Plasma miRNA-based signatures in CRC screening programs

Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT-positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real-time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low-grade adenoma [LgA], high-grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two-miRNA-based signature for CL and six-miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607–0.682), 0.670 (0.626–0.714) and 0.682 (0.580–0.785) for LgA, HgA and CL, respectively. A miRNA-based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.     

Evaluation of <i>MGMT</i> Gene Methylation in Neuroendocrine Neoplasms

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O6 -methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high-resolution, next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in welldifferentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs.     

Histological and biological developmental characterization of the human cerebellar cortex

The aim of this study was to investigate the histological and biological features of the human cerebellar cortex development and differentiation. We analyzed 52 brains of fetal and infant death victims, aged from 17 gestational weeks to 12th postnatal month. In particular, in the cerebellar cortex at different ages we evaluated, besides the structural aspects, the expression of several biomarkers implicated in proliferative processes (c-fos, PCNA and apoptosis). We observed morphological patterns progressively evolving every month, from the indefinite structure of the second gestational trimester to the four-layered structure (external granular layer, molecular layer, Purkinje cell layer, internal granular layer) of the late fetal cortex and subsequently to the three-layered postnatal definitive morphology, due to involution of the external granular layer. The evaluation of the biological features of the cerebellar cortex showed high proliferative activity mainly confined to the transient external granular layer in prenatal life, and high apoptotic index after birth. Thus, the histological examination, better with the support of biomarker investigations, allows with accuracy to describe the dynamic sequence of steps that occur in human cerebellar cortex development and to establish in each case the age, namely the pre- or postnatal month of life. Consequently, we can diagnose delayed or altered processes of differentiation during the development of the human cerebellar cortex.     

Short-term complications and resource utilization in matched subjects after on-pump or off-pump primary isolated coronary artery bypass.

BACKGROUND: Studies suggest that patients who undergo off-pump coronary artery bypass grafting (OPCABG) have fewer short-term complications and use fewer inpatient resources than do patients who undergo standard coronary artery bypass grafting (CABG) with extracorporeal circulation. However, dissimilarity between groups in risk factors for complications has hindered interpretation of results. OBJECTIVES: To compare the prevalence of selected complications (atrial fibrillation, stroke, reoperation, and bleeding) and inpatient resource utilization (length of stay, discharge disposition, total charges) between subjects undergoing primary isolated CABG or OPCABG who were matched with respect to key risk factors. METHODS: Retrospective, causal-comparative survey conducted in 1 center for 18 months. Patients who underwent primary isolated CABG or OPCABG were matched for sex, age (within 2 years), left ventricular ejection fraction (within 0.05), and graft-patient ratio (exact match) and compared for prevalence of new-onset atrial fibrillation, stroke, reoperation within 24 hours, and bleeding. Statistical analysis included Wilcoxon and t tests for paired comparisons. RESULTS: The sample (107 matched pairs) was 63% male, with a mean age of 66 (SD 9.5) years, a mean left ventricular ejection fraction of 0.51 (SD 0.13), and a mean graft-patient ratio of 3.41 (SD 0.74). The 2 groups did not differ significantly in New York Heart Association class (P = .43), Acute Physiology and Chronic Health Evaluation III score (P = .22), postoperative beta-blocker use (P = .73), or comorbid conditions. None of the complications examined differed significantly between pairs. CONCLUSION: Patients with comparable risk profiles have similar prevalences of selected complications after CABG and OPCABG.     

The radiation dose to the lens in radiology of the orbit

This paper describes research into measurement and reduction of the radiation dose to the lens during various examinations, namely skull and orbit, optic canal and optic strut, superior and inferior orbital fissure, localisation of foreign bodies in the eye, calcifications, orbital fractures, macrodacryography and orbital venography. Using rare-earth screens and high-sensitivity films, without an antiscattering grid, and with an added filtration of 0.5 mm Cu, it is possible to reduce the radiological risk during all investigations involving skull, orbit and eyeballs, while maintaining a good image quality. Particularly in those examinations with direct magnification (macrodacryography and venography, foreign bodies in the eye, orbital fractures), the dose to the lens is very low: less than 0.2 mGy/radiograph.     

Subretinal neovascularisation and snow banking in a case of sarcoidosis: case report.

A 49-year-old Japanese man presented with chronic granulomatous uveitis in his left eye. Later he developed macular subretinal neovascularisation. The chest x-ray showed bilateral hilar lymphadenopathy. Bronchoscopy and gallium-67 scanning were positive, PPD skin test negative, and serum angiotensin converting enzyme (ACE) levels increased. Ophthalmoscopy and fluorescein angiography of the left eye showed perivasculitis, retinochoroidal exudates, snow banking, and vitreous opacity. On these findings, the diagnosis of sarcoidosis was made. Treatment was based on topical corticosteroids, mydriatics, beta blockers, and oral carbonic anhydrase inhibitors. After 15 months the visual acuity decreased in the left eye, and a neovascular membrane was observed in the macula. Fluorescein angiography confirmed subretinal neovascularisation. Almost two years later the patient still has the neovascular membrane in his left eye.     

