Expression profiling of 21 biomolecules in locally advanced nasopharyngeal carcinomas of Caucasian patients

Background

Since scarce data exist on the pathogenesis of nasopharyngeal carcinoma in Caucasian patients, we attempted to elucidate the responsible molecular pathways in this patient population.

Methods

Formalin-fixed paraffin-embedded tumor tissue samples from 107 patients, diagnosed with locally-advanced nasopharyngeal carcinoma and treated with chemotherapy or chemo-radiotherapy, were analyzed by immunohistochemistry for the expression of the following proteins: E-cadherin, P-cadherin, Fascin-1, Cyclin D1, COX-2, EGFR, VEGF-A, VEGF-C, VEGFR-2, VEGFR-3, ERCC1, p53, p63, Ki67, MAPT, phospho-p44/42MAPK, PTEN, phospho-AKT, phospho-mTOR, and phospho-GSK-3β. EBER status was assessed by in situ hybridization. The majority of the cases were included in tissue microarray. All stains were performed and assessed centrally by two pathologists. The median follow-up time was 76.8 (42.3 – 99.2) months.

Results

Biomolecules expressed in >90% of cases were: p53, COX-2, P-cadherin, EBER, phospho-GSK-3β, and Fascin-1. WHO II+III tumors were more frequently EBER & PTEN positive and VEGF-A negative. Advanced age was significantly associated with positive phospho-GSK-3β and ERCC1 expression; male gender with positive phospho-AKT and phospho-p44/42MAPK; and worse performance status (1 or 2) with negative Ki67, ERCC1, PTEN, and phospho-mTOR expression. Earlier disease stage was closely associated with p63, MAPT, PTEN, and Cyclin D1 positivity. Univariate Cox regression analysis highlighted Cyclin D1 as a negative prognostic factor for disease-free survival (p=0.034) and EBER as a positive one for overall survival (p=0.048). In multivariate analysis, advanced age and stage, poor performance status, and positive ERCC1 emerged as predictors of worse disease-free and overall survival, as opposed to positive phospho-mTOR. Clustering analysis defined two protein-expression groups being predictive of better overall survival (p=0.043).

Conclusions

Our study is the first to examine the activation and interaction of established biomolecules and signaling pathways in Caucasian NPC patients in an effort to reveal new therapeutic targets.     

Posttraumatic Transdiaphragmatic Intercostal Hernia: Report of a Case and Review of the Literature

Intercostal hernias are rare, and usually occur following injuries of the thoracic wall. The scope of this report is to present a case of a 53-year-old obese patient that developed a transdiaphragmatic intercostal hernia. The patient presented with a palpable, sizeable, reducible mass in the right lateral thoracic wall, with evident bowel sounds in the area, 6 months after a motor-vehicle accident. On computed tomography (CT), the hernia sac contained part of the liver and part of the ascending colon. A surgical repair of the defect was performed, using a prosthetic patch. The patient''s postoperative course was uneventful and she remains recurrence free at 12 months after surgery. Intercostal hernias should be suspected following high-impact injuries of the thoracic wall, and CT scans will facilitate the diagnosis of intercostal hernia. We consider the surgical repair of the defect, with placement of a prosthetic mesh, as the treatment of choice to ensure a favorable outcome.Key words: Hernia, Transdiaphragmatic, Intercostal, Abdominal, MeshThe herniation of abdominal contents through the thoracic wall, as a result of the disruption of diaphragmatic and/or intercostal muscles, is an uncommon clinical entity.^1–3 This condition is usually reported to occur following penetrating or blunt injuries of the thoracic wall.⁴ However, there are several cases that have been described to be a consequence of a coughing–spell rib fracture, usually in patients with other predisposing factors such as chronic obstructive pulmonary disease, asthma, advanced age, or osteoporosis.^1,3,4The present report describes a case of a middle-aged obese patient that developed a transdiaphragmatic intercostal hernia involving the liver and the ascending colon 6 months after a traumatic incident. The underlying mechanism, the anatomical and diagnostic considerations, as well as the treatment options are also discussed.     

Variation in severity and type of sleep-disordered breathing throughout 4 nights in patients with heart failure

