Total intravenous anaesthesia with propofol and remifentanil is associated with reduction in operative time in surgery for glioblastoma when compared with inhalational anaesthesia with sevoflurane.

BACKGROUND: Total intravenous anaesthesia (TIVA) is emerging as a preferred neuroanaesthetic agent compared with inhalational anaesthetic (IA) agents. We asked if TIVA with propofol and remifentanil was associated with shorter operative times compared to IA using sevoflurane in brain tumour surgery under GA. METHODS: We performed a retrospective analysis of all patients undergoing surgery for glioblastoma (GBM). We assessed choice of GA agent (TIVA or IA) with total time patient was under GA (anaesthetic time), operative time and time taken to recover fully from GA (recovery time). RESULTS: Over a two year period 263 patients underwent surgery under GA for their GBM including 188 craniotomy operations, 63 burr hole biopsy procedures and 12 open biopsy procedures. Of these, 79 operations took place under TIVA and 184 operations under IA. TIVA was associated with significantly reduced mean operative time including time taken to wake up in theatre (104 min with TIVA, 129 min with IA; p = 0.02). TIVA was also associated with trends toward shorter mean recovery time (118 min, versus 135 min with IA; p = 0.08) and shorter mean anaesthetic time (163 min, versus 181 min with IA; p = 0.07). There was no difference between TIVA and IA groups as regards duration of inpatient stay, readmission rates, complications or survival. CONCLUSIONS: TIVA with propofol and remifentanil may reduce anaesthetic, operative and recovery times in patients undergoing surgery for their GBM. These findings may be attributable to favourable effects on intracranial pressure and cerebral perfusion, as well as rapid recovery from GA. In addition to clinical advantages, there may be financial and logistical benefits.

Modeling the mechanical stiffness of pancreatic ductal adenocarcinoma.

Despite improvements in the understanding of disease biology, pancreatic ductal adenocarcinoma (PDAC) remains the most malignant cancer of the pancreas. PDAC constitutes ∼95% of all pancreatic cancers, and it is highly resistant to therapeutics. The increased tissue rigidity, which stems from the rich fibrotic stroma in the tumor microenvironment, is central to disease development, physiology, and resistance to drug perfusion. Pancreatic stellate cells (PSCs) are responsible for overproduction of extracellular matrix in the fibrotic stroma, and this is exacerbated by the overexpression of transforming growth factor-ß (TGF-ß). However, there are few in vitro PDAC models, which include both PSCs and TGF-ß or mimic in vivo-like tumor stiffness. In this study, we present a three-dimensional in vitro PDAC model, which includes PSCs and TGF-ß, and recapitulates PDAC tissue mechanical stiffness. Using oscillatory shear rheology, we show the mechanical stiffness of the model is within range of the PDAC tissue stiffness by day 21 of culture and highlight that the matrix environment is essential to adequately capture PDAC disease. PDAC is a complex, aggressive disease with poor prognosis, and biophysically relevant in vitro PDAC models, which take into account tissue mechanics, will provide improved tumor models for effective therapeutic assessment.

Improvement of cognitive function in schizophrenia with N-acetylcysteine: A theoretical review.

Objectives: Schizophrenia is a debilitating psychiatric illness associated with positive and negative symptoms as well as significant impairments in cognition. Current antipsychotic medications do not alleviate these cognitive deficits, and more effective therapeutic options are required. Increased oxidative stress and altered antioxidant levels, including glutathione (GSH) have been observed both in individuals with cognitive impairment and in people with schizophrenia. A GSH precursor, the antioxidant N-acetylcysteine (NAC) has been investigated as a novel treatment for the cognitive symptoms of schizophrenia, and recent research suggests that NAC may be a promising adjunctive treatment option. However, the current literature lacks integration as to why NAC may effectively improve cognition in schizophrenia. The present theoretical synthesis aimed to address this gap by examining the processes by which NAC may improve cognitive function in schizophrenia. Methods: The schizophrenia literature was reviewed in three key domains: cognitive impairment, the relationship between oxidative stress and cognition, and the efficacy of NAC as a novel treatment. This led to a theoretical analysis of the neurobiological processes by which NAC may improve cognition in schizophrenia. Results: This theoretical review concluded that improved cognition may result from a combination of factors, including decreased oxidative stress, neuroprotection of cognitive networks and an increase in glutamatergic modulation of the N-methyl-d-aspartate receptor system. Whilst a number of mechanisms by which NAC may improve cognition and symptoms in schizophrenia have been proposed, there is still limited understanding of the specific metabolic pathways involved and how they interrelate and modify specific symptomology. Discussion: Exploration of how NAC treatment may act to improve cognitive function could guide clinical trials by investigation of the specific neurotransmitter systems and processes involved, allowing for targeted neurological outcome measures. Future research would benefit from the investigation of both in vivo cortical GSH concentration and peripheral plasma GSH in a population of individuals with chronic schizophrenia.

Colonic stenting for a malignant large bowel obstruction with pneumatosis coli to reduce surgical risk.

