Universal paediatric videolaryngoscopy and glottic view grading: a prospective observational study.

BACKGROUND: Although videolaryngoscopy has been proposed as a default technique for tracheal intubation in children, published evidence on universal videolaryngoscopy implementation programmes is scarce. We aimed to determine if universal, first-choice videolaryngoscopy reduces the incidence of restricted glottic views and to determine the diagnostic performance of the Cormack and Lehane classification to discriminate between easy and difficult videolaryngoscopic tracheal intubations in children. METHODS: We conducted a prospective observational study within a structured universal videolaryngoscopy implementation programme. We used C-MAC™ (Karl Storz, Tuttlingen, Germany) videolaryngoscopes in all anaesthetised children undergoing elective tracheal intubation for surgical procedures. The direct and videolaryngoscopic glottic views were classified using a six-stage grading system. RESULTS: There were 904 tracheal intubations in 809 children over a 16-month period. First attempt and overall success occurred in 607 (67%) and 903 (> 99%) tracheal intubations, respectively. Difficult videolaryngoscopic tracheal intubation occurred in 47 (5%) and airway-related adverse events in 42 (5%) tracheal intubations. Direct glottic view during laryngoscopy was restricted in 117 (13%) and the videolaryngoscopic view in 32 (4%) tracheal intubations (p < 0.001). Videolaryngoscopy improved the glottic view in 57/69 (83%) tracheal intubations where the vocal cords were only just visible, and in 44/48 (92%) where the vocal cords were not visible by direct view. The Cormack and Lehane classification discriminated poorly between easy and difficult videolaryngoscopic tracheal intubations with a mean area under the receiver operating characteristic curve of 0.68 (95%CI 0.59-0.78) for the videolaryngoscopic view compared with 0.80 (95%CI 0.73-0.87) for the direct glottic view during laryngoscopy (p = 0.005). CONCLUSIONS: Universal, first-choice videolaryngoscopy reduced substantially the incidence of restricted glottic views. The Cormack and Lehane classification was not a useful tool for grading videolaryngoscopic tracheal intubation in children.

Hyperangulated vs. Macintosh videolaryngoscopy in adults with anticipated difficult airway management: a randomised controlled trial.

BACKGROUND: It is not certain whether the blade geometry of videolaryngoscopes, either a hyperangulated or Macintosh shape, affects glottic view, success rate and/or tracheal intubation time in patients with expected difficult airways. We hypothesised that using a hyperangulated videolaryngoscope blade would visualise a higher percentage of glottic opening compared with a Macintosh videolaryngoscope blade in patients with expected difficult airways. METHODS: We conducted an open-label, patient-blinded, randomised controlled trial in adult patients scheduled to undergo elective ear, nose and throat or oral and maxillofacial surgery, who were anticipated to have a difficult airway. All airway operators were consultant anaesthetists. Patients were allocated randomly to tracheal intubation with either hyperangulated (C-MAC D-BLADE™) or Macintosh videolaryngoscope blades (C-MAC™). The primary outcome was the percentage of glottic opening. First attempt success was designated a key secondary outcome. RESULTS: We assessed 2540 adults scheduled for elective head and neck surgery for eligibility and included 182 patients with expected difficult airways undergoing orotracheal intubation. The percentage of glottic opening visualised, expressed as median (IQR [range]), was 89 (69-99 [0-100])% with hyperangulated videolaryngoscope blades and 54 (9-90 [0-100])% with Macintosh videolaryngoscope blades (p < 0.001). First-line hyperangulated videolaryngoscopy failed in one patient and Macintosh videolaryngoscopy in 12 patients (13%, p = 0.002). First attempt success rate was 97% with hyperangulated videolaryngoscope blades and 67% with Macintosh videolaryngoscope blades (p < 0.001). CONCLUSIONS: Glottic view and first attempt success rate were superior with hyperangulated videolaryngoscope blades compared with Macintosh videolaryngoscope blades when used by experienced anaesthetists in patients with difficult airways.

Impact of Intraoperative Fluctuations of Cardiac Output on Cerebrovascular Autoregulation: An Integrative Secondary Analysis of Individual-level Data.

