Rapidly progressive organising pneumonia associated with cytomegalovirus infection in a patient with psoriasis.

A 63-year-old woman experienced progressive respiratory distress and psoriatic plaques. The radiographic images showed diffuse interstitial infiltrates. The surgical open lung biopsy revealed an obliteration of the alveolar spaces by plugs of connective tissue distributed within the terminal bronchioles, alveolar ducts and spaces. No relevant cause was determined, and she was diagnosed with idiopathic organising pneumonia. The patient was discharged with oral glucocorticosteroid and supplemental oxygen therapy. One month later, the patient's pulmonary status had progressively worsened, and she was re-admitted. She required higher oxygen concentrations and mechanical ventilation. Pharmacological therapy included high-dose steroids and cyclophosphamide. Serological assays revealed high antibodies titers (both IgM and IgG) to cytomegalovirus. Therefore, ganciclovir was added to the regimen. Despite the therapy, she died as a result of the disease. The review of the current literature on the topic is also presented

Pediatric Intensive Care Unit admission criteria for haemato-oncological patients: a basis for clinical guidelines implementation

Recent advances in supportive care and progress in the development and use of chemotherapy have considerably improved the prognosis of many children with malignancy, thus the need for intensive care admission and management is increasing, reaching about 40% of patients throughout the disease course. Cancer remains a major death cause in children, though outcomes have considerably improved over the past decades. Prediction of outcome for children with cancer in Pediatric Intensive Care Unit (PICU) obviously requires clinical guidelines, and these are not well defined, as well as admission criteria. Major determinants of negative outcomes remain severe sepsis/septic shock association and respiratory failure, deserving specific approach in children with cancer, particularly those receiving a bone marrow transplantation. A nationwide consensus should be achieved among pediatric intensivists and oncologists regarding the threshold clinical conditions requiring Intensive Care Unit (ICU) admission as well as specific critical care protocols. As demonstrated for the critically ill non-oncologic child, it appears unreasonable that pediatric patients with malignancy can be admitted to an adult Intensive Care Unit ICU. On a national basis a pool of refecence institutions should be identified and early referral to an oncologic PICU is warranted

Interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in human epithelial cancer cells

Epidermal growth factor receptor (EGFR) is an important regulator of epithelial cell growth and survival in normal and cancerous tissues and is a principal therapeutic target for cancer treatment. EGFR is associated in epithelial cells with the heavily glycosylated transmembrane mucin protein MUC1, a natural ligand of galectin-3 that is overexpressed in cancer. This study reveals that the expression of cell surface MUC1 is a critical enhancer of EGF-induced EGFR activation in human breast and colon cancer cells. Both the MUC1 extracellular and intracellular domains are involved in EGFR activation but the predominant influence comes from its extracellular domain. Binding of galectin-3 to the MUC1 extracellular domain induces MUC1 cell surface polarization and increases MUC1–EGFR association. This leads to a rapid increase of EGFR homo-/hetero-dimerization and subsequently increased, and also prolonged, EGFR activation and signalling. This effect requires both the galectin-3 C-terminal carbohydrate recognition domain and its N-terminal ligand multi-merization domain. Thus, interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in epithelial cancer cells. As MUC1 and galectin-3 are both commonly overexpressed in most types of epithelial cancers, their interaction and impact on EGFR activation likely makes important contribution to EGFR-associated tumorigenesis and cancer progression and may also influence the effectiveness of EGFR-targeted cancer therapy

MUC1-associated proliferation signature predicts outcomes in lung adenocarcinoma patients

Background: MUC1 protein is highly expressed in lung cancer. The cytoplasmic domain of MUC1 (MUC1-CD) induces tumorigenesis and resistance to DNA-damaging agents. We characterized MUC1-CD-induced transcriptional changes and examined their significance in lung cancer patients. Methods: Using DNA microarrays, we identified 254 genes that were differentially expressed in cell lines transformed by MUC1-CD compared to control cell lines. We then examined expression of these genes in 441 lung adenocarcinomas from a publicly available database. We employed statistical analyses independent of clinical outcomes, including hierarchical clustering, Student's t-tests and receiver operating characteristic (ROC) analysis, to select a seven-gene MUC1-associated proliferation signature (MAPS). We demonstrated the prognostic value of MAPS in this database using Kaplan-Meier survival analysis, log-rank tests and Cox models. The MAPS was further validated for prognostic significance in 84 lung adenocarcinoma patients from an independent database. Results: MAPS genes were found to be associated with proliferation and cell cycle regulation and included CCNB1, CDC2, CDC20, CDKN3, MAD2L1, PRC1 and RRM2. MAPS expressors (MAPS+) had inferior survival compared to non-expressors (MAPS-). In the initial data set, 5-year survival was 65% (MAPS-) vs. 45% (MAPS+, p < 0.0001). Similarly, in the validation data set, 5-year survival was 57% (MAPS-) vs. 28% (MAPS+, p = 0.005). Conclusions: The MAPS signature, comprised of MUC1-CD-dependent genes involved in the control of cell cycle and proliferation, is associated with poor outcomes in patients with adenocarcinoma of the lung. These data provide potential new prognostic biomarkers and treatment targets for lung adenocarcinoma

