MALDI imaging–based identification of prognostically relevant signals in bladder cancer using large-scale tissue microarrays

ObjectiveAlthough most patients with urinary bladder cancer present with noninvasive and low-malignant stages of the disease, about 20% eventually develop life-threatening metastatic tumors. This study was designed to evaluate the potential of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify molecular markers predicting the clinical course of bladder cancer.Materials and methodsWe employed MALDI-MSI to a bladder cancer tissue microarray including paraffin-embedded tissue samples from 697 patients with clinical follow-up data to search for prognostically relevant associations.ResultsAnalysis of our MALDI imaging data revealed 40 signals in the mass spectra (m/z signals) associated with epithelial structures. The presence of numerous m/z signals was statistically related to one or several phenotypical findings including tumor aggressiveness (stage, grade, or nodal status; 30 signals), solid (5 signals) or papillary (3 signals) growth patterns, and increased (6 signals) or decreased (12 signals) cell proliferation, as determined by Ki-67 immunohistochemistry. Two signals were linked with tumor recurrence in noninvasive (pTa category) tumors, of which one was also related to progression from pTa-category to pT1-category disease. The absence of one m/z signal was linked with decreased survival in the subset of 102 muscle-invasive cancers.ConclusionOur data demonstrate the suitability of combining MSI and large-scale tissue microarrays to simultaneously identify and validate clinically useful molecular markers in urinary bladder cancer.     

Safety and effectiveness of single- versus double-anastomosis duodenal switch at a single institution

Background

Biliopancreatic diversion with duodenal switch (DS) is known to be superior in weight loss to other bariatric procedures, but with the disadvantage of increased complication rates. Single-anastomosis duodenal-ileal bypass (SADI-S) is reported to have similar weight loss with lower complication rates compared with traditional DS.

Pathophysiology of interstitial cystitis

Interstitial cystitis/bladder pain syndrome is a chronic pain syndrome whose causes remains elusive with no generally accepted treatment. A hallmark of functional pain syndromes such as interstitial cystitis/bladder pain syndrome is pain in the absence of demonstrable pathology of the viscera or associated nerves. Patients with chronic pain experience a greater impairment in quality of life than healthy controls. In addition, interstitial cystitis/bladder pain syndrome symptoms can frequently overlap with other conditions including irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, anxiety disorders, and a number of other syndromes not directly related to the urinary bladder. Because of the complex pathophysiology, a number of animal models have been studied over the years to better understand mechanisms underlying patient symptoms. These models can include: bladder centric, complex mechanisms and psychological and physical stress models. Such animal models can aid in the investigation of aspects of interstitial cystitis/bladder pain syndrome that cannot be pursued in humans as well as to develop and test potential therapies. In addition, the search for urinary factors that may be a cause of interstitial cystitis/bladder pain syndrome has resulted in the discovery of a number of potential targets that could serve as predictive biomarkers which can aid in early diagnosis and treatment of this chronic disorder.     

The role of biomechanics and inflammation in cartilage injury and repair

Osteoarthritis is a painful and debilitating disease characterized by progressive degenerative changes in the articular cartilage and other joint tissues. Biomechanical factors play a critical role in the initiation and progression of this disease, as evidenced by clinical and animal studies of alterations in the mechanical environment of the joint caused by trauma, joint instability, disuse, or obesity. The onset of these changes after joint injury generally has been termed posttraumatic arthritis and can be accelerated by factors such as a displaced articular fracture. Within this context, there is considerable evidence that interactions between biomechanical factors and proinflammatory mediators are involved in the progression of cartilage degeneration in posttraumatic arthritis. In vivo studies have shown increased concentrations of inflammatory cytokines and mediators in the joint in mechanically induced models of osteoarthritis. In vitro explant studies confirm that mechanical load is a potent regulator of matrix metabolism, cell viability, and the production of proinflammatory mediators such as nitric oxide and prostaglandin E2. Knowledge of the interaction of inflammatory and biomechanical factors in regulating cartilage metabolism would be beneficial to an understanding of the etiopathogenesis of posttraumatic osteoarthritis and in the improvement of therapies for joint injury.     

