Does preoperative symptom classification impact prognosis in patients with clinically localized upper-tract urothelial carcinoma managed by radical nephroureterectomy?

ObjectivesTo evaluate if preoperative symptom classification could refine prediction of outcomes for patients with clinically localized upper-tract urothelial carcinoma (UTUC) managed by radical nephroureterectomy (RNU).MethodsData on 654 patients with localized UTUC who underwent RNU were reviewed. Preoperative symptoms were classified as incidental (S1), local (S2), and systemic (S3). Clinical and pathologic data were compared between the cohorts. Kaplan-Meier analyses and Cox proportional hazard modeling were used to determine recurrence-free and cancer-specific survival amongst the symptom cohorts.ResultsSymptom classification was S1 in 213 (33%) patients, S2 in 402 (61%), and S3 in 39 (6%). S3 symptoms were associated with advanced pathology, including higher stage, grade, and lymph node (LN) positivity. Five and 10-year recurrence-free and cancer-specific survival estimates were similar for patients with S1 and S2 symptoms (P = 0.75 and 0.58, respectively), but was worse for patients with S3 symptoms (P < 0.001 for both). On multivariate analysis adjusting for final pathologic stage, grade, and LN status, S3 symptoms were not an independent predictor of recurrence (HR 1.44, P = 0.19) or death due to disease (HR 1.66, P = 0.07). Addition of symptom classification, however, increased the accuracy of a model consisting of stage, grade, and LNs for prediction of recurrence-free and cancer-specific survival by 1.4% and 1.3%, respectively (P < 0.001 for both).ConclusionsLocal symptoms do not confer worse prognosis compared with patients with incidentally detected UTUC. However, systemic symptoms are associated with worse outcomes despite apparently effective RNU. Patients with systemic symptoms may harbor micrometastatic disease and could potentially benefit from a more rigorous metastatic evaluation or perioperative chemotherapy regimens.     

Absorbing Boundary Conditions for Solving N-Dimensional Stationary Schrödinger Equations with Unbounded Potentials and Nonlinearities

We propose a hierarchy of novel absorbing boundary conditions for the one-dimensional stationary Schrödinger equation with general (linear and nonlinear) potential. The accuracy of the new absorbing boundary conditions is investigated numerically for the computation of energies and ground-states for linear and nonlinear Schrödinger equations. It turns out that these absorbing boundary conditions and their variants lead to a higher accuracy than the usual Dirichlet boundary condition. Finally, we give the extension of these ABCs to N-dimensional stationary Schrödinger equations.     

Invasive Breast Cancer: Recognition of Molecular Subtypes

SUMMARY: Molecular profiling has fundamentally changed our understanding of breast cancer in the last 10 years, by creating a new taxonomy of breast cancers based on the expression patterns of so-called 'intrinsic genes'. Hierarchical clustering analyses performed on microarray-based gene expression profiles of breast cancers defined distinct breast cancer subgroups (luminal type A/B, HER2-enriched type, basal-like type). Since the initial landmark study by Perou et al., the concept of intrinsic breast cancer subtypes has been corroborated and expanded by several independent research groups. Further studies revealed individual properties of the intrinsic subgroups regarding the clinical course and the responsiveness to chemotherapy. The new gene expression profile-based taxonomy of breast cancer has been enthusiastically embraced by the scientific community and hailed as a major breakthrough on the way to individually tailored therapies. However, validation of the gene signatures in prospective studies is necessary before accepting these new technologies in daily clinical practice. In this review, the current data regarding the intrinsic subtypes and the associated clinical implications as well as the methodology of molecular profiling and possible use of immunohistochemistry in identifying intrinsic subtypes are discussed.     

Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells

OBJECTIVE

Type 2 diabetes is a complex disease that is accompanied by elevated levels of nonesterified fatty acids (NEFAs), which contribute to β-cell dysfunction and β-cell loss, referred to as lipotoxicity. Experimental evidence suggests that oxidative stress is involved in lipotoxicity. In this study, we analyzed the molecular mechanisms of reactive oxygen species-mediated lipotoxicity in insulin-producing RINm5F cells and INS-1E cells as well as in primary rat islet cells.

