Outcome prioritization and preferences among older adults with cancer starting chemotherapy in a randomized clinical trial.

INTRODUCTION: Older adults with cancer facing competing treatments must prioritize between various outcomes. This study assessed health outcome prioritization among older adults with cancer starting chemotherapy. METHODS: Secondary analysis of a randomized trial addressing vulnerabilities in older adults with cancer. Patients completed three validated outcome prioritization tools: 1) Health Outcomes Tool: prioritizes outcomes (survival, independence, symptoms) using a visual analog scale; 2) Now vs. Later Tool: rates the importance of quality of life at three times-today versus 1 or 5 years in the future; and 3) Attitude Scale: rates agreement with outcome-related statements. The authors measured the proportion of patients prioritizing various outcomes and evaluated their characteristics. RESULTS: A total of 219 patients (median [range] age 71 [65-88], 68% with metastatic disease) were included. On the Health Outcomes Tool, 60.7% prioritized survival over other outcomes. Having localized disease was associated with choosing survival as top priority. On the Now vs. Later Tool, 50% gave equal importance to current versus future quality of life. On the Attitude Scale, 53.4% disagreed with the statement "the most important thing to me is living as long as I can, no matter what my quality of life is"; and 82.2% agreed with the statement "it is more important to me to maintain my thinking ability than to live as long as possible". CONCLUSION: Although survival was the top priority for most participants, some older individuals with cancer prioritize other outcomes, such as cognition and function. Clinicians should elicit patient-defined priorities and include them in decision-making.

The use of Lutetium-177 PSMA radioligand therapy with high dose rate brachytherapy for locally recurrent prostate cancer after previous definitive radiation therapy: a randomized, single-institution, phase I/II study (ROADSTER).

BACKGROUND: Isolated local failure (ILF) can occur in patients who initially receive definitive radiation therapy for prostate cancer. Salvage therapy for ILF includes high dose rate (HDR) brachytherapy. Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) can accurately detect ILF and can exclude extraprostatic disease. Lutetium-177 PSMA Radioligand Therapy (RLT) is a novel treatment for prostate cancer that can target prostate cancer accurately, while sparing radiation dose to normal tissues. METHODS: ROADSTER is a phase I/II randomized, single-institution study. Patients with an ILF of prostate cancer after definitive initial radiation therapy are eligible. The ILF will be confirmed with biopsy, magnetic resonance imaging (MRI) and PSMA PET. Patients will be randomized between HDR brachytherapy in two fractions (a standard of care salvage treatment at our institution) (cohort 1) or one treatment of intravenous Lutetium-177 PSMA RLT, followed by one fraction of HDR brachytherapy (cohort 2). The primary endpoints for the phase I portion of the study (n = 12) will be feasibility, defined as 10 or more patients completing the study protocol within 24 months of study activation; and safety, defined as zero or one patients in cohort 2 experiencing grade 3 or higher toxicity in the first 6 months post-treatment. If feasibility and safety are achieved, the study will expand to a phase II study (n = 30 total) where preliminary efficacy data will be evaluated. Secondary endpoints include changes in prostate specific antigen levels, acute toxicity, changes in quality of life, and changes in translational biomarkers. Translational endpoints will include interrogation of blood, urine, and tissue for markers of DNA damage and immune activation with each treatment. DISCUSSION: ROADSTER explores a novel salvage therapy for ILF after primary radiotherapy with combined Lutetium-177 PSMA RLT and HDR brachytherapy. The randomized phase I/II design will provide a contemporaneous patient population treated with HDR alone to facilitate assessment of feasibility, tolerability, and biologic effects of this novel therapy. TRIAL REGISTRATION: NCT05230251 (ClinicalTrials.gov).

CT perfusion measurement of postictal hypoperfusion: localization of the seizure onset zone and patterns of spread.