BACKGROUND: Intraoperative impairment of cerebral autoregulation (CA) has been associated with perioperative neurocognitive disorders. We investigated whether intraoperative fluctuations in cardiac index are associated with changes in CA. METHODS: We conducted an integrative explorative secondary analysis of individual-level data from 2 prospective observational studies including patients scheduled for radical prostatectomy. We assessed cardiac index by pulse contour analysis and CA as the cerebral oxygenation index (COx) based on near-infrared spectroscopy. We analyzed (1) the cross-correlation between cardiac index and COx, (2) the correlation between the time-weighted average (TWA) of the cardiac index below 2.5 L min-1 m-2, and the TWA of COx above 0.3, and (3) the difference in areas between the cardiac index curve and the COx curve among various subgroups. RESULTS: The final analysis included 155 patients. The median cardiac index was 3.16 [IQR: 2.65, 3.72] L min-1 m-2. Median COx was 0.23 [IQR: 0.12, 0.34]. (1) The median cross-correlation between cardiac index and COx was 0.230 [IQR: 0.186, 0.287]. (2) The correlation (Spearman ρ) between TWA of cardiac index below 2.5 L min-1 m-2 and TWA of COx above 0.3 was 0.095 (P=0.239). (3) Areas between the cardiac index curve and the COx curve did not differ significantly among subgroups (<65 vs. ≥65 y, P=0.903; 0 vs. ≥1 cardiovascular risk factors, P=0.518; arterial hypertension vs. none, P=0.822; open vs. robot-assisted radical prostatectomy, P=0.699). CONCLUSIONS: We found no meaningful association between intraoperative fluctuations in cardiac index and CA. However, it is possible that a potential association was masked by the influence of anesthesia on CA.

Stair-Climbing Tests or Self-Reported Functional Capacity for Preoperative Pulmonary Risk Assessment in Patients with Known or Suspected COPD-A Prospective Observational Study.

BACKGROUND: This prospective study aims to determine whether preoperative stair-climbing tests (SCT) predict postoperative pulmonary complications (PPC) better than self-reported poor functional capacity (SRPFC) in patients with known or suspected COPD. METHODS: A total of 320 patients undergoing scheduled for major non-cardiac surgery, 240 with verified COPD and 80 with GOLD key indicators but disproved COPD, underwent preoperative SRPFC and SCT and were analyzed. Least absolute shrinkage and selection operator (LASSO) regression was used for variable selection. Two multivariable regression models were fitted, the SRPFC model (baseline variables such as sociodemographic, surgical and procedural characteristics, medical preconditions, and GOLD key indicators plus SRPFC) and the SCT model (baseline variables plus SCTPFC). RESULTS: Within all stair-climbing variables, LASSO exclusively selected self-reported poor functional capacity. The cross-validated area under the receiver operating characteristic curve with bias-corrected bootstrapping 95% confidence interval (95% CI) did not differ between the SRPFC and SCT models (0.71; 0.65-0.77 for both models). SRPFC was an independent risk factor (adjusted odds ratio (OR) 5.45; 95% CI 1.04-28.60; p = 0.045 in the SRPFC model) but SCTPFC was not (adjusted OR 3.78; 95% CI 0.87-16.34; p = 0.075 in the SCT model). CONCLUSIONS: Our findings indicate that preoperative SRPFC adequately predicts PPC while additional preoperative SCTs are dispensable in patients with known or suspected COPD.

CNS Manifestations in Mucolipidosis Type II-A Retrospective Analysis of Longitudinal Data on Neurocognitive Development and Neuroimaging in Eleven Patients.

Mucolipidosis type II (MLII), an ultra-rare lysosomal storage disorder, manifests as a fatal multi-systemic disease. Mental inhibition and progressive neurodegeneration are commonly reported disease manifestations. Nevertheless, longitudinal data on neurocognitive testing and neuroimaging lack in current literature. This study aimed to provide details on central nervous system manifestations in MLII. All MLII patients with at least one standardized developmental assessment performed between 2005 and 2022 were included by retrospective chart review. A multiple mixed linear regression model was applied. Eleven patients with a median age of 34.0 months (range 1.6-159.6) underwent 32 neurocognitive and 28 adaptive behaviour assessments as well as 14 brain magnetic resonance imagings. The scales used were mainly BSID-III (42%) and VABS-II (47%). Neurocognitive testing (per patient: mean 2.9, standard deviation (SD) 2.0) performed over 0-52.1 months (median 12.1) revealed profound impairment with a mean developmental quotient of 36.7% (SD 20.4) at last assessment. The patients showed sustained development; on average, they gained 0.28 age-equivalent score points per month (confidence interval 0.17-0.38). Apart from common (63%) cervical spinal stenosis, neuroimaging revealed unspecific, non-progressive abnormalities (i.e., mild brain atrophy, white matter lesions). In summary, MLII is associated with profound developmental impairment, but not with neurodegeneration and neurocognitive decline.

