Traumatic brain injury imaging research roadmap.

The past decade has seen impressive advances in the types of neuroimaging information that can be acquired in patients with traumatic brain injury. However, despite this increase in information, understanding of the contribution of this information to prognostic accuracy and treatment pathways for patients is limited. Available techniques often allow us to infer the presence of microscopic changes indicative of alterations in physiology and function in brain tissue. However, because histologic confirmation is typically lacking, conclusions reached by using these techniques remain solely inferential in almost all cases. Hence, a need exists for validation of these techniques by using data from large population samples that are obtained in a uniform manner, analyzed according to well-accepted procedures, and correlated with closely monitored clinical outcomes. At present, many of these approaches remain confined to population-based research rather than diagnosis at an individual level, particularly with regard to traumatic brain injury that is mild or moderate in degree. A need and a priority exist for patient-centered tools that will allow advanced neuroimaging tools to be brought into clinical settings. One barrier to developing these tools is a lack of an age-, sex-, and comorbidities-stratified, sequence-specific, reference imaging data base that could provide a clear understanding of normal variations across populations. Such a data base would provide researchers and clinicians with the information necessary to develop computational tools for the patient-based interpretation of advanced neuroimaging studies in the clinical setting. The recent "Joint ASNR-ACR HII-ASFNR TBI Workshop: Bringing Advanced Neuroimaging for Traumatic Brain Injury into the Clinic" on May 23, 2014, in Montreal, Quebec, Canada, brought together neuroradiologists, neurologists, psychiatrists, neuropsychologists, neuroimaging scientists, members of the National Institute of Neurologic Disorders and Stroke, industry representatives, and other traumatic brain injury stakeholders to attempt to reach consensus on issues related to and develop consensus recommendations in terms of creating both a well-characterized normative data base of comprehensive imaging and ancillary data to serve as a reference for tools that will allow interpretation of advanced neuroimaging tests at an individual level of a patient with traumatic brain injury. The workshop involved discussions concerning the following: 1) designation of the policies and infrastructure needed for a normative data base, 2) principles for characterizing normal control subjects, and 3) standardizing research neuroimaging protocols for traumatic brain injury. The present article summarizes these recommendations and examines practical steps to achieve them.

Adaptation of the chronic disease self-management program for cancer survivors: feasibility, acceptability, and lessons for implementation.

Self-management in chronic disease has been shown to improve patient-reported and health care-related outcomes. However, relatively little information about its utility in cancer survivorship is known. We evaluated the feasibility and acceptability of the delivery of an adaptation of the evidence-based Chronic Disease Self-management Program (Stanford) called Cancer Thriving and Surviving (CTS). Triangulated mixed methods were used to capture baseline characteristics and post-program experiences using a combination of closed- and open-ended survey items; emergent coding and simple descriptive statistics were used to summarize the data. Twenty-seven workshops were delivered by 22 CTS leaders to 244 participants between August 2011 and January 2013 in a variety of settings (48 % community, 30 % health care, 22 % regional/community cancer center). Representing a variety of cancer types, about half the participants were 1-3 years post-diagnosis and 45 % were 4 or more years from diagnosis. Program attendance was high with 84 % of participants attending four or more of the six sessions in the workshop. Overall, 95 % of the participants were satisfied with the program content and leaders, and would recommend the program to friends and family. These results confirm the feasibility and acceptability of delivery of a high-fidelity, peer-led model for self-management support for cancer survivors. Expansion of the CTS represents a powerful tool toward improving health-related outcomes in this at-risk population.

Dendritic cells for active immunotherapy: optimizing design and manufacture in order to develop commercially and clinically viable products.

Dendritic cell (DC) active immunotherapy is potentially efficacious in a broad array of malignant disease settings. However, challenges remain in optimizing DC-based therapy for maximum clinical efficacy within manufacturing processes that permit quality control and scale-up of consistent products. In this review we discuss the critical issues that must be addressed in order to optimize DC-based product design and manufacture, and highlight the DC based platforms currently addressing these issues. Variables in DC-based product design include the type of antigenic payload used, DC maturation steps and activation processes, and functional assays. Issues to consider in development include: (a) minimizing the invasiveness of patient biological material collection; (b) minimizing handling and manipulations of tissue at the clinical site; (c) centralized product manufacturing and standardized processing and capacity for commercial-scale production; (d) rapid product release turnaround time; (e) the ability to manufacture sufficient product from limited starting material; and (f) standardized release criteria for DC phenotype and function. Improvements in the design and manufacture of DC products have resulted in a handful of promising leads currently in clinical development.