RESEARCH DESIGN AND METHODS

The toxicity of saturated NEFAs with different chain lengths upon insulin-producing cells was determined by MTT and propidium iodide (PI) viability assays. Catalase or superoxide dismutase overexpressing cells were used to analyze the nature and the cellular compartment of reactive oxygen species formation. With the new H₂O₂-sensitive fluorescent protein HyPer H₂O₂ formation induced by exposure to palmitic acid was determined.

RESULTS

Only long-chain (>C14) saturated NEFAs were toxic to insulin-producing cells. Overexpression of catalase in the peroxisomes and in the cytosol, but not in the mitochondria, significantly reduced H₂O₂ formation and protected the cells against palmitic acid-induced toxicity. With the HyPer protein, H₂O₂ generation was directly detectable in the peroxisomes of RINm5F and INS-1E insulin-producing cells as well as in primary rat islet cells.

CONCLUSIONS

The results demonstrate that H₂O₂ formation in the peroxisomes rather than in the mitochondria are responsible for NEFA-induced toxicity. Therefore, we propose a new concept of fatty acid-induced β-cell lipotoxicity mediated via reactive oxygen species formation through peroxisomal β- oxidation.Type 2 diabetes is a complex metabolic syndrome characterized by peripheral insulin resistance and pancreatic β-cell dysfunction (1,2), resulting in defective glucose-induced insulin secretion (3–5) and β-cell dysfunction and loss through apoptosis (6–8). Obesity and the metabolic syndrome typically precede diabetes manifestation, which is accompanied by elevated levels of nonesterified fatty acids (NEFAs) (9). NEFA elevation can suppress insulin secretion and cause β-cell dysfunction, which may ultimately lead to β-cell loss, a phenomenon referred to as lipotoxicity (10,11).Saturated long-chain fatty acids are toxic to primary β-cells and insulin-producing cell lines (12,13). However, the molecular mechanisms underlying lipotoxicity are only partially understood (14,15). Recent evidence suggested that lipotoxic β-cell damage is accompanied by endoplasmic reticulum (ER) stress and calcium depletion in the ER, ultimately leading to β-cell apoptosis via caspase activation (16). On the other hand, the fact that nonmetabolizable methylated fatty acids are nontoxic and induce little or no ER stress provides an indication for the necessity of fatty acid metabolism to the toxic action (15,17). In 2008, Lai et al. (18) showed that overexpression of the ER chaperone Bip could not protect against palmitic acid-induced toxicity, supporting the argument against ER stress as the main molecular mechanism of lipotoxicity.NEFA catabolism via mitochondrial β-oxidation is an important source of energy for pancreatic β-cells (19–21). It has been proposed that increased β-oxidation and oxidative phosphorylation cause lipotoxicity by enhancing formation of reactive oxygen species (ROS) in the mitochondria (15). Superoxide radicals are generated at complexes I and III of the respiratory chain (22) and can give rise to toxic hydrogen peroxide (H₂O₂) and hydroxyl radicals (23,24). Interestingly, some studies have suggested that mitochondrial β-oxidation can be protective, whereas inhibition of β-oxidation increases lipotoxicity (25,26). However, neither concept fully explains the molecular mechanism of lipotoxicity.Herein, we provide experimental evidence in support of an entirely new concept of NEFA-induced β-cell lipotoxicity based on peroxisomal metabolism of NEFAs. Long-chain NEFAs, such as palmitic and stearic acid, can be metabolized through β-oxidation in the peroxisomes as well as in the mitochondria (27,28). In contrast to mitochondrial β-oxidation, the acyl-CoA oxidases in the peroxisomes form H₂O₂ and not reducing equivalents (28). For H₂O₂ inactivation, the oxidoreductase catalase is typically expressed in peroxisomes (28). However, expression of H₂O₂-inactivating catalase is virtually absent in the peroxisomes of insulin-producing cells (29,30). This lack of a low-affinity, high-capacity H₂O₂-inactivating enzyme (29,30) impedes inactivation of peroxisome-generated H₂O₂, thereby increasing the vulnerability of pancreatic β-cells to ROS-mediated lipotoxicity (15,23).     

