Mechanisms of synergistic suppression of ALK-positive lung cancer cell growth by the combination of ALK and SHP2 inhibitors.

Lung cancer is a major cause of cancer-related deaths. Alectinib is the first line of treatment for patients with ALK-positive lung cancer, but the survival rate beyond 2-3 years is low. Co-targeting secondary oncogenic drivers such as SHP2 is a potential strategy for improving drug efficacy. This is because SHP2 is expressed ubiquitously, but ALK expression is largely restricted to cancer cells. Thus, the combination of ALK and SHP2 inhibitors may provide a way to restrict synergistic cytotoxicity to cancer cells only, by reducing the dose of SHP2 inhibitors required for anticancer action and minimising SHP2-dependent systemic toxicity. The objective of this study was to investigate whether the combination of a SHP2 inhibitor (SHP099) with alectinib would synergistically suppress the growth of ALK-positive lung cancer cells. Our results demonstrated that the drug combination significantly and synergistically decreased cell viability at relatively low concentrations in ALK-positive H3122 and H2228 cells, due to G1 cell cycle arrest and increased apoptosis because of suppressed downstream RAS/MAPK signalling. The drug combination also induced the expression of mediators of the intrinsic apoptotic pathway, Bim and cleaved caspase-3, and modulated the expression of cell cycle mediators cyclin D1, cyclin B1, and phosphorylated CDK1.

Electronic prescribing systems as tools to improve patient care: a learning health systems approach to increase guideline concordant prescribing for venous thromboembolism prevention.

BACKGROUND: Venous thromboembolism (VTE) causes significant mortality and morbidity in hospitalised patients. Risk factors for VTE are well known and there are validated risk assessment tools to support the use of prophylactic therapies. In England, reporting the percentage of patients with a completed VTE risk assessment is mandated, but this does not include whether that risk assessment resulted in appropriate prescribing. Full guideline compliance, defined as an assessment which led to an appropriate action-here prescribing prophylactic low molecular weight heparin where indicated, is rarely reported. Education, audit and feedback enhance guideline compliance but electronic prescribing systems (EPS) can mandate guideline-compliant actions. We hypothesised that a systems-based EPS intervention (prescribing rules which mandate approval or rejection of a proposed prescription of prophylactic low molecular weight heparin based on the mandated VTE assessment) would increase full VTE guideline compliance more than interventions which focused on targeting individual prescribers. METHODS: All admitted patients within University Hospitals Birmingham NHS Foundation Trust were included for analysis between 2011 and 2020. The proportion of patients who received a fully compliant risk assessment and action was assessed over time. Interventions included teaching sessions and face-to-face feedback based on measured performance (an approach targeting individual prescribers) and mandatory risk assessment and prescribing rules into an EPS (a systems approach). RESULTS: Data from all 235,005 admissions and all 5503 prescribers were included in the analysis. Risk assessments were completed in > 90-95% of all patients at all times, but full guideline compliance was lower (70% at the start of this study). Face-to-face feedback improved full VTE guideline compliance from 70 to 77% (p ≤ 0.001). Changes to the EPS to mandate assessment with prescribing rules increased full VTE compliance to 95% (p ≤ 0.001). Further amendments to the EPS system to reduce erroneous VTE assessments slightly reduced full compliance to 92% (p < 0.001), but this was then maintained including during changes to the low molecular weight heparin used for VTE prophylaxis. DISCUSSION: An EPS-systems approach was more effective in improving sustained guideline-compliant VTE prevention over time. Non-compliance remained at 8-5% despite this mandated system. Further research is needed to assess the potential reasons for this.

Predictors of mortality and length of stay for neonates admitted to children's hospital neonatal intensive care units.

OBJECTIVE: Current scoring systems, which adjust prediction for severity of illness, do not account for higher observed mortality in neonatal intensive care units (NICUs) of children's hospitals than that of perinatal centers. We hypothesized that three potential predictors, (a) admission from another NICU, (b) presence of congenital anomalies and (c) need for surgery, would modify expected mortality and/or length of stay for infants admitted to NICUs in children's hospitals. STUDY DESIGN: We reviewed consecutive admissions to two NICUs in children's hospitals in Canada. We performed regression analyses to evaluate these potential predictors and severity-of-illness indices for the outcomes of mortality and length of stay. RESULT: Of 625 neonatal admissions, transfer from another NICU, congenital anomalies requiring admission and surgery were identified in 371 (59%). Using logistic regression, mortality was predicted based on admission from another NICU (odds ratio (OR) 1.92; 95% confidence interval (CI) 1.04, 3.57), congenital anomalies (OR 7.28; 95% CI 3.69, 14.36) and a validated severity-of-illness score, the Score for Neonatal Acute Physiology Perinatal Extension Version II (SNAPPE-II; OR 1.07; 95% CI 1.05, 1.09 per point). By contrast, surgical intervention was predictive of survival (OR 0.35; 95% CI 0.18, 0.67). Length of stay >or=21 days was predicted by SNAPPE-II (OR 1.02; 95% CI 1.01, 1.03 per point), congenital anomalies (OR 2.47; 95% CI 1.60, 3.79) and surgery (OR 2.73; 95% CI 1.77, 4.21). CONCLUSION: Fair performance comparisons of NICUs with different case-mixes, such as children's hospital and perinatal NICUs, in addition to severity-of-illness indices, should account for admissions from another NICU, congenital anomalies and surgery.

