival, and oral provocation tests. RESULTS: All patients had positive skin tests and serum IgE against egg yolk, chicken serum, chicken meat, bird feathers, and chicken albumin. The presence of airborne chicken albumin in the domestic environment was confirmed. Specific bronchial challenge to chicken albumin elicited early asthmatic responses in six patients with asthma. An oral challenge with chicken albumin provoked digestive and systemic allergic symptoms in the two patients challenged. IgE reactivity to chicken albumin was reduced by 88% after heating at 90 degrees C for 30 min. ELISA inhibition demonstrated only partial cross-reactivity between chicken albumin and conalbumin. CONCLUSION: Chicken albumin (Gal d 5) is a partially heat-labile allergen that may cause both respiratory and food-allergy symptoms in patients with the bird-egg syndrome.     

KLRG1 expression identifies short-lived Foxp3+ Treg effector cells with functional plasticity in islets of NOD mice

A progressive waning in Foxp3⁺ regulatory T (T_reg) cell function provokes autoimmunity in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D), a cellular defect rescued by prophylactic IL-2 therapy. We showed that most islet-infiltrating T_reg cells express inducible T-cell co-stimulator (ICOS) in pre-diabetic NOD mice, and that ICOS⁺ T_reg cells display enhanced fitness and suppressive function in situ. Moreover, T1D progression is associated with decreased expansion and suppressive activity of ICOS⁺Foxp3⁺ T_reg cells, in islets, an observation consistent with the exacerbated T1D seen in NOD.BDC2.5 mice in which the ICOS pathway is abrogated. Here, we show that a large proportion of islet-resident T_reg cells express the KLRG1 marker of terminally differentiation, in contrast to islet-infiltrating ICOS^? T_reg or T_eff cells. We hypothesized that KLRG1 expression designates a subpopulation of ICOS⁺ T_reg cells in islets that progressively loses function, and contributes to the immune dysregulation observed at T1D onset. Indeed, KLRG1-expressing ICOS⁺ T_reg cells are prone to apoptosis, and have an impaired proliferative capacity and suppressive function in vitro and in vivo. T1D protective low-dose IL-2 treatment in vivo could not rescue the loss of KLRG1-expressing T_reg cells in situ. While the global pool of Foxp3⁺ T_reg cells displays some degree of functional plasticity in vivo, the KLRG1⁺ ICOS⁺ T_reg cell subset is particularly susceptible to lose Foxp3 expression and reprogram into Th1- or Th17-like effector T (T_eff) cells in the pancreas microenvironment. Overall, KLRG1 expression delineates a subpopulation of dysfunctional T_reg cells during T1D progression in autoantigen-specific TCR transgenic NOD mice.     

Decompressive percutaneous endoscopic gastrostomy in advanced cancer patients with small-bowel obstruction is feasible and effective: a large prospective study

Purpose

The purpose of this study was to evaluate patient-centered outcomes of decompressive percutaneous endoscopic gastrostomy (dPEG) in patients with malignant bowel obstruction due to advanced gynecological and gastroenteric malignancies.

Methods

This is a prospective analysis of 158 consecutive patients with small-bowel obstruction from advanced gynecological and gastroenteric cancer who underwent PEG or percutaneous endoscopic jejunostomy (PEJ) positioning for decompressive purposes from 2002 to 2012. All of them had previous abdominal surgery and were unfit for any other surgical procedures. Symptom relief, procedural complications, and post dPEG palliation were assessed. Global Quality of Life (QoL) was evaluated in the last 2 years (25 consecutive patients) before and 7 days after dPEG placement using the Symptom Distress Scale (SDS).

Results

dPEG was successfully performed in 142 out of 158 patients (89.8 %). Failure of tube placement occurred in 16 patients (10.1 %). In 8/142 (5.6 %) patients, dPEG was guided by abdominal ultrasound. In 3/142 patients, dPEG was CT-guided. In 14 (9.8 %) patients, who had previously undergone total or subtotal gastrectomy, decompressive percutaneous endoscopic jejunostomy (dPEJ) was performed. In 1/14 patients, dPEJ was CT-guided. Out of 142 patients, 110 (77.4 %) experienced relief from nausea and vomiting 2 days after PEG.Out of 142 patients, 116 (81.6 %) were discharged. The median postoperative hospital stay was 9 days (range 3–60). Peristomal infection (14 %) and intermittent obstruction (8.4 %) were the most frequent complications associated with PEG. Median survival time was 57 days (range 4–472) after PEG placement.Twenty-five patients had QoL properly evaluated with SDS score before and 7 days after dPEG. Sixteen patients (64 %) out of 25 exhibited an improvement of QoL (p?<?0.05), 7 (28 %) patients exhibited a non-significant worsening of QoL (p?=?0.18), and in 2 (8 %) patients, it remained unmodified.

Conclusions

dPEG is feasible, effective, relieves nausea and vomiting in patients with unremitting small-bowel obstruction from advanced gynecological and gastroenteric cancer, and improves QoL.