Renal sparing treatment of upper tract malignant urothelial tumours using photodynamic therapy (PDT)-three case reports.

Urothelial cancers of the upper urinary tract are usually treated by excision of the kidney, ureter and cuff of the bladder on the affected side. These three cases demonstrate the feasibility, safety and efficacy of photodynamic therapy as a renal sparing procedure for urothelial tumours.

Prediction of operative mortality after valve replacement surgery.

OBJECTIVES: We sought to develop national benchmarks for valve replacement surgery by developing statistical risk models of operative mortality. BACKGROUND: National risk models for coronary artery bypass graft surgery (CABG) have gained widespread acceptance, but there are no similar models for valve replacement surgery. METHODS: The Society of Thoracic Surgeons National Cardiac Surgery Database was used to identify risk factors associated with valve surgery from 1994 through 1997. The population was drawn from 49,073 patients undergoing isolated aortic valve replacement (AVR) or mitral valve replacement (MVR) and from 43,463 patients undergoing CABG combined with AVR or MVR. Two multivariable risk models were developed: one for isolated AVR or MVR and one for CABG plus AVR or CABG plus MVR. RESULTS: Operative mortality rates for AVR, MVR, combined CABG/AVR and combined CABG/ MVR were 4.00%, 6.04%, 6.80% and 13.29%, respectively. The strongest independent risk factors were emergency/salvage procedures, recent infarction, reoperations and renal failure. The c-indexes were 0.77 and 0.74 for the isolated valve replacement and combined CABG/valve replacement models, respectively. These models retained their predictive accuracy when applied to a prospective patient population undergoing operation from 1998 to 1999. The Hosmer-Lemeshow goodness-of-fit statistic was 10.6 (p = 0.225) for the isolated valve replacement model and 12.2 (p = 0.141) for the CABG/valve replacement model. CONCLUSIONS: Statistical models have been developed to accurately predict operative mortality after valve replacement surgery. These models can be used to enhance quality by providing a national benchmark for valve replacement surgery.

Sex differences in neurological outcomes and mortality after cardiac surgery: a society of thoracic surgery national database report.

BACKGROUND: The purpose of this study was to evaluate whether women undergoing cardiac surgery are more likely to suffer neurological complications than men and whether these complications could explain, at least in part, their higher perioperative mortality. METHODS AND RESULTS: The Society of Thoracic Surgery National Cardiac Surgery Database was examined for the years 1996 and 1997 to determine the frequency of new neurological events (stroke, transient ischemic attack, or coma) occurring after cardiac surgery. We reviewed clinical information on 416 347 patients (32% women) for whom complete neurological outcome data were available. New neurological events after surgery were higher for women than for men (3.8% versus 2.4%, P=0.001). For the whole group, the 30-day mortality was higher for women than for men (5.7% versus 3.5%, P=0.001), and among those patients who suffered a perioperative neurological event, mortality was also significantly higher for women than men (32% versus 28%, P=0.001). After adjustment for other risk factors (eg, age, history of hypertension and/or diabetes, duration of cardiopulmonary bypass, and other comorbid conditions) by multivariable logistic regression, female sex was independently associated with significantly higher risk of suffering new neurological events after cardiac surgery (OR 1.21, 95% CI 1.14 to 1.28, P=0.001). CONCLUSIONS: Women undergoing cardiac surgery are more likely than men to suffer new perioperative neurological events, and they have higher 30-day mortality when these complications occur. The higher incidence of perioperative neurological complications in women cannot be explained by currently known risk factors.

The effect of race on coronary bypass operative mortality.

OBJECTIVES: The study was done to determine whether race is an independent predictor of operative mortality after coronary artery bypass graft (CABG) surgery. BACKGROUND: Blacks are less frequently referred for cardiac catheterization and CABG than are whites. Few reports have investigated the relative fate of patients who undergo CABG as a function of race. METHODS: The Society of Thoracic Surgeons National Database was used to retrospectively review 25,850 black and 555,939 white patients who underwent CABG-alone from 1994 through 1997. A multivariate logistic regression model was developed to determine whether race affected risk-adjusted operative mortality. RESULTS: Operative mortality was 3.83% for blacks versus 3.14% for whites (unadjusted black/white odds ratio [OR] 1.23 [1.15-1.31]). Blacks were younger, more likely female, hypertensive, diabetic and in heart failure. Nonetheless, the influence of these and other preoperative risk factors on procedural mortality was quite similar in black and white patients. After controlling for all risk factors, race remained a significant independent predictor of mortality in the multivariate logistic model (adjusted black/white OR 1.29 [1.21, 1.38]). Proportionately, these differences were greatest among lower-risk patients. The race-by-gender interaction was significant (p<0.05). The unadjusted mortality for black men, 3.30% and white men, 2.64% differed significantly (p<0.05), whereas for women there was no difference (black, 4.49%; white 4.41%). CONCLUSIONS: Black race is an independent predictor of operative mortality after CABG except for very high-risk patients. The difference in mortality is greatest for male patients and, though statistically significant, is small in absolute terms. Therefore, patients should be referred for CABG based on clinical characteristics irrespective of race.