Preoperative Spirometry in Patients With Known or Suspected Chronic Obstructive Pulmonary Disease Undergoing Major Surgery: The Prospective Observational PREDICT Study.

BACKGROUND: Pulmonary function tests (PFTs) such as spirometry and blood gas analysis have been claimed to improve preoperative pulmonary risk assessment, but the scientific literature is conflicting. The Preoperative Diagnostic Tests for Pulmonary Risk Assessment in Chronic Obstructive Pulmonary Disease (PREDICT) study aimed to determine whether preoperative PFTs improve the prediction of postoperative pulmonary complications (PPCs) in patients with known or suspected chronic obstructive pulmonary disease (COPD) undergoing major surgery. A secondary aim was to determine whether the Global Initiative for Chronic Obstructive Lung Diseases (GOLD) classification of airflow limitation severity (grades I-IV) is associated with PPC. METHODS: In this prospective, single-center study, patients with GOLD key indicators for COPD scheduled for major surgery received PFTs. Patients with confirmed COPD (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] ≤0.7) were included in the COPD cohort and compared with a reference cohort without COPD. We developed 3 multivariable risk prediction models and compared their ability to predict PPC: the "standard model" (medical preconditions, and sociodemographic and surgical data), the "COPD assessment model" (additional GOLD key indicators, pack-years, and poor exercise capacity), and the "PFT model" (additional PFT parameters selected by adaptive least absolute shrinkage and selection operator [LASSO] regression). Multiple LASSO regressions were used for cross-validation. RESULTS: A total of 31,714 patients were assessed for eligibility; 1271 individuals received PFTs. Three hundred twenty patients (240 with confirmed COPD: 78 GOLD I, 125 GOLD II, 28 GOLD III, 9 GOLD IV, and 80 without COPD) completed follow-up. The diagnostic performance was similar among the standard model (cross-validated area under the curve [cvAUC], 0.723; bias-corrected bootstrapped [bc-b] 95% confidence interval [CI], 0.663-0.775), COPD assessment model (cvAUC, 0.724; bc-b 95% CI, 0.662-0.777), and PFT model (cvAUC, 0.729; bc-b 95% CI, 0.668-0.782). Previously known COPD was an independent predictor in the standard and COPD assessment model. %FEV1 PRED was the only PFT parameter selected by LASSO regression and was an independent predictor in the PFT model (adjusted odds ratios [OR], 0.98; 95% CI, 0.967-.0.998; P = .030). The risk for PPC significantly increased with GOLD grades ( P < .001). COPD was newly diagnosed in 53.8% of the patients with confirmed COPD; however, these individuals were not at increased risk for PPC ( P = .338). CONCLUSIONS: COPD is underdiagnosed in surgical patients. Patients with newly diagnosed COPD commonly presented with low GOLD severity grades and were not at higher risk for PPC. Neither a structured COPD-specific assessment nor preoperative PFTs added incremental diagnostic value to the standard clinical preassessment in patients with known or suspected COPD. Unnecessary postponement of surgery and undue health care costs can be avoided.

Anaesthesia-Relevant Disease Manifestations and Perianaesthetic Complications in Patients with Mucolipidosis-A Retrospective Analysis of 44 Anaesthetic Cases in 12 Patients.