The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma.

BACKGROUND: Assessment of eosinophilic airway inflammation may be helpful in the management of asthma. Nitric oxide (NO) has potential advantages as a tool to monitor airway inflammation although little is known about the relationship between NO and eosinophilic airway inflammation and the factors which influence it. METHODS: We set out to define the relationship between exhaled NO and the sputum eosinophil count, identify the exhaled NO concentration that best identified a sputum eosinophil count >3% and investigate the impact of several potential confounding factors in 566 consecutive patients with varying severity of asthma. Finally we examined the ability of exhaled NO concentrations measured at differing exhalation flows to identify the presence of a sputum eosinophilia. RESULTS: We found a significant positive relationship between exhaled NO and sputum eosinophil count (R(2)=0.26, P<0.001) which was best described using a non-linear model. There were no clinically important confounding factors to this model. In non-smokers an exhaled NO concentration of >8.3 p.p.b. at 250 mL/s gave 71% sensitivity and 72% specificity for identifying a sputum eosinophil count of >3%. CONCLUSIONS: This value of exhaled NO would seem to be the best for identifying significant eosinophilic airway inflammation. It is applicable to a wide range of non-smoking patients with asthma; exhalation flow does not alter the ability of exhaled NO concentration to detect a sputum eosinophilia.

Observational study of the natural history of eosinophilic bronchitis.

BACKGROUND: Eosinophilic bronchitis is an important cause of chronic cough. Treatment with inhaled corticosteroids is associated with a short-term improvement in cough and reduced sputum eosinophil count but the long-term outcome is uncertain. OBJECTIVE: To determine the long-term outcome in patients diagnosed with and treated for eosinophilic bronchitis. METHODS: We have performed a longitudinal study of symptoms, eosinophilic airway inflammation, spirometry and airway hyper-responsiveness in all patients diagnosed with eosinophilic bronchitis over 7 years. RESULTS: We identified 52 patients with eosinophilic bronchitis and longitudinal data of greater than 1 year (mean 3.1 years) was available in 32 patients, all of whom were treated with inhaled steroids. Three (9%) patients developed symptoms consistent with asthma and a methacholine PC20<8 mg/mL on one or more occasion. Five (16%) patients developed fixed airflow obstruction defined by a persistent post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity<70%. One (3%) patient had complete resolution of symptoms and eosinophilic airway inflammation off treatment. The remaining patients had ongoing eosinophilic airway inflammation and/or continuing symptoms. Multiple linear regression identified smoking, female gender and area under the curve of sputum eosinophil count over time as the most important predictors of decline in FEV1. CONCLUSIONS: The most common outcome in eosinophilic bronchitis is continuing disease and complete resolution is rare. Asthma and fixed airflow obstruction developed in relatively few patients. The most important factors associated with a more rapid decline in FEV1 were female gender, smoking and prolonged eosinophilic airway inflammation.

Expression of CXCR6 and its ligand CXCL16 in the lung in health and disease.

BACKGROUND: Chemokine receptors (CR) play an important role in T cell migration, but their contribution to lung trafficking is unclear. OBJECTIVE: We hypothesized that if a particular CR was involved in T cell homing its expression would be enriched on lung T cells compared with peripheral blood T cells (PBT). METHODS: We have measured the CR expression on BAL T cells from patients with sarcoid, other interstitial lung diseases (ILD), asthma and healthy volunteers. RESULTS: Of 14 CR studied in sarcoid, CXCR6 expression was the most markedly increased in the lung compared with the blood, a finding that was also seen in ILD patients. A striking although lesser increase was also seen in asthmatics and healthy controls. Analysis of expression of the CXCR6 ligand, CXCL16, by immunohistochemistry suggested that alveolar macrophages (AM) were the major source of CXCL16 in the lung. AM expressed mRNA for CXCL16 and released nanogram quantities after adhesion to plastic as shown by RT-PCR, Western blotting and ELISA. Bronchoalveolar lavage (BAL) fluid from all subjects contained large amounts of CXCL16. The full-length CXCL16 was the predominant isoform in AM lysates, supernatants and BAL. CONCLUSION: This data suggests that CXCR6 and CXCL16 may play a role in T cell recruitment to the lung.