Patients with a malignant large bowel obstruction are often late in seeking medical attention and are usually in poor health by the time a complete blockage is apparent. Emergency surgery in this setting, particularly in a patient with significant comorbidities, often requires the creation of an ostomy and can result in postoperative complications that delay the administration of adjuvant chemotherapy. This recent case at our center illustrates how the use of a colon stent, as a bridge to surgery, can help patients avoid the need for a stoma and reduce surgical complications.

Assessing the Potential of Folded Globular Polyproteins As Hydrogel Building Blocks.

The native states of proteins generally have stable well-defined folded structures endowing these biomolecules with specific functionality and molecular recognition abilities. Here we explore the potential of using folded globular polyproteins as building blocks for hydrogels. Photochemically cross-linked hydrogels were produced from polyproteins containing either five domains of I27 ((I27)5), protein L ((pL)5), or a 1:1 blend of these proteins. SAXS analysis showed that (I27)5 exists as a single rod-like structure, while (pL)5 shows signatures of self-aggregation in solution. SANS measurements showed that both polyprotein hydrogels have a similar nanoscopic structure, with protein L hydrogels being formed from smaller and more compact clusters. The polyprotein hydrogels showed small energy dissipation in a load/unload cycle, which significantly increased when the hydrogels were formed in the unfolded state. This study demonstrates the use of folded proteins as building blocks in hydrogels, and highlights the potential versatility that can be offered in tuning the mechanical, structural, and functional properties of polyproteins.

Bowel management in spinal cord injury patients.

Spinal cord injuries are common in the United States, affecting approximately 12,000 people per year. Most of these patients lack normal bowel function. The pattern of dysfunction varies with the spinal level involved. Most patients use a bowel management program, and elements of successful programs are discussed. Surgical treatment, when indicated, could include sacral nerve stimulation, Malone antegrade continence enema, and colostomy.

Case Report: A case of hypertrophic lupus erythematosus with negative CD123 staining and absence of transepidermal elimination of elastin.

We report the case of a 49-year-old male with clinical and histological findings consistent with hypertrophic lupus erythematosus (HLE). HLE must be clinically and histologically differentiated from keratoacanthoma, hypertrophic lichen planus, squamous cell carcinoma and plaque type psoriasis. CD123 positivity and transepidermal elimination of elastin have recently been reported as tools to distinguish HLE. Interestingly, in this case, biopsies of two separate lesions failed to reveal these two features. The etiology of this discrepancy is unknown and further studies are needed to clarify the utility of CD123 positivity and transepidermal elimination of elastin in the diagnosis of hypertrophic lupus erythematosus.

Electrical stimulation for chronic non-specific low back pain in a working-age population: a 12-week double blinded randomized controlled trial.

BACKGROUND: Non-invasive electrotherapy is commonly used for treatment of chronic low back pain. Evidence for efficacy of most electrotherapy modalities is weak or lacking. This study aims to execute a high-quality, double-blinded randomized controlled clinical trial comparing 1) H-Wave(®) Device stimulation plus usual care with 2) transcutaneous electrical nerve stimulation (TENS) plus usual care, and 3) Sham electrotherapy plus usual care to determine comparative efficacy for treatment of chronic non-specific low back pain patients. PATIENTS: Chronic non-specific low back pain patients between ages of 18-65 years, with pain of at least 3 months duration and minimal current 5/10 VAS pain. Patients will have no significant signs or symptoms of lumbosacral nerve impingement, malignancy, spinal stenosis, or mood disorders. STUDY DESIGN: Double blind RCT with 3 arms and 38 subjects per arm. Randomization by permuted blocks of random length, stratified by Workers Compensation claim (yes vs. no), and use of opioids. The null hypothesis of this study is that there are no statistically significant differences in functional improvement between treatment types during and at the end of a 12-week week treatment period. DATA COLLECTION: Subjective data will be collected using Filemaker Pro™ database management collection tools. Objective data will be obtained through functional assessments. Data will be collected at enrollment and at 1, 4, 8, and 12 weeks for each participant by a blinded assessor. INTERVENTIONS: H-Wave(®) device stimulation (Intervention A) plus usual care, transcutaneous electrical nerve stimulation (TENS) (Intervention B) plus usual care, and sham electrotherapy plus usual care (control). Each treatment arm will have identical numbers of visits (4) and researcher contact time (approximately 15 hours). PRIMARY OUTCOME MEASURE: Oswestry Disability Index. Secondary measures include: Rowland Morris Instrument, VAS pain score, functional evaluation including strength when pushing and pulling, pain free range of motion in flexion and extension. Outcome measures assessed at baseline, 1, 4, 8, and 12 weeks. Treatment failure will be defined if patient terminates assigned treatment arm for non-efficacy or undergoes invasive procedure or other excluded cointerventions. Data will be analyzed using intention-to-treat analysis and adjusted for covariates related to LBP (e.g. age) as needed. DISCUSSION: Study strengths include complex randomization, treatment group allocation concealment, double blinding, controlling for co-interventions, rigorous inclusion criteria, assessment of compliance, plans for limiting dropout, identical assessment methods and timing for each treatment arm, and planned intention-to-treat analyses.

MOLECULAR BASIS OF HEREDITARY COLORECTAL CANCER.