Mucolipidosis (ML) type II, intermediate, and III are lysosomal storage disorders with progressive multiorgan manifestations predisposing patients to a high risk of perioperative morbidity. The aims of the study were to systematically assess disease manifestations relevant to anaesthesia as well as anaesthesia-related complications. This retrospective study includes ML patients who underwent anaesthesia in two centres between 2008 and 2022. We reviewed patients' demographics, medical history, disease manifestations, as well as procedure- and outcome-related data. A total of 12 patients (7 MLII, 2 ML intermediate, 3 MLIII) underwent 44 anaesthesia procedures (per patient: median 3, range 1-11). The median age was 3.3 years (range 0.1-19.1). At least one complication occurred in 27.3% of the anaesthesia procedures. The vast majority of complications (94%) occurred in children with MLII and ML intermediate. A predicted difficult airway was found in 100% and 80% of the MLII and ML intermediate patients, respectively. Accordingly, most complications (59%) occurred during the induction of anaesthesia. Altogether, respiratory complications were the most frequent (18%), followed by difficult airway management (14%). The risk for anaesthesia-related complications is alarmingly high in patients with ML, particularly in those with MLII and ML intermediate. Multidisciplinary risk-benefit analysis and thoughtful anaesthesia planning are crucial in these patients.

Intraoperative impaired cerebrovascular autoregulation and delayed neurocognitive recovery after major oncologic surgery: a secondary analysis of pooled data.

Cerebral blood flow is tightly regulated by cerebrovascular autoregulation (CVA), and intraoperative impairment of CVA has been linked with perioperative neurocognitive disorders. We aim to assess whether impairment of CVA during major oncologic surgery is associated with delayed neurocognitive recovery (DNCR) postoperatively. We performed a secondary analysis of prospectively collected data. Patients were included if they had undergone complete pre- and postoperative neuropsychological assessments, continuous intraoperative measurement of CVA, and major oncologic surgery for visceral, urological, or gynecological cancer. Intraoperative CVA was measured using the time-correlation method based on near-infrared-spectroscopy, and DNCR was assessed with a neuropsychological test battery. A decline in cognitive function before hospital discharge compared with a preoperative baseline assessment was defined as DNCR. One hundred ninety-five patients were included in the analysis. The median age of the study population was 65 years (IQR: 60-68); 11 patients (5.6%) were female. Forty-one patients (21.0%) fulfilled the criteria for DNCR in the early postoperative period. We found a significant association between impaired intraoperative CVA and DNCR before hospital discharge (OR = 1.042 [95% CI: 1.005; 1.080], p = 0.028). The type of surgery (radical prostatectomy vs. other major oncologic surgery; OR = 0.269 [95% CI: 0.099; 0.728], p = 0.010) and premedication with midazolam (OR = 3.360 [95% CI: 1.039; 10.870], p = 0.043) were significantly associated with the occurrence of DNCR in the early postoperative period. Intraoperative impairment of CVA is associated with postoperative neurocognitive function early after oncologic surgery. Therefore, intraoperative monitoring of CVA may be a target for neuroprotective interventions. The initial studies were retrospectively registered with primary clinical trial registries recognized by the World Health Organization (ClinicalTrials.gov Identifiers: DRKS00010014, 21.03.2016 and NCT04101006, 24.07.2019).

Pulmonary Function Tests for the Prediction of Postoperative Pulmonary Complications.

BACKGROUND: Pulmonary function tests (PFTs) such as spirometry and blood gas analysis have been claimed to improve preoperative risk assessment. This systematic review summarizes the available scientific literature regarding the ability of PFTs to predict postoperative pulmonary complications (PPC) in non-thoracic surgery. METHODS: We systematically searched MEDLINE, CINAHL, and the Cochrane Library for pertinent original research articles (PROSPERO CRD42020215502), framed by the PIT-criteria (PIT, participants, index test, target conditions), respecting the PRISMA-DTA recommendations (DTA, diagnostic test accuracy). RESULTS: 46 original research studies were identified that used PFT-findings as index tests and PPC as target condition. QUADAS-2 quality assessment revealed a high risk of bias regarding patient selection, blinding, and outcome definitions. Qualitative synthesis of prospective studies revealed inconclusive study findings: 65% argue for and 35% against preoperative spirometry, and 43% argue for blood gas analysis. A (post-hoc) subgroup analysis in prospective studies with low-risk of selection bias identified a possible benefit in upper abdominal surgery (three studies with 959 participants argued for and one study with 60 participants against spirometry). CONCLUSION: As the existing literature is inconclusive it is currently unknown if PFTs improve risk assessment before non-thoracic surgery. Spirometry should be considered in individuals with key indicators for chronic obstructive pulmonary disease (COPD) scheduling for upper abdominal surgery.