Long-term home ventilation of children in Italy: A national survey.

BACKGROUND: Improved technology, as well as professional and parental awareness, enable many ventilator-dependent children to live at home. However, the profile of this growing population, the quality and adequacy of home care, and patients' needs still require thorough assessment. OBJECTIVES: To define the characteristics of Italian children receiving long-term home mechanical ventilation (HMV) in Italy. METHODS: A detailed questionnaire was sent to 302 National Health Service hospitals potentially involved in the care of HVM in children (aged <17 years). Information was collected on patient characteristics, type of ventilation, and home respiratory care. RESULTS: A total of 362 HMV children was identified. The prevalence was 4.2 per 100,000 (95% CI: 3.8-4.6), median age was 8 years (interquartile range 4-14), median age at starting mechanical ventilation was 4 years (1-11), and 56% were male. The most frequent diagnostic categories were neuromuscular disorders (49%), lung and upper respiratory tract diseases (18%), hypoxic (ischemic) encephalopathy (13%), and abnormal ventilation control (12%). Medical professionals with nurses (for 62% of children) and physiotherapists (20%) participated in the patients' discharge from hospital, though parents were the primary care giver, and in 47% of cases, the sole care giver. Invasive ventilation was used in 41% and was significantly related to young age, southern regional residence, longer time spent under mechanical ventilation, neuromuscular disorders, or hypoxic (ischemic) encephalopathy. CONCLUSIONS: Care and technical assistance of long-term HMV children need assessment, planning, and resources. A wide variability in pattern of HMV was found throughout Italy. An Italian national ventilation program, as well as a national registry, could be useful in improving the care of these often critically ill children

MUC1 Contributes to BPDE-Induced Human Bronchial Epithelial Cell Transformation through Facilitating EGFR Activation

Although it is well known that epidermal growth factor receptor (EGFR) is involved in lung cancer progression, whether EGFR contributes to lung epithelial cell transformation is less clear. Mucin 1 (MUC1 in human and Muc1 in animals), a glycoprotein component of airway mucus, is overexpressed in lung tumors; however, its role and underlying mechanisms in early stage lung carcinogenesis is still elusive. This study provides strong evidence demonstrating that EGFR and MUC1 are involved in bronchial epithelial cell transformation. Knockdown of MUC1 expression significantly reduced transformation of immortalized human bronchial epithelial cells induced by benzo[a]pyrene diol epoxide (BPDE), the active form of the cigarette smoke (CS) carcinogen benzo(a)pyrene (BaP)s. BPDE exposure robustly activated a pathway consisting of EGFR, Akt and ERK, and blocking this pathway significantly increased BPDE-induced cell death and inhibited cell transformation. Suppression of MUC1 expression resulted in EGFR destabilization and inhibition of the BPDE-induced activation of Akt and ERK and increase of cytotoxicity. These results strongly suggest an important role for EGFR in BPDE-induced transformation, and substantiate that MUC1 is involved in lung cancer development, at least partly through mediating carcinogen-induced activation of the EGFR-mediated cell survival pathway that facilitates cell transformation

Influence of angiogenetic factors and matrix metalloproteinases upon tumour progression in non-small-cell lung cancer