PURPOSE: Seizures are often followed by a period of transient neurological dysfunction and postictal alterations in cerebral blood flow may underlie these symptoms. Recent animal studies have shown reduced local cerebral blood flow at the seizure onset zone (SOZ) lasting approximately 1 h following seizures. Using arterial spin labelling (ASL) MRI, we observed postictal hypoperfusion at the SOZ in 75% of patients. The clinical implementation of ASL as a tool to identify the SOZ is hampered by the limited availability of MRI on short notice. Computed tomography perfusion (CTP) also measures blood flow and may circumvent the logistical limitations of MRI. Thus, we aimed to measure the extent of postictal hypoperfusion using CTP. METHODS: Fourteen adult patients with refractory focal epilepsy admitted for presurgical evaluation were prospectively recruited and underwent CTP scanning within 80 min of a habitual seizure. Patients also underwent a baseline scan after they were seizure-free for > 24 h. The acquired scans were qualitatively assessed by two reviewers by visual inspection and quantitatively assessed through a subtraction pipeline to identify areas of significant postictal hypoperfusion. RESULTS: Postictal blood flow reductions of > 15 ml/100 g-1/min-1 were seen in 12/13 patients using the quantitative method of analysis. In 10/12 patients, the location of the hypoperfusion was partially or fully concordant with the presumed SOZ. In all patients, additional areas of scattered hypoperfusion were seen in areas corresponding to seizure spread. CONCLUSION: CTP can reliably measure postictal hypoperfusion which is maximal at the presumed SOZ.

Wood Preference of Reticulitermes virginicus (Blattodea: Rhinotermitidae) Using No-, Two-, and Four-Choice Designs and Seven Different Measures of Wood Consumption.

Three hundred Reticulitermes virginicus (Banks) workers were exposed to three 1-cm3 wood blocks of either Quercus sp. (Red Oak), Populus sp. (Poplar), Pinus sp. (Pine), or Sequoia sp. (Redwood) placed into one of the three bioassay designs (no-, two-, and four-choice) for 21 d. Termite wood consumption was measured by wood weight loss, resistance class, and visual rating. Wood consumption rates were determined using four formulas in addition to two standardized visual rating scales (American Society for Testing and Materials [ASTM] and American Wood Protection Association [AWPA]) and a preference ranking obtained for each measure. The wood consumption formula, rating scale, and preference rankings were compared by bioassay design. The overall preference ranking of the four wood types as determined by the combination of all three designs was­1) Pine, 2) Red Oak, 3) Redwood, and 4) Poplar. Results indicate that bioassay design influenced both wood consumption and preference rankings. A no-choice design can determine aversion; a four-choice design the most preferred wood; and a two-choice design can illuminate the fine details of comparative preference. The different formulas employed for calculation of consumption rate influenced preference ranking in the no- and four-choice designs but not the two-choice design.

Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma.

BACKGROUND: The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS). RESULTS: The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival. CONCLUSIONS: Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01210495.

Dissecting alternative splicing in the formation of Miltenberger glycophorin subtype III (GYP.Mur).

BACKGROUND AND OBJECTIVES: Miltenberger subtype III (Mi.III, GP.Mur) is one of the most important red cell phenotypes in the fields of transfusion in South-East Asia. GP.Mur is believed to evolve from homologous gene recombination events between glycophorin A (GYPA) and glycophorin B (GYPB). GYP.Mur differs from GYPB in only seven nucleotides dispersed near the region of 3' exon 3 of GYP.Mur. The goal of this study was to dissect how these nucleotide variants affected splicing of exon 3. MATERIALS AND METHODS: We first designed two minigene constructs: one containing GYP.Mur from exon 2 to exon 4 and the other containing GYPB in the same region. To test how these nucleotide variations between GYP.Mur and GYPB affected the splicing, a repertoire of the GYP.Mur-like minigene constructs with different point mutations were created. These minigene variants were evaluated for their abilities to induce splicing of exon 3 using a heterologous expression system. RESULTS: (1) GYP.Mur minigene expressed exons 2, 3 and 4, whereas GYPB minigene expressed only exon 2 and exon 4. (2) The single nucleotide alteration at the position of the 5' splice site of glycophorin intron 3 reversed the splicing decision. (3) The nucleotide variations between GYP.Mur and GYPB other than that at the 5' splice site showed very little or no effect on splicing of exon 3. CONCLUSION: Splicing of the glycophorin B-A-B hybrids (GYP.Mur and GYP.BUN) and unsplicing of GYPB follow the GU-AG rule strictly.

Fulminant Type 1 diabetes in a pregnant woman as an initial manifestation of the insulin autoimmune syndrome.