Disease Manifestations in Mucopolysaccharidoses and Their Impact on Anaesthesia-Related Complications-A Retrospective Analysis of 99 Patients.

Patients with mucopolysaccharidoses (MPS) frequently require anaesthesia for diagnostic or surgical interventions and thereby experience high morbidity. This study aimed to develop a multivariable prediction model for anaesthesia-related complications in MPS. This two-centred study was performed by retrospective chart review of children and adults with MPS undergoing anaesthesia from 2002 until 2018. We retrieved the patients' demographics, medical history, clinical manifestations, and indication by each anaesthesia. Multivariable mixed-effects logistic regression was calculated for a clinical model based on preoperative predictors preselected by lasso regression and another model based on disease subtypes only. Of the 484 anaesthesia cases in 99 patients, 22.7% experienced at least one adverse event. The clinical model resulted in a better forecast performance than the subtype-model (AICc 460.4 vs. 467.7). The most relevant predictors were hepatosplenomegaly (OR 3.10, CI 1.54-6.26), immobility (OR 3.80, CI 0.98-14.73), and planned major surgery (OR 6.64, CI 2.25-19.55), while disease-specific therapies, i.e., haematopoietic stem cell transplantation (OR 0.45, CI 0.20-1.03), produced a protective effect. Anaesthetic complications can best be predicted by surrogates for advanced disease stages and protective therapeutic factors. Further model validation in different cohorts is needed.

Airway management and perioperative adverse events in children with mucopolysaccharidoses and mucolipidoses: A retrospective cohort study.

BACKGROUND: Children suffering from mucopolysaccharidoses (subtypes I, II, III, IV, VI, and VII) or mucolipidoses often require anesthesia, but are at high risk for perioperative adverse events. However, the impact of the disease subtype and the standard of care for airway management are still unclear. AIMS: This study aimed to assess independent risk factors for perioperative adverse events in individuals with mucopolysaccharidoses/mucolipidoses and to analyze the interaction with the primary airway technique implemented. METHODS: This retrospective study included individuals with mucopolysaccharidoses/mucolipidoses who underwent anesthesia at two high-volume centers from 2002 to 2016. The data were analyzed in a multivariate hierarchical model, accounting for repeated anesthesia procedures within the same patient and for multiple events within a single anesthesia. RESULTS: Of 141 identified inpatients, 67 (63 mucopolysaccharidoses and 4 mucolipidoses) underwent 269 anesthesia procedures (study cases) for 353 surgical or diagnostic interventions. At least one perioperative adverse event occurred in 25.6% of the cases. The risk for perioperative adverse events was higher in mucopolysaccharidoses type I (OR 8.0 [1.5-42.7]; P = .014) or type II (OR 8.8 [1.3-58.6]; P = .025) than in type III. Fiberoptic intubation through a supraglottic airway was associated with the lowest risk for perioperative adverse events and lowest conversion rate. Direct laryngoscopy was associated with a significantly higher risk for airway management problems than indirect techniques (estimated event rates 47.8% vs 10.1%, OR 24.05 [5.20-111.24]; P < .001). The risk for respiratory adverse events was significantly higher for supraglottic airway (22.6%; OR 31.53 [2.79-355.88]; P = .001) and direct laryngoscopy (14.8%; OR 14.70 [1.32-163.44]; P = .029) than for fiberoptic intubation through a supraglottic airway (2.1%). CONCLUSIONS: The disease subtype and primary airway technique were the most important independent risk factors for perioperative adverse events. Our findings indicate that in MPS/ML children with predicted difficult airway indirect techniques should be favored for the first tracheal intubation attempt.

Correction: Cerebral Hemodynamics in Patients with Hemolytic Uremic Syndrome Assessed by Susceptibility Weighted Imaging and Four-Dimensional Non-Contrast MR Angiography.

[This corrects the article DOI: 10.1371/journal.pone.0164863.].

Cerebral Hemodynamics in Patients with Hemolytic Uremic Syndrome Assessed by Susceptibility Weighted Imaging and Four-Dimensional Non-Contrast MR Angiography.