We attempted to investigate immunohistochemical expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PD-ECGF), c-erbB-2, matrix metalloproteinase-2 (MMP-2), and MMP-9 using surgical specimens of 119 non-small-cell lung carcinoma (NSCLC) cases and to evaluate the relationship between the expression levels of each molecule and clinicopathological factors or prognosis. VEGF expression levels were significantly associated with the local invasion (P = 0.0001), lymph node involvement (pN-factor) (P = 0.0019), pathological stage (p-stage) (P = 0.0027) and lymphatic permeation (P = 0.0389). PD-ECGF expression levels were associated with pN-factor (P = 0.0347). MMP-2 expression levels were associated with pN-factor (P = 0.004) and lymphatic permeation (P = 0.0056). Also, MMP-9 expression levels showed a significant correlation to local invasion (P = 0.0012), pN-factor (P = 0.0093) and p-stage (P = 0.0142). Multivariate analysis showed VEGF to be the most related to local invasion (P = 0.0084), and MMP-2 was the only factor with significant independent impact on lymphatic permeation (P = 0.0228). Furthermore, log-rank analysis showed significant association with poor survival by VEGF, bFGF, MMP-2 and MMP-9. Especially, combined overexpression of VEGF and MMP-2 revealed poor prognosis, our study might provide a basis for the better evaluation of biological characteristics and a new therapeutic strategy based on chemotherapy. © 2001 Cancer Research Campaign http://www.bjcancer.co

Difficult tracheal intubation in neonates and infants. NEonate and Children audiT of Anaesthesia pRactice IN Europe (NECTARINE): a prospective European multicentre observational study

Background: Neonates and infants are susceptible to hypoxaemia in the perioperative period. The aim of this study was to analyse interventions related to anaesthesia tracheal intubations in this European cohort and identify their clinical consequences. Methods: We performed a secondary analysis of tracheal intubations of the European multicentre observational trial (NEonate and Children audiT of Anaesthesia pRactice IN Europe [NECTARINE]) in neonates and small infants with difficult tracheal intubation. The primary endpoint was the incidence of difficult intubation and the related complications. The secondary endpoints were the risk factors for severe hypoxaemia attributed to difficult airway management, and 30 and 90 day outcomes. Results: Tracheal intubation was planned in 4683 procedures. Difficult tracheal intubation, defined as two failed attempts of direct laryngoscopy, occurred in 266 children (271 procedures) with an incidence (95% confidence interval [CI]) of 5.8% (95% CI, 5.1e6.5). Bradycardia occurred in 8% of the cases with difficult intubation, whereas a significant decrease in oxygen saturation (SpO2&lt;90% for 60 s) was reported in 40%. No associated risk factors could be identified among comorbidities, surgical, or anaesthesia management. Using propensity scoring to adjust for confounders, difficult anaesthesia tracheal intubation did not lead to an increase in 30 and 90 day morbidity or mortality. Conclusions: The results of the present study demonstrate a high incidence of difficult tracheal intubation in children less than 60 weeks post-conceptual age commonly resulting in severe hypoxaemia. Reassuringly, the morbidity and mortality at 30 and 90 days was not increased by the occurrence of a difficult intubation event. Clinical trial registration: NCT02350348

Morbidity and mortality after anaesthesia in early life: results of the European prospective multicentre observational study, neonate and children audit of anaesthesia practice in Europe (NECTARINE)

BACKGROUND: Neonates and infants requiring anaesthesia are at risk of physiological instability and complications, but triggers for peri-anaesthetic interventions and associations with subsequent outcome are unknown. METHODS: This prospective, observational study recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. The primary aim was to identify thresholds of pre-determined physiological variables that triggered a medical intervention. The secondary aims were to evaluate morbidities, mortality at 30 and 90 days, or both, and associations with critical events. RESULTS: Infants (n=5609) born at mean (standard deviation [sd]) 36.2 (4.4) weeks postmenstrual age (35.7% preterm) underwent 6542 procedures within 63 (48) days of birth. Critical event(s) requiring intervention occurred in 35.2% of cases, mainly hypotension (>30% decrease in blood pressure) or reduced oxygenation (SpO2 <85%). Postmenstrual age influenced the incidence and thresholds for intervention. Risk of critical events was increased by prior neonatal medical conditions, congenital anomalies, or both (relative risk [RR]=1.16; 95% confidence interval [CI], 1.04–1.28) and in those requiring preoperative intensive support (RR=1.27; 95% CI, 1.15–1.41). Additional complications occurred in 16.3% of patients by 30 days, and overall 90-day mortality was 3.2% (95% CI, 2.7–3.7%). Co-occurrence of intraoperative hypotension, hypoxaemia, and anaemia was associated with increased risk of morbidity (RR=3.56; 95% CI, 1.64–7.71) and mortality (RR=19.80; 95% CI, 5.87–66.7). CONCLUSIONS: Variability in physiological thresholds that triggered an intervention, and the impact of poor tissue oxygenation on patient's outcome, highlight the need for more standardised perioperative management guidelines for neonates and infants