The fish-hook configuration of the distal ureter indicates bladder outlet obstruction due to benign prostatic hyperplasia

Purpose

The aim of this retrospective study was to evaluate in a historical series of patients whether morphological changes of the urinary tract imaged on intravenous urography (IVU) are associated with clinical or urodynamic data.

Methods

During a 1-year period, every man 45?years or older with lower urinary tract symptoms suggestive of benign prostatic hyperplasia was systematically evaluated with multi-channel computer-urodynamic investigation and IVU. Men with urinary retention, known bladder stones or diverticula, severely impaired renal function, or allergy to iodine contrast media were excluded. Structural alterations of the urinary tract were correlated with clinical and urodynamic data using logistic regression analysis.

Results

Data on 203 consecutive patients were available for analysis. Multivariate analysis demonstrated that the ??fish-hook?? configuration of the distal ureter (also known as ??hockey-stick??, or ??J-shaped?? ureter) was the only sign significantly associated with benign prostatic obstruction (BPO) (odds-ratio 3.64; 95% confidence interval 1.69?C7.83; P?Conclusions The ??fish-hook?? shape of the distal ureter(s) indicates BPO and may be a result of prostate median lobe enlargement.     

Perfusion measurements of the brain: using dynamic CT for the quantitative assessment of cerebral ischemia in acute stroke

Objective: Perfusion CT has been successfully used as a functional imaging technique for the differential diagnosis of patients with hyperacute stroke. We investigated to what extent this technique can also be used for the quantitative assessment of cerebral ischemia. Methods and material: We studied linearity, spatial resolution and noise behaviour of cerebral blood flow (CBF) determination with computer simulations and phantom measurements. Statistical ROI based analysis of CBF images of a subset of 38 patients from a controlled clinical stroke study with currently more than 75 patients was done to check the power of relative cerebral blood flow (rCBF) values to predict definite infarction and ischemic penumbra. Classification was performed using follow-up CT and MR data. Results: Absolute CBF values were systematically underestimated, the degree depended on the cardiac output of the patients. Phantom measurements and simulations indicated very good linearity allowing reliable calculation of rCBF values. Infarct and penumbra areas in 19 patients receiving standard heparin therapy had mean rCBF values of 0.19 and 0.62, respectively. The corresponding values for 19 patients receiving local intraarterial fibrinolysis were 0.18 and 0.57. The difference between infarct and penumbra values was highly significant (P<0.0001) in both groups. No penumbra area was found with an rCBF value of less than 0.20. While in the heparin group only 25% of all areas with an rCBF between 0.20 and 0.35 survived, in the fibrinolytic group 61% of these areas could be saved (P<0.05). Conclusion: Perfusion CT is a fast and practical technique for routine clinical application. It provides substantial and important additional information for the selection of the optimal treatment strategy for patients with hyperacute stroke. Relative values of cerebral blood flow discriminate very well between areas of reversible and irreversible ischemia; an rCBF value of 0.20 appears to be a definite lower limit for brain tissue to survive an ischemic injury.     

Progress of the treatment for extended aortic aneurysms; is the frozen elephant trunk technique the next standard in the treatment of complex aortic disease including the arch?

Patients with extensive aortic aneurysms involving the ascending aorta, aortic arch, and the descending aorta are still considered to be a challenge for many cardiovascular surgeons. The introduction of the elephant trunk technique by Borst et al. in 1983 has greatly facilitated surgery on this kind of pathology and this technique has been recognized as a standard modality for treatment of extended aortic aneurysms. As a next step, the frozen elephant trunk technique has been introduced in some institutes in the late 1990s. With this technique, surgery is performed through a median sternotomy, and an endovascular stent-graft is placed into the descending aorta in an antegrade fashion through the opened aortic arch. Then the ascending aorta and the aortic arch are replaced conventionally. The frozen elephant trunk technique enables one-stage repair of extended aortic aneurysms in a certain patient cohort with similar operative mortality as with the conventional elephant trunk technique, in which a second-stage operation is a prerequisite. Although the surgical strategy should be adjusted specifically to each patient's individual pathology, the frozen elephant trunk technique may become the next standard treatment for extended aortic aneurysm instead of its conventional variant.