BACKGROUND AND PURPOSE: Conventional magnetic resonance imaging (MRI) of patients with hemolytic uremic syndrome (HUS) and neurological symptoms performed during an epidemic outbreak of Escherichia coli O104:H4 in Northern Europe has previously shown pathological changes in only approximately 50% of patients. In contrast, susceptibility-weighted imaging (SWI) revealed a loss of venous contrast in a large number of patients. We hypothesized that this observation may be due to an increase in cerebral blood flow (CBF) and aimed to identify a plausible cause. MATERIALS AND METHODS: Baseline 1.5T MRI scans of 36 patients (female, 26; male, 10; mean age, 38.2±19.3 years) were evaluated. Venous contrast was rated on standard SWI minimum intensity projections. A prototype four-dimensional (time resolved) magnetic resonance angiography (4D MRA) assessed cerebral hemodynamics by global time-to-peak (TTP), as a surrogate marker for CBF. Clinical parameters studied were hemoglobin, hematocrit, creatinine, urea levels, blood pressure, heart rate, and end-tidal CO2. RESULTS: SWI venous contrast was abnormally low in 33 of 36 patients. TTP ranged from 3.7 to 10.2 frames (mean, 7.9 ± 1.4). Hemoglobin at the time of MRI (n = 35) was decreased in all patients (range, 5.0 to 12.6 g/dL; mean, 8.2 ± 1.4); hematocrit (n = 33) was abnormally low in all but a single patient (range, 14.3 to 37.2%; mean, 23.7 ± 4.2). Creatinine was abnormally high in 30 of 36 patients (83%) (range, 0.8 to 9.7; mean, 3.7 ± 2.2). SWI venous contrast correlated significantly with hemoglobin (r = 0.52, P = 0.0015), hematocrit (r = 0.65, P < 0.001), and TTP (r = 0.35, P = 0.036). No correlation of SWI with blood pressure, heart rate, end-tidal CO2, creatinine, and urea level was observed. Findings suggest that the loss of venous contrast is related to an increase in CBF secondary to severe anemia related to HUS. SWI contrast of patients with pathological conventional MRI findings was significantly lower compared to patients with normal MRI (mean SWI score, 1.41 and 2.05, respectively; P = 0.04). In patients with abnormal conventional MRI, mean TTP (7.45), mean hemoglobin (7.65), and mean hematocrit (22.0) were lower compared to patients with normal conventional MRI scans (mean TTP = 8.28, mean hemoglobin = 8.63, mean hematocrit = 25.23). CONCLUSION: In contrast to conventional MRI, almost all patients showed pathological changes in cerebral hemodynamics assessed by SWI and 4D MRA. Loss of venous contrast on SWI is most likely the result of an increase in CBF and may be related to the acute onset of anemia. Future studies will be needed to assess a possible therapeutic effect of blood transfusions in patients with HUS and neurological symptoms.

ABO blood group IgM isoagglutinins interact with tumor-associated O-glycan structures in pancreatic cancer.

PURPOSE: The ABO gene locus is associated with the risk of developing pancreatic ductal adenocarcinoma (PDAC) resulting in an increased incidence in individuals with non-O blood groups. Up to 90% of PDAC specimens display alterations in mucin type O-GalNAc glycosylation. Because aberrant O-GalNAc glycans (Tn and T antigen) are structurally related to blood group A and B glycans, we investigated the role of IgM isoagglutinins in PDAC. EXPERIMENTAL DESIGN: Binding studies of IgM isoagglutinins toward blood group A, B, Tn antigen, and T antigen glycoconjugates from patients with PDAC and healthy individuals were conducted. Isoagglutinin titers and total IgM were compared between patients with PDAC and control group. An anti-A antibody was used for immunoprecipitation of aberrant O-glycosylated tumor proteins and subsequent mass spectromic analysis. RESULTS: We found that IgM isoagglutinins bind blood group antigens, Tn and T glycoconjugates as well as tumor-derived glycoproteins. Blood group A isoagglutinins exhibited a strong binding toward blood group B antigen and T antigen, whereas blood group B showed binding to blood group A antigen and Tn antigen. Furthermore, we confirmed a decreased frequency in individuals with blood group O and observed a significant decrease of IgM isoagglutinin titers in PDAC sera compared with control sera, whereas total IgM levels were unaltered. We identified new PDAC-derived O-GalNAc glycoproteins by mass spectrometry using a blood group A-specific antibody. CONCLUSION: Our data elucidated a novel interaction of blood group IgM isoagglutinins and PDAC O-GalNAc glycoproteins that may contribute to the pathogenesis and progression of pancreatic cancer.