Transcommissural valvuloplasty: technique and results.

PURPOSE: The purpose of this study was to describe the technique of a variation of closed external venous valve repair (transcommissural valvuloplasty), its complication rate, and duplex scan durability. METHODS: The "blind" transcommissural valve repair of the vein was performed by placing transluminal sutures along the valve attachment lines, which simultaneously closed the valve attachment angle and also tightened the valve cusps. A total of 179 successfully repaired valve sites of 141 limbs in 129 patients were followed up 1 to 42 months through clinical observation and with duplex Doppler ultrasound scan. RESULTS: Postoperative complications (< 30 days) occurred in 12 (9%) of 141 limbs: superficial (1) and deep (1) wound infection, large wound hematoma (4), seroma (1), and deep vein thrombosis (5), with associated pulmonary embolus in one patient. Seventy-eight percent (reflux time

Endovascular surgery in the treatment of chronic primary and post-thrombotic iliac vein obstruction.

OBJECTIVES: To compare the results and complications of endovascular surgery in limbs with post-thrombotic and non-thrombotic disease and to detail some technical aspects of the procedure. DESIGN: A single centre, prospective study. MATERIALS AND METHODS: Between March 1997 and August 1999, 139 consecutive lower extremities with chronic iliac venous obstruction (61 limbs with primary disease [MTS] and 78 with post-thrombotic disease [PTS]) were treated by balloon dilation and stenting. History, clinical examination, procedure and follow-up data were recorded. RESULTS: Mortality was zero. Non-thrombotic complication rate was only 3%. Postoperative (8%, 6/78) and late occlusion (3%, 2/69) occurred only in post-thrombotic limbs. Primary, primary-assisted and secondary cumulative patency rates of the stented area at 2 years were 52%, 88% and 90%, respectively, in the PTS group as compared to 60%, 100% and 100% in the MTS group. Clinical improvement in pain and swelling was significant in both groups. Half of active venous ulcers healed after the procedure. CONCLUSIONS: Chronic iliac vein obstruction appears to be a symptomatic lesion that can be treated safely and effectively by endovascular surgery regardless of aetiology. Generous use of IVUS is suggested in both diagnosis and treatment since phlebography is unreliable. The clinical improvement was significant in both groups; however, more excessive neointimal hyperplasia and a higher early and late occlusion rate were observed in post-thrombotic disease. Stenting after balloon dilation is advised in all venoplasties; stents should be inserted well into the IVC when treating iliocaval junction stenosis. A wide-diameter (16 mm) stent is recommended. The stent should cover the entire lesion as outlined by the IVUS.

Conservative treatment of recognized laparoscopic colonic injury.

Injuries associated with insufflation needles and trocar insertion have been reported extensively in the literature. Two millimeter laparoscopy is a more recent technique that has been used for laparoscopic cholecystectomy. This case illustrates a 2 mm trocar colonic injury, recognized during a routine laparoscopic cholecystectomy; management was non-operative and ambulatory, with a successful outcome.

Factors associated with growth of extremely premature infants during initial hospitalization.

OBJECTIVE: To quantify the factors associated with growth of very small premature infants during initial hospitalization. POPULATION: Study patients were 109 infants who were appropriate for gestational age, weighed <1000 g at birth, and were fed intravenous hyperalimentation then calcium-supplemented 81-kcal preterm formula according to a protocol. ANALYSIS: Multiple regression analysis was performed for periods of 0 to 56, 0 to 14, and 15 to 56 days of age. Growth was determined as change in weight during the period. Variables assessed in the initial model were caloric intake, protein intake, respiratory support duration, patent ductus arteriosus, dexamethasone use, infection, birth weight ratio (weight divided by expected intrauterine weight for gestation), gestational age, sex, calendar time from study start, maternal betamethasone administration, and necrotizing enterocolitis. For the 0 to 14-day period, maximum oxygen requirement for respiratory distress syndrome replaced respiratory support duration, and 5-minute Apgar score was added, whereas dexamethasone and necrotizing enterocolitis were deleted. RESULTS: Mean change in weight was 785 g for 0 to 56 days, -16 g for 0 to 14 days, and 770 g for 15 to 56 days. Mean weight was 94% (13 SD) of mean intrauterine at birth, 73% (10 SD) at 14 days, and 73% (12 SD) at 56 days. Regression models explained 85%, 43%, and 80%, respectively, of variation in growth. Of the initial variables assessed, the following were the independent prognostic determinants of growth. There was a positive association with caloric intake at 0 to 56 days and 15 to 56 days, and with protein intake at 0 to 14 days. Negative associations were found for birth weight ratio and gestational age at 0 to 56 and 0 to 14 days. Respiratory support duration was negatively associated at 15 to 56 days, and dexamethasone was negatively associated at 0 to 56 and 15 to 56 days. Formulas to predict growth were established from the final regression models. CONCLUSION: The growth failure in appropriate-for-gestational-age, <1000-g birth weight infants can be related in part to dexamethasone use and respiratory support duration. Increasing caloric intake and early protein intake improves growth. However, for the majority of these patients, early losses are not corrected completely by 56 days using currently recommended intakes.