Growth characteristics of early passage cell lines compared with established TCC bladder lines.

The growth patterns of established cell lines from bladder transitional cell carcinoma (TCC) were compared with early passage cell lines. The growth of established cell line 5637 was uninhibited in both serum free (basal) and serum containing media. The early passage line (DR) grew only in serum containing medium. This confirms the unreliability of results from biological studies on established (continuous) cell lines.

Reduced expression of TGF beta is associated with advanced disease in transitional cell carcinoma.

The gene structure and expression of the related peptide regulatory factors TGF beta 1 and TGF beta 2 were studied in a panel of seven urothelial carcinoma cell lines and 40 transitional cell carcinomas. The latter comprised 15 grade 1, 18 grade 2 and 5 grade 3 tumours and two cases of carcinoma in situ. Control tissues included ten matched 'field' biopsies and 17 other biopsies including 11 biopsies of macroscopically normal urothelium, two of which were from patients with no history of bladder cancer. No amplification of rearrangements of either TGF beta 1 or TGF beta 2 were detected in any sample. A complex pattern of expression or the two genes was found in the urothelial cell lines. High, but variable levels of the 2.5 kb TGF beta 1 transcript were detected and lower and more variable levels of the three (4.1 kb, 5.1 kb and 6.5 kb) transcripts of TGF beta 2 were detected. Although those cell lines expressing most TGF beta 1 tended to express less TGF beta 2 transcript there was no clear-cut relationship. In comparison, no TGF beta 2 transcript was identified in any primary transitional cell carcinoma or control tissue. Markedly reduced or undetectable levels of TGF beta 1 transcript were detected in 4/15 (26%) grade 1, 5/18 (28%) grade 2 and 3/5 (60%) grade 3 tumours. There was no clear relationship to tumour stage, lymphocytic infiltration or stromal content of the tumours. Clinical review one year after the 2 year period of tumour collection showed that 6/9 (66%) of patients with tumours with reduced levels of transcript had died or had disease which was not controllable by local resection and 3/9 (33%) had developed tumour re-occurrences. In comparison, in the group with normal levels of expression of TGF beta 1, 3/18 (17%) had disease which was not controllable by local means, 9/18 (50%) had tumour re-occurrence and 6/18 (33%) had no evidence of disease. The association of reduced expression of TGF beta 1 and advanced disease was statistically significant P < 0.02 (Fisher's test). Although the sample size is small, we suggest that the loss of expression of TGF beta 1 may be a potential marker of progressive disease or prognosis in transitional cell carcinoma and warrants further study.

Immunocytochemical localization of c-erbB-2 protein in transitional cell carcinoma of the urinary bladder.

The level of expression and cellular localization of the c-erbB-2 gene product in transitional cell carcinoma of the urinary tract is controversial. Analysis of the c-erbB-2 gene structure and comparison of its expression in the same cells by Southern, Northern and immunoblotting, and by immunocytochemistry minimize the errors of interpretation inherent in one technique. Such a 'correlative study' has been performed on tumours from 82 patients. c-erbB-2 gene amplification was detected in 14 per cent of initial tumours and was associated with grade (P < 0.001). Raised levels of mRNA were seen in those tumours with increased gene copy number and in 13 per cent of the remainder. Immunoblotting detected the expected 185 kD immunoreactive protein and a 155 kD protein associated with high gene copy number. Immunocytochemistry localized c-erbB-2 immunoreactivity to the cell membrane and cytoplasm, and the latter predominated. Four antibodies to c-erbB-2 (AB-3, 21N, pAb 1, and NCL CB11) were compared on contiguous sections of the same tumour and showed the same pattern of immunoreactivity. Similarly, analyses carried out in three independent laboratories identified the same cellular localization. Membrane and cytoplasmic immunoreactivity was demonstrated in all tumours with gene amplification or increased mRNA levels and in 40 per cent of the remaining tumours. We showed that immunocytochemistry requires careful standardization of techniques and quantitation between different groups. However, despite variations in the intensity of immunoreactivity, the total number of positive cells remained constant. Therefore quantitation must be based on the number of positive cells and, ideally, their immunoreactive content relative to normal and positive tissue controls.

