Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial

BACKGROUND One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes. METHODS We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771. FINDINGS From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery. INTERPRETATION Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer. FUNDING Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.

Pharmacological Modulation of Hemodynamics in Adult Zebrafish In Vivo

INTRODUCTION: Hemodynamic parameters in zebrafish receive increasing attention because of their important role in cardiovascular processes such as atherosclerosis, hematopoiesis, sprouting and intussusceptive angiogenesis. To study underlying mechanisms, the precise modulation of parameters like blood flow velocity or shear stress is centrally important. Questions related to blood flow have been addressed in the past in either embryonic or ex vivo-zebrafish models but little information is available for adult animals. Here we describe a pharmacological approach to modulate cardiac and hemodynamic parameters in adult zebrafish in vivo. MATERIALS AND METHODS: Adult zebrafish were paralyzed and orally perfused with salt water. The drugs isoprenaline and sodium nitroprusside were directly applied with the perfusate, thus closely resembling the preferred method for drug delivery in zebrafish, namely within the water. Drug effects on the heart and on blood flow in the submental vein were studied using electrocardiograms, in vivo-microscopy and mathematical flow simulations. RESULTS: Under control conditions, heart rate, blood flow velocity and shear stress varied less than ± 5%. Maximal chronotropic effects of isoprenaline were achieved at a concentration of 50 μmol/L, where it increased the heart rate by 22.6 ± 1.3% (n = 4; p < 0.0001). Blood flow velocity and shear stress in the submental vein were not significantly increased. Sodium nitroprusside at 1 mmol/L did not alter the heart rate but increased blood flow velocity by 110.46 ± 19.64% (p = 0.01) and shear stress by 117.96 ± 23.65% (n = 9; p = 0.03). DISCUSSION: In this study, we demonstrate that cardiac and hemodynamic parameters in adult zebrafish can be efficiently modulated by isoprenaline and sodium nitroprusside. Together with the suitability of the zebrafish for in vivo-microscopy and genetic modifications, the methodology described permits studying biological processes that are dependent on hemodynamic alterations.

Biomechanical effects of environmental and engineered particles on human airway smooth muscle cells

The past decade has seen significant increases in combustion-generated ambient particles, which contain a nanosized fraction (less than 100 nm), and even greater increases have occurred in engineered nanoparticles (NPs) propelled by the booming nanotechnology industry. Although inhalation of these particulates has become a public health concern, human health effects and mechanisms of action for NPs are not well understood. Focusing on the human airway smooth muscle cell, here we show that the cellular mechanical function is altered by particulate exposure in a manner that is dependent upon particle material, size and dose. We used Alamar Blue assay to measure cell viability and optical magnetic twisting cytometry to measure cell stiffness and agonist-induced contractility. The eight particle species fell into four categories, based on their respective effect on cell viability and on mechanical function. Cell viability was impaired and cell contractility was decreased by (i) zinc oxide (40-100 nm and less than 44 microm) and copper(II) oxide (less than 50 nm); cell contractility was decreased by (ii) fluorescent polystyrene spheres (40 nm), increased by (iii) welding fumes and unchanged by (iv) diesel exhaust particles, titanium dioxide (25 nm) and copper(II) oxide (less than 5 microm), although in none of these cases was cell viability impaired. Treatment with hydrogen peroxide up to 500 microM did not alter viability or cell mechanics, suggesting that the particle effects are unlikely to be mediated by particle-generated reactive oxygen species. Our results highlight the susceptibility of cellular mechanical function to particulate exposures and suggest that direct exposure of the airway smooth muscle cells to particulates may initiate or aggravate respiratory diseases.

Combining 3D tracking and surgical instrumentation to determine the stiffness of spinal motion segments: a validation study

The spine is a complex structure that provides motion in three directions: flexion and extension, lateral bending and axial rotation. So far, the investigation of the mechanical and kinematic behavior of the basic unit of the spine, a motion segment, is predominantly a domain of in vitro experiments on spinal loading simulators. Most existing approaches to measure spinal stiffness intraoperatively in an in vivo environment use a distractor. However, these concepts usually assume a planar loading and motion. The objective of our study was to develop and validate an apparatus, that allows to perform intraoperative in vivo measurements to determine both the applied force and the resulting motion in three dimensional space. The proposed setup combines force measurement with an instrumented distractor and motion tracking with an optoelectronic system. As the orientation of the applied force and the three dimensional motion is known, not only force-displacement, but also moment-angle relations could be determined. The validation was performed using three cadaveric lumbar ovine spines. The lateral bending stiffness of two motion segments per specimen was determined with the proposed concept and compared with the stiffness acquired on a spinal loading simulator which was considered to be gold standard. The mean values of the stiffness computed with the proposed concept were within a range of ±15% compared to data obtained with the spinal loading simulator under applied loads of less than 5 Nm.