Fulminant Type 1 diabetes is a subtype of Type 1 diabetes characterized by (1) abrupt onset of diabetes, (2) very short duration of hyperglycaemia with mildly elevated HbA(1c) (< 69 mmol/mol, 8.5%), (3) rapid progression to diabetic ketoacidosis, (4) very low C-peptide level, and (5) often associated with elevated serum pancreatic enzymes, and absence of diabetes-related autoantibodies. We encountered a case of fulminant Type 1 diabetes that developed with an initial manifestation of the insulin autoimmune syndrome and rapidly progressed to diabetic ketoacidosis during pregnancy. A 31-year-old Korean woman presented with recurrent sudden onset of sweating and change of consciousness during sleep at 19 weeks gestation. During a 72-h fasting test, hypoglycaemia (1.72 mmol/l) occurred at 4 h after the start of the test. At that time, there was a high insulin level (370.2 µU/ml), a paradoxically low C-peptide level (0.01 nmol/l) and a positive insulin autoantibody test. An oral glucose tolerance test revealed postprandial hyperglycaemia. She was initially diagnosed as the insulin autoimmune syndrome. On the day 5 of admission, she developed diabetic ketoacidosis. Her HbA(1c) was 62 mmol/mol (7.8%). The rapid progression of diabetic ketoacidosis altered the diagnosis to fulminant Type 1 diabetes. This case differed from typical fulminant Type 1 diabetes because it presented with hypoglycaemia, and positive insulin and anti-phospholipid antibody tests. Her HLA typing was HLA-DQA1*0302, 0501, HLA-DRB1*0301 (DR3), 0901(DR9). Her glucose level was subsequently very well controlled with multiple insulin injections and she successfully delivered a healthy baby.

Expression of the Rh/RhAG complex is reduced in Mi.III erythrocytes.

BACKGROUND AND OBJECTIVES: Miltenberger blood group antigen subtype III (Mi.III) is characterized by expression of a glycophorin B-A-B hybrid (Gp.Mur) on the erythrocyte surface. The two alleles of glycophorin B are substituted with the B-A-B hybrid alleles in homozygous Mi.III (Mi.III(+/+)), and thus, Mi.III(+/+) erythrocytes lack glycophorin B (GPB) and express Gp.Mur only. Because GPB is a major component of the Rh complex on RBCs, in this study, we explored how the absence of GPB might affect Rh expression in Mi.III RBCs. MATERIALS AND METHODS: (1) Mi.III+ RBCs were serologically identified and further differentiated their homozygosity or heterozygosity by immunoblot or direct sequencing. (2) RhD and RhCcEe mRNA was cloned, and their sequences analysed. (3) The expression levels of Rh antigen, Rh-associated glycoprotein (RhAG) and the U antigen in MI.III vs. non-Mi.III RBCs were assessed by flow cytometry and Western blot. RESULTS: Compared with the non-Mi.III samples, the surface expression of the Rh antigen was reduced to 76·4% in Mi.III(+/+) RBCs and 93·6% in Mi.III(+/-). RhAG expression was also significantly reduced in Mi.III(+/+), but not in Mi.III(+/-). The U antigen expression in Mi.III(+/-) was only 14·9% relative to the control RBCs, while GPB was half the level of the controls. The mRNA sequences of Rh polypeptides from Mi.III+ samples were identical to the NCBI reference sequences. CONCLUSION: Substitution of GPB with Gp.Mur significantly reduced the expression of Rh antigen and RhAG on the Mi.III(+/+) erythrocyte membrane. The Mi.III phenotype is predicted to induce considerable structural variations within the band 3/Rh-associated macrocomplexes.

Current status and guidelines for the assessment of tumour vascular support with dynamic contrast-enhanced computed tomography.

Dynamic contrast-enhanced computed tomography (DCE-CT) assesses the vascular support of tumours through analysis of temporal changes in attenuation in blood vessels and tissues during a rapid series of images acquired with intravenous administration of iodinated contrast material. Commercial software for DCE-CT analysis allows pixel-by-pixel calculation of a range of validated physiological parameters and depiction as parametric maps. Clinical studies support the use of DCE-CT parameters as surrogates for physiological and molecular processes underlying tumour angiogenesis. DCE-CT has been used to provide biomarkers of drug action in early phase trials for the treatment of a range of cancers. DCE-CT can be appended to current imaging assessments of tumour response with the benefits of wide availability and low cost. This paper sets out guidelines for the use of DCE-CT in assessing tumour vascular support that were developed using a Delphi process. Recommendations encompass CT system requirements and quality assurance, radiation dosimetry, patient preparation, administration of contrast material, CT acquisition parameters, terminology and units, data processing and reporting. DCE-CT has reached technical maturity for use in therapeutic trials in oncology. The development of these consensus guidelines may promote broader application of DCE-CT for the evaluation of tumour vascularity. Key Points • DCE-CT can robustly assess tumour vascular support • DCE-CT has reached technical maturity for use in therapeutic trials in oncology • This paper presents consensus guidelines for using DCE-CT in assessing tumour vascularity.