Advances in molecular biology have defined the molecular basis for colorectal cancer (CRC). Though only a fraction of CRC has been determined to have a hereditary component, the discovery of genetic alterations in these clinical syndromes has permitted definition of similar discoveries in sporadic CRC. Here we will delineate the molecular basis for the most common of these defined syndromes, including familial adenomatous polyposis, hereditary non-polyposis colon cancer, MUTYH associated polyposis, Juvenile polyposis, Peutz-Jeghers syndrome, and Cowden's syndrome. The newest paradigm with implications for the pathogenesis of sporadic CRC is called the cancer stem cell hypothesis. As this paradigm also implicates aberrations in molecular pathways, a brief discussion of this hypothesis is included.

The role of sirolimus in the prevention of cutaneous squamous cell carcinoma in organ transplant recipients.

Skin cancers are common in organ transplant recipients (OTRs). In this review, we discuss the epidemiology of and risk factors for cutaneous neoplasms, particularly squamous cell carcinoma (SCC) in OTRs. The pathogenesis of SCC is reviewed, as well as the potential mechanisms for tumor progression and metastasis associated with two commonly used immunosuppressive medications: tacrolimus and cyclosporine. Finally, we discuss the mechanism of action and potential preventative use of sirolimus, a member of a newer class of immunosuppressants, the mammalian target of rapamycin inhibitors. The authors have indicated no significant interest with commercial supporters.

The predictive value of incidental PET/CT findings suspicious for breast cancer in women with non-breast malignancies.

BACKGROUND: On occasion, patients followed with positron emission tomographic (PET)/computed tomographic (CT) imaging for nonbreast malignancies will have incidental breast findings concerning for second primary breast cancers. The aim of this study was to determine the predictive value of PET/CT imaging to identify breast cancers in these patients. METHODS: Patients with primary nonbreast malignancies and findings concerning for second primary breast cancers were identified from a prospectively acquired nuclear medicine database from January 2005 to July 2008. Chart reviews were then performed. RESULTS: Nine hundred two women underwent PET/CT imaging to evaluate nonbreast malignancies. Nine women (1%) had concerning breast findings, and 5 (56%) had subsequent breast cancer diagnoses. The positive predictive value of PET/CT imaging in these patients was 63%. Evidence of compliance with current screening guidelines was present in only 22% of these patients. CONCLUSIONS: The data suggest that findings concerning for an additional primary breast cancer should be evaluated and that age-appropriate screening tools should not be abandoned.

Incidental PET/CT findings in the cancer patient: how should they be managed?

BACKGROUND: Despite a paucity of evidence-based guidelines, the use of PET/CT (positron emission tomography/computed tomography) in the management of cancer patients is increasing. As widespread clinical application increases, unexpected radiographic findings are occasionally identified. These incidental findings are often suspicious for a second primary malignancy. The purpose of this study was to determine the clinical impact of these incidental PET/CT findings. METHODS: A query of our prospectively acquired Nuclear Medicine database was performed to identify patients with a known malignancy being staged or serially imaged with PET/CT. Patients with incidental findings suggestive of a second primary malignancy were selected. Statistical analysis was performed to determine the ability of PET/CT to identify a second primary malignancy. All PET/CT were interpreted by board certified nuclear radiologists. RESULTS: Of 3,814 PET/CT scans performed on 2,219 cancer patients at our institution from January 1, 2005, to December 29, 2008, 272 patients (12% of all patients) had findings concerning for a second primary malignancy. An invasive work-up was performed on 49% (133/272) of these patients, while 15% (40/272) had no further evaluation due to an advanced primary malignancy. The remaining 36% (99/272) had no further evaluation secondary to a low clinical suspicion determined by the treating team, a clinical plan of observation, or patients lost to follow-up. Of the 133 patients evaluated further, clinicians identified a second primary malignancy in 41 patients (31%), benign disease in 62 patients (47%), and metastatic disease from their known malignancy in 30 patients (23%). The most common sites for a proven second primary malignancy were: lung (N = 10), breast (N = 7), and colon (N = 5). Investigation of these lesions was performed using several techniques, including 24 endoscopies (6 malignant). A surgical procedure was performed in 74 patients (29 malignant), and a percutaneous biopsy was performed on 34 patients (12 malignant). The overall positive predictive value for PET/CT to detect a second primary malignancy was 31% in this subgroup. At a median follow-up of 22 months, 9 of 41 patients with a second primary were dead of a malignancy, 20 were alive with disease, and 12 had no evidence of disease. CONCLUSION: Incidental PET/CT findings consistent with a second primary are occasionally encountered in cancer patients. In our data, approximately half of these findings were benign, a third were consistent with a second primary malignancy or a metastatic focus, and the remainder were never evaluated due to physician and patient decision. Advanced primary tumors are unlikely to be impacted by a second primary tumor suggesting that this subset of patients will not benefit from further investigation. Our data suggests that, despite the high rate of false positivity, incidental PET/CT findings should be investigated when the results will impact treatment algorithms. The timing and route of investigation should be dictated by clinical judgment and the status of the primary tumor. Further investigation will need to be performed to determine the long-term clinical impact of incidentally identified second primary malignancies.