Efficacy of flecainide for the reversion of acute onset atrial fibrillation.

The efficacy and safety of intravenous flecainide to convert recent-onset atrial fibrillation (AF) (present for greater than or equal to 30 minutes and less than or equal to 72 hours and a ventricular response greater than or equal to 120 beats/min) was investigated. A total of 102 patients without severe heart or circulatory failure were randomized to receive either intravenous flecainide (2 mg/kg, maximum dose 150 mg; 51 patients) or placebo (51 patients) in a double-blind trial. Digoxin (500 micrograms intravenously) was administered to all patients who had not previously been receiving digoxin. The electrocardiogram was monitored continuously during the study. In 29 (57%) patients stable sinus rhythm was restored within 1 hour after flecainide and in only 7 (14%) given placebo (chi square 18.9; p = 0.000013; odds ratio 8.3; 95% confidence interval 2.9-24.8). Reversion to sinus rhythm within 1 hour after starting the trial medication was considered a pretrial end point and likely to be due to a drug effect. At the end of the 6-hour monitoring period, 34 patients (67%) in the flecainide group were in sinus rhythm whereas only 18 (35%) in the placebo group had reverted (chi square 8.83, p = 0.003; odds ratio 3.67; 95% confidence interval 1.5-9.1). Significant hypotension, although short lived, was more common in the flecainide group. One patient given flecainide developed torsades de pointes and was successfully electrically cardioverted. Flecainide is useful for the management of recent-onset AF both for control of the ventricular response and conversion to sinus rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)

Amplification at chromosome 11q13 in transitional cell tumours of the bladder.

Amplification of several markers which map to chromosome 11q13 was detected by Southern blotting in transitional cell tumours of the urinary bladder. The oncogenes INT2 and HST and the BCL1 locus were co-amplified in 20/97 (20.6%) tumours and the locus-specific minisatellite probe pMS51 (D11S97) detected amplification in 17/97 (17.5%) tumours. The high frequency of heterozygosity (greater than 70%) detected by this latter probe on HaeIII-digested DNAs provided a sensitive means to measure low levels of gene amplification (2-fold) by comparing signals obtained from each allele. A number of probes which map to 11q were used in an attempt to map the region of amplification more precisely. PGA, PGR, STMY, D11Z1 and D11S149 were not amplified in any tumours studied. SEA was amplified in 1/59 tumours and D11S146 in 12/89 tumours. A comparison of the patterns of co-amplification of individual markers in this series of tumours revealed that of the 23 tumours with amplification at this site, 11 had co-amplification of D11S97, D11S146, BCL1, INT2 and HST, 3 had co-amplification of D11S97, BCL1, INT2 and HST, 6 had co-amplification of BCL1, INT2 and HST, 1 had co-amplification of D11S97 and D11S146 and 2 had amplification of D11S97 alone. Based on available linkage data for these markers, this suggests that a putative target gene within this amplicon lies centromeric to BCL1. Amplification at 11q13 showed no correlation with tumour grade or with HER2 amplification.

Amplification and over-expression of c-erbB-2 in transitional cell carcinoma of the urinary bladder.

The structure and expression of the proto-oncogene c-erbB-2 was studied in 86 patients with transitional cell carcinoma. Initial tissue samples comprised 37 grade 1, 32 grade 2 and 13 grade 3 tumours and four cases of carcinoma in situ. At the time of this first tumour sample, amplification of the c-erbB-2 gene was demonstrated by Southern blotting in 1/37 grade 1, 5/32 grade 2 and 6/13 grade 3 tumours (0.005 less than P less than 0.01). Tumour 're-occurrences' were obtained from 23 of these patients on one or more occasions. Amplification was detected in re-occurrences from seven of these 23, none of whom showed amplification in the first tumour sample. DNA was also extracted from exfoliated cells in urine collected from five cases of carcinoma in situ and c-erbB-2 amplification was demonstrated in one of these. No gene amplification was identified in patients' lymphocytes, ten biopsies of normal urothelium and 22 various intravesical pathologies. Increased expression of c-erbB-2 mRNA correlated with amplification of the gene. In addition, raised levels of mRNA were seen in the absence of gene amplification in six tumours. Immunoblotting using the polyclonal antibody 21N, raised against the c-terminus of the c-erbB-2 protein demonstrated increased amounts of a 185 kD immunoreactive protein in tumours with increased c-erbB-2 gene copy number compared with control tissues. In some tumours with high c-erbB-2 gene copy number, a 155 kD immunoreactive protein not detected in controls was expressed at higher level than the 185 kD protein. Immunocytochemistry using a monoclonal antibody AB-3, raised against the c-terminus of the c-erbB-2 protein, showed a positive reaction in the cytoplasm and cell membrane of tumours with gene amplification and in 40% of tumours with no amplification. An association was found between c-erbB-2 amplification and over-expression and the development of tumour re-occurrences. We suggest that c-erbB-2 amplification and over-expression may provide a useful molecular marker in transitional cell carcinoma of the bladder and merits further investigation as a potential prognostic indicator.