Miltenberger blood group antigen subtype III (Mi.III) supports Wr(b) expression.

BACKGROUND AND OBJECTIVES: Miltenberger blood group antigens belong to the complex MNS system. Miltenberger antigen subtype III (Mi.III) was previously found to promote the expression of band 3. Here, we investigated whether the direct interaction between band 3 and Mi.III-specific Gp.Mur (a glycophorin B-A-B hybrid) might affect the expression of related blood group antigens such as the Wright b (Wr(b) ) antigen. MATERIALS AND METHODS: (1) Band 3 genes of Mi.III+ and non-Mi.III (control) donors were sequenced to determine the genotypes of the Wright antigens. (2) The expression levels of Wr(b) , glycophorin A (GPA) and band 3 in Mi.III and the control erythrocytes were quantitatively assessed by flow cytometry. RESULTS: Mi.III erythrocytes expressed 22·5±6·6% more Wr(b) antigen than the control cells. The increase in Wr(b) in Mi.III cells was independent of their GPA levels. CONCLUSION: The elevated Wr(b) levels in Mi.III RBCs were likely linked to their higher band 3 levels. Higher band 3 densities on the Mi.III+ cell surface conceivably could drive complex formation between band 3 and GPA/Gp.Mur, thereby increasing the expression of Wr(b) .

Operative outcomes using a side-branched thoracoabdominal aortic graft (STAG) for thoraco-abdominal aortic repair.

BACKGROUND: Pre-manufactured branched grafts now allow an endovascular approach to the repair of thoraco-abdominal aortic aneurysm (TAAA) with visceral vessels' involvement. Similar grafts have been employed in open surgery, generally as a second choice for TAAAs, which are not amenable to patch/inclusion technique for visceral vessel attachment. Results with branched grafts have not been reported in series of open TAAA repairs. The purpose of this report is to describe perioperative risks and outcomes in a consecutive series of patients with pre-manufactured side-branched thoracoabdominal aortic grafts (STAGs) for surgical TAAA repair. METHODS: Between 1996 and 2009, pre-manufactured STAGs were used in 50 patients with TAAA that required reattachment of the visceral and renal arteries. Operative details, perioperative mortality and ischaemic complications were examined. RESULTS: Mean age was 53 years; 18 patients were females. The cases included redo (n = 24), patients affected by genetic disorder (Marfan) (n = 20) and patients with aortic dissection (n = 27). The mean clamp time was 84.1 min. Perioperative mortality was 12.0% (6/50). Neurologic deficits occurred in 2% (1/50). Postoperative renal dysfunction was detected in 19 patients (38%). CONCLUSION: The use of a STAG produced acceptable mortality, bowel and neurological ischaemic risks. Improved strategies to prevent renal ischaemia before and during repair of TAAA with visceral involvement are needed.

Quantitatively detecting postictal hypoperfusion in patients with focal epilepsy using CT perfusion: Determining cross-modality comparisons and electrode artifacts.

BACKGROUND: We previously showed that CT perfusion (CTP) and arterial spin labelled (ASL) MRI can localize the seizure onset zone in humans via postictal perfusion patterns. As a step towards improving the feasibility/ease of collecting postictal CBF data, we determined whether EEG electrodes need to be removed for CTP data collection and whether a cross-modality comparison between baseline ASL and postictal CTP data is possible. NEW METHOD: Five patients with epilepsy underwent postictal CTP scanning. Three patients had an interictal ASL scan; one patient had both an ASL and CTP interictal scan. Postictal CTP maps were quantitatively compared to 1) ASL maps averaged from 100 healthy controls, 2) each patient's baseline ASL map and 3) each patient's baseline CTP map. To assess for electrode artifacts, a phantom and one patient underwent CTP scanning with EEG electrodes in place. The acquired scans were assessed for artifacts and for postictal hypoperfusion. RESULTS: Focal postictal hypoperfusion was observable only in intra-modality comparisons (CTP to CTP) and not in cross-modality comparisons (CTP to ASL). EEG electrodes produced streaking artifact that decreased image quality and precluded quantitative analysis. COMPARISON WITH EXISTING METHODS(S): An intra-modality comparison of baseline CTP to postictal CTP was the only comparison method that showed localized hypoperfusion. CONCLUSIONS: Quantitative comparison between postictal CTP and baseline ASL scans is not feasible. Postictal hypoperfusion can be detected by CTP only when two CTP scans are collected and when metallic EEG electrodes are removed.