[Sarcomas and mixed mesodermal tumors of the uterus]

Malignant mesodermal tumors of the uterus are an inhomogenous group of uterine malignancies with different pathogenesis, clinical presentation and prognosis. These rare tumors represent approximately 1 % of all uterine malignancies. The aggressive carcinosarcomas or mixed muellerian tumors are defined by mixed malignant epithelial and malignant mesodermal histopathology and are of the same precursor cell origin like endometrial cancer. Thus, carcinosarcomas were reclassified by the FIGO as an aggressive type of endometrial cancer and treated like type II endometrial cancer. Adenosarcomas are also mixed tumors with benign epithelial proliferation and malignant mesodermal cell growth, have a good prognosis and represent less than 5 % of all mesodermal uterine malignancies. Besides carcinosarcomas, the pure mesodermal leiomyosarcomas are the most common mesodermal malignancies. Patients with leiomyosarcamos are usually perimenopausal, and although more than half of the patients present with symptoms, diagnosis occurs incidentally in most cases in final histopathologic workup of an excised putative myoma or uterus. Adequate anamnesis, gynecologic examination and careful imaging by transvaginal ultrasound in the preoperative setting might hint to correct differential diagnosis in many cases. Overall the prognosis of uterine leiomyomas is poor. Malignancies of the endometrial stroma are very rare and divided in two subgroups, the mostly estrogen receptor positive endometrial stromal sarcoma, which occur preferably in premenopausal women and show a favorable prognosis, and the very aggressive undifferentiated endometrial sarcomas. The more rare undifferentiated endometrial sarcomas occur in postmenopausal women and most patients die in the first two years after diagnosis. Risk stratification of preoperative differential diagnosis requires improvements and the correct histopathologic workup of mesodermal uterine malignancies is still a challenge for pathologists.

Tumor budding cells, cancer stem cells and epithelial-mesenchymal transition-type cells in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a 5-year survival rate of less than 5%. Moreover, PDAC escapes early detection and resists treatment. Multiple combinations of genetic alterations are known to occur in PDAC including mutational activation of KRAS, inactivation of p16/CDKN2A and SMAD4 (DPC4) and dysregulation of PTEN/PI3K/AKT signaling. Through their interaction with Wingless-INT pathway, the downstream molecules of these pathways have been implicated in the promotion of epithelial-mesenchymal transition (EMT). Emerging evidence has demonstrated that cancer stem cells (CSCs), small populations of which have been identified in PDAC, and EMT-type cells play critical roles in drug resistance, invasion, and metastasis in pancreatic cancer. EMT may be histologically represented by the presence of tumor budding which is described as the occurrence of single tumor cells or small clusters (<5) of dedifferentiated cells at the invasive front of gastrointestinal (including colorectal, oesophageal, gastric, and ampullary) carcinomas and is linked to poor prognosis. Tumor budding has recently been shown to occur frequently in PDAC and to be associated with adverse clinicopathological features and decreased disease-free and overall survival. The aim of this review is to present a short overview on the morphological and molecular aspects that underline the relationship between tumor budding cells, CSCs, and EMT-type cells in PDAC.

[Goiter and nodular thyroid disease: clinical guidelines for diagnosis and treatment. (Waiting? Hormone therapy? Surgery? radioiodine?)]