BACKGROUND: Over 50% of patients with chronic heart failure (CHF) have sleep-disordered breathing (SDB). Any variation in the type of SDB in CHF will have implications for patient management. Currently there is good evidence for treatment of obstructive sleep apnea (OSA) in CHF with continuous positive airway pressure; however, for central sleep apnea (CSA) the treatment is less clear. AIMS: The aim of this study was to investigate the variation in the severity and type of SDB (OSA vs. CSA) throughout 4 consecutive nights in CHF patients with SDB. METHODS: Nineteen male CHF patients (mean+/-sd: age 61+/-9 years; left ventricular ejection fraction: 34+/-10% and percent predicted peak VO2: 67+/-19%) underwent cardiorespiratory monitoring in their own home throughout 4 consecutive nights. RESULTS: There was minimal variation in apnea-hypopnea index (AHI) throughout 4 nights in CHF patients with SDB [intraclass correlation coefficient (95% confidence interval (CI)): 0.97 (95% CI 0.76 and 0.97)]. Eight patients [42% (95% CI 20% and 64%)] demonstrated a shift in the type of their SDB, from CSA to OSA or vice versa; these patients had significantly smaller neck circumference (group mean+/-sd) 42+/-2 vs. 44+/-2 cm; p=0.04), and had significant variation in the central AHI [intraclass correlation coefficient: 0.51 (95% CI 0.16 and 0.85)]. CONCLUSIONS: A single night of cardiorespiratory monitoring is representative of moderate-to-severe SDB in patients with CHF. However, a high proportion of patients shift their type of SDB over 4 nights. These findings may have implications for the management of SDB in CHF.     

Incremental value of arterial wave reflections in the determination of left ventricular diastolic dysfunction in untreated patients with essential hypertension

Systemic arterial stiffness is an indicator of cardiovascular disease and an independent marker of morbidity and cardiovascular mortality. We investigated the association of arterial wave reflections with left ventricular (LV) diastolic dysfunction and their incremental value to other determinants of LV diastolic dysfunction in patients with essential hypertension. In total 143 patients and 20 controls with similar atherosclerotic risk factors were examined by applanation tonometry of the radial artery (Sphygmocor) and echocardiography. Central augmentation index (CAI%) of reflected arterial waves as well as aortic strain (AoS) assessed by echocardiography were estimated. Doppler diastolic abnormalities were defined as proposed by the European Study Group on diastolic heart failure by measurement of E/A ratio (the ratio of the mitral inflow velocities), isovolumic relaxation time, deceleration time and flow propagation velocity. AoS and CAI were impaired in patients compared with controls (4.67 +/- 2.94 vs 6.06 +/- 4.91% and 145.8 +/- 22.7 vs. 135.7 +/- 20.3%, P < 0.01) as well as in patients with LV diastolic dysfunction compared to patients without, (5.52 +/- 4.29 vs. 10.73 +/- 5.77% and 139.5 +/- 21.7 vs. 124.5 +/- 17.0%, P < 0.05). The odds ratio (OR) of AoS and CAI for diastolic dysfunction was OR:0.918, 95% confidence interval (CI):0.837-0.99, P = 0.04 and OR:1.023, 95% CI: 1.023-1.040 P = 0.010, respectively. The addition of CAI to the multivariable model including age, LV mass index, AoS and mean arterial pressure increased the power of the model for determination of LV diastolic dysfunction (-2 log likelihood = 139.368, change of chi2 = 4.2, P-value for change=0.04). In untreated patients with newly diagnosed essential hypertension, wave reflections are independent and additive determinants of LV diastolic dysfunction.     

Oral L-arginine improves endothelial dysfunction in patients with essential hypertension

BACKGROUND: L-Arginine is a nitric oxide precursor, which augments endothelium-dependent vasodilatation in hypercholesterolemic humans and animals. Endothelium-dependent vasodilation is attenuated in patients with hypertension; however the effects of oral L-arginine on endothelial function of the conduit arteries in patients with essential hypertension have not previously been investigated. METHODS: In a prospective randomized double blind trial, 35 patients with essential hypertension received either 6 g L-arginine (18 subjects) or placebo (17 subjects). Patients were examined for flow-mediated endothelium-dependent dilatation of the brachial artery before and 1.5 h after administration of L-arginine or placebo. At the end of the protocol the nitrate-induced, endothelium-independent vasodilatation was evaluated. RESULTS: Two groups of L-arginine and placebo were similar regarding age, sex, blood lipids, smoking, diabetes, coronary artery disease, body mass index, intima-media thickness of the common carotid artery, clinics blood pressure and baseline brachial artery parameters. Administration of L-arginine or placebo did not change significantly heart rate, blood pressure, baseline diameter, blood flow or reactive hyperemia. L-Arginine resulted in a significant improvement of flow-mediated dilatation (1.7+/-3.4 vs. 5.9+/-5.4%, P=0.008) while placebo did not significantly change this parameter (3.0+/-2.7 vs. 3.1+/-2.2%, P=ns). The effect of L-arginine on flow-mediated dilatation was significantly different from the effect of placebo (P=0.05). L-Arginine did not significantly influence nitrate-induced dilatation (16+/-6.9 vs. 17.7+/-6.7%, P=ns). CONCLUSIONS: Oral administration of L-arginine acutely improves endothelium-dependent, flow-mediated dilatation of the brachial artery in patients with essential hypertension. The long-term effects of L-arginine in these patients require further investigation.