A Phase II Trial of Older Adults With Metastatic Breast Cancer Receiving nab-Paclitaxel: Melding the Fields of Geriatrics and Oncology.

INTRODUCTION: Phase II clinical trials including geriatric assessment (GA) measures are critical for improving the evidence base for older adults with cancer. We assessed the efficacy and tolerability of nab-paclitaxel in older adults with metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients aged ≥ 65 years with MBC and ≤ 1 previous line of chemotherapy received 100 mg of nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle. A GA was completed pre-chemotherapy, and the validated Cancer and Aging Research Group (CARG) chemotherapy toxicity risk score was calculated. Relationships between tolerability (number of courses, hospitalizations, dose reductions, and toxicity) and risk score were assessed using general linear models, Student t tests, and the Fisher test. Response rate and progression-free survival were evaluated using the Kaplan-Meier method. RESULTS: Forty patients (mean age, 73 years; range, 65-87 years) were included. The median number of cycles was 6, 75% (n = 30) of patients had ≥ 1 dose hold, and 50% (n = 20) had ≥ 1 dose reduction. Fifty-eight percent (n = 23) had treatment-related ≥ grade 3 toxicities, and 30% (n = 12) were hospitalized owing to toxicity. Thirty-five percent (n = 14) responded, and the median progression-free survival was 6.5 months (95% confidence interval, 5.5 months to undefined). Patients with intermediate/high toxicity risk scores had higher risk of grade ≥ 3 toxicity than those with low risk scores (odds ratio, 5.8; 95% confidence interval, 1.3-33.1; P = .01). A higher mean risk score was associated with higher likelihood of dose reductions and hospitalizations. CONCLUSIONS: Among older adults with MBC receiving weekly nab-paclitaxel, more than one-half experienced ≥ grade 3 chemotherapy toxicity. However, a GA-based risk score could predict treatment tolerability.

Designing Triple Adult Liver Grafts From an Ideal Deceased Liver.

Splitting deceased donor livers and creating 3 grafts from a whole liver may be feasible and shorten the waiting time for organ donation in patients with high mortality rates. We hypothesized that it might be reasonable to procure 3 grafts for donation from one deceased donor liver by splitting the liver into left (segment II, III, IV), right anterior (segment V, VIII), and right posterior lobes (segment VI, VII) for liver transplantation according to the portal system trifurcated variations. We designed the right anterior branch with the main portal trunk and middle hepatic artery to become inflow of right anterior lobe, the left portal vein and left hepatic artery to become the inflow of left lobe and right posterior branch, and right hepatic artery to become the inflow of right posterior lobe. We retrospectively reviewed the volumetric computed tomography and magnetic resonance cholangiopancreatography of 153 liver donors. The hepatic and portal veins, hepatic artery, and biliary system were reorganized and classified. The volumetric proportions of the liver grafts were measured. Trifurcation of the portal vein variation was found in approximately 13.7% of portal systemic variations. The left lobe accounted for 29.18% of the total liver volume, the right anterior lobe, 35.22%, and the right posterior lobe, 35.6%. We validated this principle by dissecting the explanted liver and identified the triple grafts' weights, percentages, vessels, and biliary ducts system. The splitting of deceased donor livers into 3 split liver grafts for use in liver transplantation surgery can be clinically useful.

Prospective Multicenter Study of Changes in MTT after Aneurysmal SAH and Relationship to Delayed Cerebral Ischemia in Patients with Good- and Poor-Grade Admission Status.