Nodular thyroid disease is a common problem. We present clinical guidelines for the management of patients with thyroid nodules, multinodular goiters and thyroid cysts for use by primary physicians. In the initial evaluation ultrasonography of the thyroid and fine-needle aspiration biopsy (FNAB) is recommended. FNAB has become the cornerstone in the evaluation of solitary thyroid nodules, cysts and dominant nodules within multinodular goiters. If the procedure is done properly, it should have a false-negative rate of less than 5% and a false-positive rate of not more than 1%. Thyroid radionuclide scans are less frequently used in the initial evaluation of a nodular goiter. Surgery is the primary therapy for patients with nodular thyroid disease. Other available treatment options are radioiodine and TSH-suppression with thyroxine. The main indications for surgery in euthyroid patients with thyroid nodule or with nontoxic multinodular goiter are recently documented or suspected malignancy, compression of the trachea and esophagus, significant growth of the nodule, recurrence of a cyst after aspiration, neck discomfort and cosmetic concern.

[Autonomic neuropathy in somatization disorders]

AIM: We conducted a study to investigate whether patients with somatization disorder show abnormal values in autonomic testing, especially in the central baroreceptor sensitivity. PATIENTS AND METHODS: Seventy-one patients were included. All had a diagnosis of somatization disorder (ICD-10, F45.0). Psychometric testing was performed by means of validated questionnaires (STAI, STAXI, FPI, GBB, ADS, SOMS, SCL-90-R). Autonomic regulation was analyzed by international standards using frequency spectral calculation by fast Fourier transformation. Thereby 3 different groups were detected: 12 patients with a baroreceptor sensitivity (BRS) of less than 3.0 ms/mm Hg, 20 patients with normal BRS (> 9.0 ms/mm Hg), and an in-between group (n = 39) with intermediate BRS. Controlling for age, a covariance analysis was calculated. RESULTS: The two extreme groups showed no difference in psychometric testing. However, significant differences were discernible in spectral values of mid-frequency-band (p < 0.05) in a covariance analysis with age as covariate. Equally the 24 h blood pressure determination showed significantly higher values for the group with BRS < 3.0 ms/mm Hg (p < 0.05 to 0.001). CONCLUSIONS: In a high percentage (17 %) of patients diagnosed to have somatization disorder autonomic dysregulation becomes apparent and is accompanied by increased blood pressure. Therefore it doesn't seem accurate to overlook concomitant organic lesions in somatization disorders despite patients lacking overtly clinical signs but suffering from various unspecific symptoms.

Effects of Carnoy's solution on blood vessels of the axillary fossa of rats

Carnoy's solution is applied to reduce the recurrence of odontogenic keratocysts and unicystic ameloblastomas. The deleterious action of this fixative on nerves has been studied but no attention has been paid to its effects on nearby vessels. The aim of this study was to investigate the effects of Carnoy's solution on blood vessels. The rat axillary artery and vein were surgically exposed, soaked with Carnoy's solution and kept in place for 2, 5 or 10 min, depending on the treatment group. The 5-min group was followed for 1, 2 and 3 weeks postoperatively. The vessels in the 2-min and 5-min exposure groups showed histological changes to the vessels, represented by focal loss of the endothelium and hyalinization of the wall. These alterations increased in the 10-min group. The vessels in the 3-week observation period revealed signs of recovery. It is concluded that Carnoy's solution can damage blood vessels but the process is reversible for exposure times less than 5 min.

Extracorporeal shock wave lithotripsy for distal ureteral calculi: what a powerful machine can achieve

PURPOSE: We assessed the efficacy of extracorporeal shock wave lithotripsy (ESWL, Dornier Medical Systems, Inc., Marietta, Georgia) for distal ureteral calculi with the HM3 (Dornier Medical Systems, Inc.) lithotriptor. MATERIALS AND METHODS: A total of 585 consecutive patients with distal ureteral calculi were treated with ESWL using an unmodified HM3 lithotriptor. Of these patients 67 referred for treatment only for whom no followup was available were excluded from further analysis. The remaining 518 cases were followed until they were radiologically documented to be stone-free or considered treatment failures. Before ESWL additional procedures were performed in 144 patients, including stone push back, ureteral catheter or Double-J (Medical Engineering Corp., New York, New York) stent placement, percutaneous nephrostomy, ureteral endoscopic maneuvers or stone basket manipulation. A total of 374 patients needed no preliminary treatment before ESWL. RESULTS: Of the 518 patients 469 (91%) were successfully treated with 1 ESWL session, while 49 (9%) needed 2 or 3. Manipulation after ESWL was performed in 22 cases, including stent placement, percutaneous nephrostomy, ureteral endoscopic stone removal and a stone basket procedure. On day 1 after ESWL 327 patients (63%) were stone-free, 158 (30%) had less than 5 mm. fragments and 33 (7%) had more than 5 mm. fragments. At 3 months the stone-free rate increased to 97%. CONCLUSIONS: These data show that ESWL for distal ureteral calculi with the powerful unmodified HM3 lithotriptor has a high success rate with a low rate of minimally traumatic manipulations before and after intervention. Results in terms of the re-treatment and stone-free rates are superior to those of any other second or third generation lithotriptor and comparable to the results of the best ureteroscopic series.