Inflammatory mediators and growth factors in obstructive renal injury

Obstruction of the upper urinary tract poses a significant clinical challenge to the urologist, and the cascade of renal cellular and molecular events triggered by upper urinary tract obstruction result in a progressive, and eventually permanent, loss in renal function. These pathological changes include the development of renal fibrosis, tubular atrophy, interstitial inflammation, and apoptotic renal cell death. A myriad of cytokines and growth factors have been identified as major contributors to obstruction-induced renal fibrosis and apoptotic cell death, including transforming growth factor-beta1, angiotensin II, nuclear factor-kappaB, and tumor necrosis factor-alpha. This review examines the role of these mediators in obstruction-induced renal injury.     

Comparison of two superparamagnetic viral-sized iron oxide particles ferumoxides and ferumoxtran-10 with a gadolinium chelate in imaging intracranial tumors

BACKGROUND AND PURPOSE: Ultrasmall superparamagnetic iron oxide particles result in shortening of T1 and T2 relaxation time constants and can be used as MR contrast agents. We tested four hypotheses by evaluating MR images of intracranial tumors after infusion of two iron oxide agents in comparison with a gadolinium chelate: 1) Ferumoxtran in contrast to ferumoxides can be used as an intravenous MR contrast agent in intracranial tumors; 2) ferumoxtran enhancement, albeit delayed, is similar to gadolinium enhancement; 3) ferumoxtran-enhanced MR images in contrast to gadolinium-enhanced MR images may be compared with histologic specimens showing the cellular location of iron oxide particles; 4) ferumoxtran can serve as a model for viral vector delivery. METHODS: In 20 patients, ferumoxides and ferumoxtran were intravenously administered at recommended clinical doses. MR imaging was performed 30 minutes and 4 hours after ferumoxides infusion (n = 3), whereas ferumoxtran-enhanced MR imaging (n = 17) was performed 6 and 24 hours after infusion in the first five patients and 24 hours after infusion in the remaining 12. MR sequences were spin-echo (SE) T1-weighted, fast SE T2- and proton density-weighted, gradient-recalled-echo T2*-weighted, and, in four cases, echo-planar T2-weighted sequences. Representative regions of interest were chosen on pre- and postcontrast images to compare each sequence and signal intensity. RESULTS: Despite some degree of gadolinium enhancement in all tumors, no significant T1 or T2 signal intensity changes were seen after ferumoxides administration at either examination time. Fifteen of 17 patients given ferumoxtrans had T1 and/or T2 shortening consistent with iron penetration into tumor. Histologic examination revealed minimal iron staining of the tumor with strong staining at the periphery of the tumors. CONCLUSION: 1) Ferumoxtran can be used as an intravenous MR contrast agent in intracranial tumors, mostly malignant tumors. 2) Enhancement with ferumoxtran is comparable to but more variable than that with the gadolinium chelate. 3) Histologic examination showed a distribution of ferumoxtran particles similar to that on MR images, but at histology the cellular uptake was primarily by parenchymal cells at the tumor margin. 4) Ferumoxtran may be used as a model for viral vector delivery in malignant brain tumors.     

Sleep disorders in patients with postural tachycardia syndrome

Objective

Patients with postural tachycardia syndrome (POTS) often describe symptoms of fatigue, sleepiness, and lack of refreshing sleep. We aimed to provide further objective measures of sleep in patients with POTS.

Methods

POTS patients (n = 18) were selected based on autonomic testing and evaluation at our center. Controls (n = 16) of similar age, gender, and BMI were selected from new patients referred to the Stanford Sleep Disorders Clinic for any sleep-related complaint. All patients underwent polysomnography and completed several sleep questionnaires and a 2-week sleep diary.

Results

POTS patients and control subjects were of similar age (27 ± 10.2 vs. 29 ± 5.4 years, p = 0.92) and Body Mass Index (21 ± 3.8 vs. 24 ± 4.1, p = 0.14). The majority of subjects in both groups were females (72 % POTS vs. 81 % controls). POTS patients scored higher on subjective fatigue scales but not sleepiness scales. POTS patients scored in the normal range on the BDI and the “evening” category on the MEQ. Their sleep diaries were not different from controls. With the exception of mild OSA, slightly reduced %REM and prolonged REM latency, their PSG data were normal and no different from controls.

Conclusions

It is unlikely that the sleep-related complaints of POTS patients are the result of a primary sleep disorder unique to POTS. We propose that a combination of factors such as body fatigue, chronic pain, and other somatic symptoms common in POTS patients might be the underlying reason for sleep-related symptoms in POTS.