Esophageal carcinoma cell line with high EGFR polysomy is responsive to gefitinib.

PURPOSE: It has previously been shown that gefitinib-treated patients with epidermal growth factor receptor (EGFR) gene amplification or high polysomy had a statistically significant improvement in response, time to progression, and survival in non-small cell lung cancer (NSCLC). Only few studies utilizing anti-EGFR treatment in advanced esophageal adenocarcinomas have been performed and the results have been heterogeneous. The aim of this study was to evaluate EGFR-targeted therapy with gefitinib in esophageal adenocarcinoma with a high EGFR polysomy. METHODS: Novel esophageal cell lines PT6216 and LN6216c were established from primary tumor and lymph node metastasis of a patient with highly aggressive and metastatic adenocarcinoma. Pathological examination including tumor differentiation and prognostic marker analysis, immunohistochemical EGFR expression analysis, EGFR fluorescence in situ hybridization, and mutation analysis were performed. Response of novel cell lines to gefitinib treatment was evaluated by cell proliferation and vitality assays. Fifty-four esophageal adenocarcinoma specimens were evaluated for EGFR gene copy gain. RESULTS: The primary tumor cell line PT6216 and the lymph node cell line LN6216c show a homogenously high polysomy for EGFR determined by FISH analysis. Cell proliferation and vitality are highly sensitive to the tyrosine kinase inhibitor gefitinib compared to esophageal control cells without a high polysomy for EGFR. High polysomy for EGFR was found in 35 % of patients. CONCLUSION: We show for the first time a significant treatment response to the EGFR tyrosine kinase inhibitor gefitinib in esophageal tumor cells with a high polysomy for EGFR, suggesting a future role of anti-EGFR therapy for esophageal adenocarcinoma patients with a high EGFR polysomy.

Effective inhibition of metastases and primary tumor growth with CTCE-9908 in esophageal cancer.

BACKGROUND: In spite of multimodular treatment, the therapeutic options for esophageal carcinoma are limited, and metastases remain the leading cause of tumor-related mortality. Expression of the chemokine receptor CXCR4 significantly correlates with poor survival rates in patients with esophageal carcinoma and is associated with lymph node and bone marrow metastases. The aim of this study was to evaluate the effect of the CXCR4 antagonist CTCE-9908 on metastatic homing and primary tumor growth in vitro and in vivo in an orthotopic xenograft model of esophageal cancer. MATERIALS AND METHODS: OE19 cells were examined for stromal cell-derived factor 1 alpha-mediated migration under CTCE-9908 treatment. The CTCE-9908 treatment was further evaluated in an in vitro proliferation assay and orthotopic esophageal model, accompanied by magnetic resonance imaging. Tumor and metastases were immunohistochemically examined for CXCR4 expression. RESULTS: CTCE-9908 has an inhibitory effect on stromal cell-derived factor 1 alpha-mediated migration and proliferation of OE19 cells. Treatment with CTCE-9908 in the orthotopic esophageal model leads to a reduction of metastatic spread and primary tumor growth. This was confirmed by magnetic resonsance imaging. Treatment with CTCE-9908 results in altered CXCR4 expression pattern exhibiting a high degree of variability. CONCLUSION: CTCE-9908 effectively inhibits OE19 cell migration and proliferation in vitro, reduces metastases to lung, liver, and lymph nodes in vivo, and moreover leads to tumor growth reduction in an orthotopic model of esophageal carcinoma.

The T393C polymorphism of GNAS1 is a predictor for relapse and survival in resectable non-small cell lung cancer.