Growth of very premature infants fed intravenous hyperalimentation and calcium-supplemented formula.

OBJECTIVE: To describe growth during initial hospitalization for very small premature infants fed intravenous hyperalimentation, then calcium supplemented 1460 mg/L (36.5 mmol/L) 81 kcal preterm formula. POPULATION: A total of 109 survivors whose <1000 g birth weight was appropriate for gestational age. Mean gestational age was 25.8 weeks. RESULTS: Graphs were constructed for weight, length, and head circumference by week of age. Mean and +/- 2 SD lines were depicted, with mean intrauterine growth lines for comparison. Separate graphs showed mean weight, length, and head circumference growth by 100 g birth weight cohorts. Mean Z scores based on normal intrauterine growth curves were calculated. Weight Z scores were -.35 at birth, -1.79 at 14 days, and -1.87 at 56 days. Length Z scores were -.32 at birth, -1.29 at 14 days, and -2.24 at 56 days. Head circumference Z scores were 0.01 at birth, -1.26 at 14 days, and -1.06 at 56 days. (Z score = [measured parameter - intrauterine mean for gestation]/intrauterine SD for gestation). Repeated-measures multivariate ANOVAs showed the following significant Z score changes. There were decreases in Z scores for weight, length, and head circumference between birth and 14 days and an additional decrease for length between 14 and 56 days. Head circumference Z scores increased from day 14 to day 56, but remained smaller at day 56 than at day 0. Initially, head circumference Z scores were better than weight or length (possibly because of late head measurement timing). At day 14, the Z scores for weight were lower than those for length and head circumference. At day 56, the head circumference Z scores were higher than those for length or weight. CONCLUSION: Compared with intrauterine standards, weight, length, and head circumference were all worse at day 56 than at birth, although there was relative head-sparing and weight growth paralleled intrauterine growth after 14 days. Length worsened from day 14 to day 56 in spite of the use of calcium and phosphorus-enriched formula.

The alternate iron transport pathway: mobilferrin and integrin in reticulocytes.

Iron transport in reticulocytes is known to occur via the well-described transferrin-receptor-endosome pathway. An alternative pathway for iron transport independent of transferrin has been postulated in reticulocytes and other cells. Transport of iron into reticulocytes from ferric citrate solutions was shown to be saturable and independent of transferrin. During transport of iron from ferric citrate, both cell surface integrins, and a soluble protein, mobilferrin, were labelled. This demonstrated that the reticulocyte transferrin independent pathway for iron transport involved integrins and mobilferrin similar to intestinal absorptive cells. This pathway would be expected to transport iron into cells under conditions of iron overload and was capable of providing iron for haemoglobin synthesis. Mobilferrin was also radiolabelled when radioiron labelled transferrin was incubated with reticulocytes and this occurred with a different time course than was observed following reticulocyte exposure to radiolabelled ferric citrate. This suggested that mobilferrin may serve as an intermediary in both pathways.

Gastrointestinal lavage for colon cleansing.

Colon cleansing preparations for diagnostic and surgical procedures continue to be evaluated in an effort to improve the quality of colon exam. Modifications of older barium enema x-ray preparations have led to the development of many alternative forms of bowel cleansing. Formal study has allowed carefui comparison of gut lavage, diet and cathartic as well as oral sodium phosphate preparation. Gut lavage with electrolyte lavage solutions represents the most popular form of bowel preparation. Patient variability and special circumstances such as gastroparesis, surgically altered anatomy or patient preferences may dictate selection of colon cleansing preparations.

Pericarditis causing exercise test induced ST-elevations.

Pericarditis has not been well associated with exercise test induced ST-elevations. This case report of a pericarditis patient who underwent exercise stress testing and other similar cases found in the literature suggest that this is an unrecognized clinical manifestation of pericarditis.

Review article: orthograde gut lavage for colonoscopy.

Most colon cleansing regimens for surgical and diagnostic procedures such as colonoscopy are modifications of older barium enema X-ray preparations which have evolved in gastrointestinal laboratories influenced by empiric experience. Recent formal study allows for careful comparison of gut lavage, diet and cathartic, and oral sodium phosphate preparations. This review will evaluate oral lavage solutions and address their safety, tolerance and efficacy. Administration options are discussed as well as other diet and cathartic methods previously referred to as 'standard preps'.