Anatomical characteristics and dimensions of edentulous sites in the posterior maxillae of patients referred for implant therapy

The purpose of this study was to analyze the width and height of edentulous sites in the posterior maxilla using cone beam computed tomography (CBCT) images from patients referred for implant therapy. A total of 122 CBCT scans were included in the analysis, resulting in a sample size of 252 edentulous sites. The orofacial crest width was measured in coronal slices, perpendicular to the alveolar ridge. The bone height was analyzed in the respective sagittal slices. Additionally, the following secondary outcome parameters were evaluated: the morphology of the sinus floor, the presence of septa in the maxillary sinus, and the thickness of the sinus membrane. The mean crest width for all analyzed sites was 8.28 mm, and the mean bone height was 7.22 mm. The percentage of patients with a crest width of less than 6 mm was 27% in premolar sites and 7.8% in molar sites. The bone height decreased from premolar to molar areas, with a high percentage of first and second molar sites exhibiting a bone height of less than 5 mm (54.12% and 44.64%, respectively). Regarding the morphology of the sinus floor, 53% of the edentulous sites exhibited a flat configuration. A septum was present in 67 edentulous sites (26.59%). Analysis of the sinus membrane revealed 88 sites (34.9%) with increased mucosal thickness (> 2 mm). For the crest width, the location of the edentulous site and the morphology of the sinus floor were both statistically significant variables. For the crest width and mean bone height, the location of the edentulous site and the morphology of the sinus floor were both statistically significant variables. The study confirmed that a high percentage of edentulous sites in the posterior maxilla do require sinus floor elevation to allow the placement of dental implants. Therefore, a detailed three-dimensional radiograph using CBCT is indicated in most patients for proper treatment planning.

Genetic of catecholaminergic polymorphic ventricular tachycardia: basic concepts.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac channelopathy characterized by altered intracellular calcium handling resulting in ventricular arrhythmias and high risk of cardiac sudden death in young cases with normal structural hearts. Patients present with exertional syncope and the trademark dysrhythmia is polymorphic and/or bidirectional ventricular tachycardia during exercise or adrenergic stimulation. Early detection of CPVT is crucial because opportune medical intervention prevents sudden cardiac death. Mutations in the ryanodine receptor RYR2 explain nearly 70% of the CPVT cases and cause the autosomic dominant form of the disease. Mutations in calsequestrin 2 causes a recessive form and explain less than 5% of all cases. Genetic screening in CPVT, besides providing early detection of asymptomatic carriers at risk, has provided important insights in the mechanism underlying the disease. Mutational analysis of RYR2 has been a challenge due to the large size of the gene, 105 exons encoded for 4,967 amino-acids. In this review we analyze general concepts of the disease, differential diagnosis and strategies for genetic screening.

3D Face Reconstruction from 2D Pictures: First Results of a Web-Based Computer Aided System for Aesthetic Procedures

The human face is a vital component of our identity and many people undergo medical aesthetics procedures in order to achieve an ideal or desired look. However, communication between physician and patient is fundamental to understand the patient’s wishes and to achieve the desired results. To date, most plastic surgeons rely on either “free hand” 2D drawings on picture printouts or computerized picture morphing. Alternatively, hardware dependent solutions allow facial shapes to be created and planned in 3D, but they are usually expensive or complex to handle. To offer a simple and hardware independent solution, we propose a web-based application that uses 3 standard 2D pictures to create a 3D representation of the patient’s face on which facial aesthetic procedures such as filling, skin clearing or rejuvenation, and rhinoplasty are planned in 3D. The proposed application couples a set of well-established methods together in a novel manner to optimize 3D reconstructions for clinical use. Face reconstructions performed with the application were evaluated by two plastic surgeons and also compared to ground truth data. Results showed the application can provide accurate 3D face representations to be used in clinics (within an average of 2 mm error) in less than 5 min.