INTRODUCTION: The GNAS1 T393C single nucleotide polymorphism (T393C-SNP) correlates with Gαs mRNA stability and protein expression and augmented apoptosis. Genetic germ line variations as stable and reproducible markers potentially serve as prognostic marker in oncology. The aim of this study was to evaluate the potential prognostic value of T393C-SNP in complete resected non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In total 163 Caucasian patients, who had been surgically treated for NSCLC between 1998 and 2010, were included in this study. Genotyping of peripheral blood cells was performed by polymerase chain reaction and digestion using the restriction enzyme FokI. The T393C-SNP was correlated with clinic-pathological parameters and survival. Chi-square test, Kaplan-Meier estimator and cox regression hazard model were used to assess the prognostic value of the T393C-SNP. RESULTS: C-allele carriers had a higher recurrence rate (p=0.018) and a shorter disease-free survival compared to homozygous T-allele carriers (12.26 months vs. 44.65 months, p=0.009). The overall survival in homozygous C allele carriers was shorter (19.10 months vs. 53.95 months, p=0.019). Multivariate Cox regression identified the CC genotype as a negative independent prognostic factor for recurrence (hazard ratio 2.36, p=0.007) and survival (hazard ratio 2.51, p=0.008). CONCLUSION: Determination of T393C-SNP preoperatively potentially allows allocation of NSCLC patients into different risk profiles and may influence the therapeutic strategy.

Involvement of CXCR4 chemokine receptor in metastastic HER2-positive esophageal cancer.

A functional linkage of the structurally unrelated receptors HER2 and CXCR4 has been suggested for breast cancer but has not been evaluated for esophageal carcinoma. The inhibition of HER2 leads to a reduction of primary tumor growth and metastases in an orthotopic model of esophageal carcinoma. The chemokine receptor CXCR4 has been implicated in metastatic dissemination of various tumors and correlates with poor survival in esophageal carcinoma. The aim of this study was to investigate a correlation between the expression levels of HER2 and CXCR4 and to evaluate the involvement of CXCR4-expression in HER2-positive esophageal carcinoma. The effects of HER2-inhibition with trastuzumab and of CXCR4-inhibition with AMD3100 on primary tumor growth, metastatic homing, and receptor expression were evaluated in vitro and in an orthotopic model of metastatic esophageal carcinoma using MRI for imaging. The clinical relevance of HER2- and CXCR4-expression was examined in esophageal carcinoma patients. A significant correlation of HER2- and CXCR4-expression in primary tumor and metastases exists in the orthotopic model. Trastuzumab and AMD3100 treatment led to a significant reduction of primary tumor growth, metastases and micrometastases. HER2-expression was significantly elevated under AMD3100 treatment in the primary tumor and particularly in the metastases. The positive correlation between HER2- and CXCR4-expression was validated in esophageal cancer patients. The correlation of CXCR4- and HER2-expression and the elevation of HER2-expression and reduction of metastases through CXCR4-inhibition suggest a possible functional linkage and a role in tumor dissemination in HER2-positive esophageal carcinoma.

Orthotopic fluorescent peritoneal carcinomatosis model of esophageal cancer.

AIM: Orthotopic models utilizing orthotopic implantation have been used for developing cancer models of multiple tumor entities. The aim of this study was to evaluate the role of orthotopic injection in establishing a model of esophageal cancer using a human green fluorescent protein (GFP) cell line of human esophageal carcinoma. MATERIALS AND METHODS: Nude mice were orthotopically injected in the abdominal esophagus with stably transfected GFP-PT1590 cells. Tumor progression was examined by fluorescence imaging. RESULTS: Fifty percent of animals developed extensive peritoneal spread without a distinct primary tumor at the injection site. Continuous and metastatic spread to the liver, lungs, and lymph nodes was also observed. Fluorescence imaging enabled fast and specific visualization of tumor progression without the need for anesthesia. Intraperitoneal and metastatic tumor spread of GFP-PT1590 esophageal carcinoma demonstrated a highly aggressive but heterogeneous behaviour. Although injection of the esophageal carcinoma cell line GFP-PT1590 did not lead to primary esophageal tumor development at the site of injection, 50% of the mice developed extensive peritoneal spread, as well as lymph node and organ metastasis. CONCLUSION: The orthotopic cell injection model resulted in peritoneal carcinomatosis of esophageal adenocarcinoma, which could be visualized in real time using fluorescence imaging.