Reversion of recent-onset atrial fibrillation to sinus rhythm by intravenous flecainide.

Spontaneous reversion to sinus rhythm is a frequent occurrence in recent-onset atrial fibrillation (AF). In a randomized, double-blind, controlled study, intravenous flecainide (2 mg/kg, maximum dose 150 mg) was compared with placebo in the treatment of recent-onset AF (present for greater than or equal to 30 minutes and less than or equal to 72 hours' duration and a ventricular response greater than or equal to 120 beats/min). Intravenous digoxin (500 micrograms) was administered concurrently to all patients in both groups who had not previously taken digoxin. The trial medication was administered over 30 minutes. Exclusion criteria included hemodynamic instability, severe heart failure, recent antiarrhythmic therapy, hypokalemia and pacemaker dependence. One hundred two consecutive patients with recent-onset AF were enrolled in the study. All patients underwent continuous electrocardiographic monitoring in the intensive care or coronary care unit. Twenty-nine (57%) patients given flecainide and digoxin, but only 7 (14%) given placebo and digoxin, reverted to sinus rhythm in less than or equal to 1 hour after starting the trial medication infusion and remained in stable sinus rhythm (chi-square 18.9, p = 0.000013; odds ratio 8.3, 95% confidence interval 2.9 to 24.8). At the end of the 6-hour monitoring period, 34 patients (67%) in the flecainide-digoxin group were in stable sinus rhythm, whereas only 18 patients (35%) in the placebo-digoxin group had reverted (chi-square 8.83, p = 0.003; odds ratio 3.67, 95% confidence interval 1.5 to 9.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Simultaneous isolation of DNA, RNA, and antigenic protein exhibiting kinase activity from small tumor samples using guanidine isothiocyanate.

Correlative studies of genes and their expression in human tumors are often hampered by the small sample size and the need to use differing and incompatible techniques to obtain DNA, RNA, and protein. We describe an extension of the established guanidine isothiocyanate method for isolation of DNA and RNA which allows the simultaneous isolation of total cellular protein. The protein obtained by this method (from solid tumors and cell lines) was comparable to protein extracted by a standard detergent solubilization method. Antigenicity was retained as demonstrated by Western blotting for epidermal growth factor receptor and actin and by immunoprecipitation of p53. Kinase activity was similar in proteins extracted by the two methods. It seems probable that most monomeric proteins can be obtained in a form suitable for Western analysis and immunoprecipitation and that these may also retain some functional activity.

Treatment of invasive bladder cancer by cisplatin and radiation in patients unsuited for surgery.

Seventy patients with muscle-invading bladder carcinoma (clinical stages T2 to T4) who were not candidates for cystectomy were treated with combined cisplatin and full-dose external-beam radiation on a multi-institutional prospective protocol from 1980 through 1985. Thirty-six patients are alive, all but three without evidence of cancer. The complete response rate is 77% in the 62 patients completing planned irradiation and 70% for all patients. Among the complete responders, 73% are currently maintained, and this group has a significantly higher four-year survival than those not having a complete response and those with recurrence of disease--57% vs 11%. The observed high complete response rates in patients in all stages and the high survival rates suggest irradiation plus cisplatin therapy offers an important therapeutic gain over radiation therapy alone for invasive cancer of the bladder. These results encourage further evaluation of combining cisplatin-based, multidrug chemotherapy with irradiation in patients with locally very-advanced bladder tumors who are not suited for surgery.

Clinical examination of patients in the intensive care unit.

The severity of their illness ensures that many patients requiring intensive care have abnormal physical signs. Clinical examination remains a useful and effective way of detecting these and monitoring the patient's response to treatment.