Ultrasound-determined fetal subcutaneous tissue thickness for a birthweight prediction model

AIM: The aim of this study was to explore a birthweight prediction model using ultrasound determined tissue thickness (SCTT) parameters. METHODS: We measured routine ultrasonographic biometric parameters and in addition, fetal SCTT in 201 healthy singleton pregnancies. Mid-arm fat and lean mass, mid-thigh fat and lean mass, subscapular fat mass and abdominal fat mass (AFM) were measured in order to calculate a birthweight prediction model. Ultrasound measurements were analyzed using an 'anovarepeated measures model'. The growth rate (beta-slope) of the selected parameters was computed and the correlation coefficient with the birthweight and the Kendall rank correlation tau, were calculated. RESULTS: From the ultrasound determined SCTT parameters, only abdominal circumference (AC), AFM, and MTLM showed a statistically significant trend. The beta-slope of mid-thigh lean mass was excluded since it exhibited significant correlation with the beta-slope of AFM. The final regression model could be calculated as: birthweight (gr.) = intercept +alpha(1)(AFM beta-slope) + alpha(2)(AC beta-slope), where alpha(1), alpha(2) represent regression coefficients. CONCLUSIONS: We provide a graphical birthweight prediction model for clinical practice using conventional and specific ultrasound measurements of fetal subcutaneous tissue thickness. This model is based upon an overall analysis of the ultrasound estimated body components.     

The risk of pneumonectomy over the age of 70. A case-control study.

OBJECTIVE: A higher mortality has been reported after pneumonectomy over the age of 70. The aim of the study was to quantify the additional risk due to age after standard pneumonectomy for lung cancer by a case-control study. METHODS: Our clinical database was reviewed to search for patients aged 70 years or more who underwent standard pneumonectomy for lung cancer between 1998 and 2005. A control group of patients younger than 70 (one case/two controls) was matched for sex, cardiovascular disease, American Association of Anaesthetists score, respiratory function, side of pneumonectomy, induction chemotherapy and stage. Overall mortality and morbidity were compared. Long-term survival data were also analysed. RESULTS: During the considered period, 35 patients aged 70 years or more underwent pneumonectomy (30 males, median age 73 years, 15 right-sided procedures). The control group was composed of 70 patients. The two groups were homogeneous in the variables used for matching. Overall mortality and morbidity were 11.4 and 54.2% in the elderly group as compared to 4.3 and 41.6% in controls (p-value not significant). Elderly patients experienced a higher rate of respiratory complications (25.7%) as compared to controls (8.3%, p=0.01). At univariate analysis, the only risk factor for death was the occurrence of respiratory complications (OR 6.5, CI 1.8-18.2). At multivariate analysis, age >or=70 years (OR 5.36, CI 1.48-19.3) and preoperative chemotherapy (OR 7.65, CI 2.04-28.6) were confirmed as predictors of respiratory complications. Five-year survival was 17.5% in the elderly group and 53.6% in the control group (p=0.003). Elderly patients with a better respiratory function (FEV1>70%) had a 5-year survival of 45.4%. CONCLUSIONS: In the elderly patients, the risk of respiratory complications after pneumonectomy is increased as compared to younger patients with equivalent respiratory function. Age and preoperative chemotherapy are independent risk factors for respiratory complications. A lower mortality and a better long-term survival are obtained in elderly patients with a better respiratory function (FEV1>or=70%).     

Bicarbon valve - European multicenter clinical evaluation

Objective: Fifteen collaborating centers in eight countries present their pooled experience with the new Bicarbon™ bileaflet valve. Methods: Between 4/90 and 4/96, 1351 patients, 806 males and 545 females, aged 10 to 83, mean 58.4±12.4, underwent valve implantation. Operations: AVR, 726; MVR, 475; DVR, 150. Additional procedures: CABG, 211; TV repair, 64; other, 152. Results: Mortality: 67 early (seven valve related) and 56 late (40 valve related). Valve thrombosis: six obstructive, three non-obstructive; embolism: nine major cerebral, 37 other. Major bleeding: 29. Hemolysis: two clinically significant. Non-structural dysfunction: 24 paravalvular leaks, one leaflet interference. No structural failure! Endocarditis: 24. Reoperation 48: 22 non-structural dysfunctions, 14 endocarditis, seven thrombosis and embolism, five other. Estimated 5-year freedom from valve-related deaths is 97.2% for AVR and 92.4% for MVR; 4-year freedom from valve related deaths for DVR is 90.5%. Mean calculated NYHA improvement is 1.24. Conclusions: The Bicarbon mechanical prosthesis is well designed, durable, has good hemodynamic features and an acceptably low incidence of complications.     

Thoracoscopic esophagomyotomy. Initial experience with a new approach for the treatment of achalasia.

The authors treated 17 patients with achalasia by a thoracoscopic (15 patients) or laparoscopic (2 patients) Heller myotomy. All patients had dysphagia and an upper gastrointestinal series demonstrating a dilated esophagus with a bird-beak deformity at the cardia. Manometry showed a mean lower esophageal sphincter (LES) pressure of 32 +/- 4 mmHg, incomplete sphincter relaxation on swallowing, and no primary esophageal peristalsis. After operation, mean LES pressure was 10 +/- 2 mmHg. Fifteen patients were fed on the second postoperative day. The average hospital stay was 3 days, and there were no deaths or major complications. In three early patients, the myotomy was not carried far enough onto the stomach, and dysphagia persisted until a second myotomy was performed (laparoscopically in two patients). The authors found that having an endoscope in the esophagus during the operation facilitated exposure and was vital to determine the appropriate length of the myotomy. With regard to dysphagia, final results were excellent in 12 patients (70%), good in two patients (12%), fair in two patients (12%), and poor in one patient (6%). Heller myotomy can be safely and reliably performed with minimally invasive techniques. Dysphagia is relieved, postoperative pain is minimal, hospital stay is short, and the patient can return quickly to normal activity.