REE and Hf distribution among mineral phases in the CV-CK clan : a way to explain present-day Hf isotopic variations in chondrites

Chondrites are among the most primitive objects in the Solar System and constitute the main building blocks of telluric planets. Among the radiochronometers currently used for dating geological events, Sm–Nd and Lu–Hf are both composed of refractory, lithophile element. They are thought to behave similarly as the parent elements (Sm and Lu) are generally less incompatible than the daughter elements (Nd and Hf) during geological processes. As such, their respective average isotopic compositions for the solar system should be well defined by the average of chondrites, called Chondritic Uniform Reservoir (CHUR). However, while the Sm–Nd isotopic system shows an actual spread of less than 4% in the average chondritic record, the Lu–Hf system shows a larger variation range of 28% [Bouvier A., Vervoort J. D. and Patchett P. J. (2008) The Lu–Hf and Sm–Nd isotopic composition of CHUR: Constraints from unequilibrated chondrites and implications for the bulk composition of terrestrial planets. Earth Planet. Sci. Lett.273, 48–57]. To better understand the contrast between Sm–Nd and Lu–Hf systems, the REE and Hf distribution among mineral phases during metamorphism of Karoonda (CK) and Vigarano-type (CV) carbonaceous chondrites has been examined. Mineral modes were determined from elemental mapping on a set of five CK chondrites (from types 3–6) and one CV3 chondrite. Trace-element patterns are obtained for the first time in all the chondrite-forming minerals of a given class (CK chondrites) as well as one CV3 sample. This study reveals that REE are distributed among both phosphates and silicates. Only 30–50% of Sm and Nd are stored in phosphates (at least in chondrites types 3–5); as such, they are not mobilized during early stages of metamorphism. The remaining fraction of Sm and Nd is distributed among the same mineral phases; these elements are therefore not decoupled during metamorphism. Of the whole-rock total of Lu, the fraction held in phosphate decreases significantly as the degree of metamorphism increases (30% for types 3 and 4, less than 5% in type 6). In contrast to Lu, Hf is mainly hosted by silicates with little contribution from phosphates throughout the CK metamorphic sequence. A significant part of Sm and Nd are stored in phosphates in types 3–5, and these elements behave similarly during CK chondrite metamorphism. That explains the robustness of the Sm/Nd ratios in chondrites through metamorphism, and the slight discrepancies observed in the present-day isotopic Nd values in chondrites. On the contrary, Lu and Hf are borne by several different minerals and consequently they are redistributed during metamorphism–induced recrystallization. The Lu/Hf ratios are therefore significantly disturbed during chondrites metamorphism, leading to the high discrepancies observed in present-day Hf isotopic values in chondrites.

Differentiation between Staphylococcus aureus and coagulase-negative Staphylococcus species by real-time PCR including detection of methicillin resistants in comparison to conventional microbiology testing.

BACKGROUND Staphylococcus aureus has long been recognized as a major pathogen. Methicillin-resistant strains of S. aureus (MRSA) and methicillin-resistant strains of S. epidermidis (MRSE) are among the most prevalent multiresistant pathogens worldwide, frequently causing nosocomial and community-acquired infections. METHODS In the present pilot study, we tested a polymerase chain reaction (PCR) method to quickly differentiate Staphylococci and identify the mecA gene in a clinical setting. RESULTS Compared to the conventional microbiology testing the real-time PCR assay had a higher detection rate for both S. aureus and coagulase-negative Staphylococci (CoNS; 55 vs. 32 for S. aureus and 63 vs. 24 for CoNS). Hands-on time preparing DNA, carrying out the PCR, and evaluating results was less than 5 h. CONCLUSIONS The assay is largely automated, easy to adapt, and has been shown to be rapid and reliable. Fast detection and differentiation of S. aureus, CoNS, and the mecA gene by means of this real-time PCR protocol may help expedite therapeutic decision-making and enable earlier adequate antibiotic treatment.