BACKGROUND AND PURPOSE: Patients with aneurysmal SAH and good clinical status at admission are considered at a lower risk for delayed cerebral ischemia. Prolonged MTT may be associated with an increased risk. It is unclear whether this is dependent on clinical status. Our purpose was to determine whether increased MTT within 3 days of aneurysmal SAH compared with baseline is associated with a higher risk of delayed cerebral ischemia in patients with good (World Federation of Neurosurgical Societies I-III) versus poor (World Federation of Neurosurgical Societies IV-V) admission status. MATERIALS AND METHODS: This prolonged MTT was a multicenter, prospective cohort investigation of 87 patients with aneurysmal SAH. MTT was measured at admission before aneurysm treatment (MTT1) and following repair (MTT2) within 3 days of admission; MTTdiff was calculated as the difference between MTT2 and MTT1. Changes in MTT across time were assessed with repeated measures analyses. Risk of delayed cerebral ischemia or death was determined with multivariate logistic regression analysis. RESULTS: In patients with a good grade (n = 49), MTT was prolonged in patients who developed delayed cerebral ischemia, with MTTdiff significantly greater (0.82 ± 1.5) compared with those who did not develop delayed cerebral ischemia (-0.14 ± 0.98) (P = .03). Prolonged MTT was associated with a significantly higher risk of delayed cerebral ischemia or death (OR = 3.1; 95% CI, 1.3-7.4; P = .014) on multivariate analysis. In patients with poor grades (n = 38), MTTdiff was not greater in patients who developed delayed cerebral ischemia; MTT1 was significantly prolonged compared with patients with a good grade. CONCLUSIONS: Patients in good clinical condition following aneurysmal SAH but with increasing MTT in the first few days after aneurysmal SAH are at high risk of delayed cerebral ischemia and warrant close clinical monitoring.

Serial changes in CT cerebral blood volume and flow after 4 hours of middle cerebral occlusion in an animal model of embolic cerebral ischemia.

BACKGROUND AND PURPOSE: Neuroimaging techniques have the potential to improve acute stroke treatment by selecting the appropriate patients for thrombolytic therapy. In this study, we examined changes in cerebral blood flow (CBF) and cerebral blood volume (CBV) in an animal model of middle cerebral artery occlusion and used these to identify the parameters that best differentiate between oligemic and infarct regions. MATERIALS AND METHODS: Permanent middle cerebral artery occlusion was performed in 17 New Zealand white rabbits. CT perfusion imaging was performed before (baseline), 10, and 30 minutes after the stroke, and then every 30 minutes up to 3 hours. After a final scan at 4 hours, the brain was removed, cut corresponding to CT sections, and stained with 2,3,5-triphenyltetrazolium chloride (TTC) to identify infarcted tissue. A logistic regression model with the 4-hour post-CBF and -CBV values as independent variables was used to determine the binary tissue outcome variable (oligemia or infarction). RESULTS: Infarcted regions were characterized by a significant decrease (P < .005) in both CBV and CBF, whereas oligemic (CBF < 25 mL . 100 g(-1) . min(-1), not infarcted) regions showed a significant decrease (P < .005) in CBF with maintenance of CBV at or near baseline values. From the perfusion parameters at the 4-hour time point, logistic regression by using CBV*CBF resulted in a sensitivity of 90.6% and a specificity of 93.3% for infarction. CONCLUSION: CBF and CBV values obtained from CT perfusion imaging can be used to distinguish between oligemic and infarct regions. This information could be used to assess the viability of ischemic brain tissue.

Permeability surface area product analysis in malignant brain edema prediction - A pilot study.

BACKGROUND AND PURPOSE: Using an extended CT perfusion acquisition (150s), we sought to determine the association between perfusion parameters and malignant edema after ischemic stroke. METHODS: Patients (from prospective study PROVE-IT, NCT02184936) with terminal internal carotid artery±proximal middle cerebral occlusion were involved. CTA was assessed for clot location and status of leptomeningeal collaterals. The following CTP parameters were calculated within the ischemic territory and contralaterally: permeability surface area product (PS), cerebral blood flow (CBF) and cerebral blood volume (CBV). PS was calculated using the adiabatic approximation to the Johnson and Wilson model. Outcome was evaluated by midline shift and infarction volume on follow-up imaging. RESULTS: Of 200 patients enrolled, 7 patients (3.5%) had midline shift≥5mm (2 excluded for poor-quality scans). Five patients with midline shift and 5 matched controls were analysed. There was no significant difference in mean PS, CBF and CBV within the ischemic territory between the two groups. A CBV threshold of 1.7ml/100g had the highest AUC=0.72, 95% CI=0.54-0.90 for early midline shift prediction, sensitivity and specificity were 0.83 and 0.67 respectively. CONCLUSION: Our preliminary results did not show significant differences in permeability surface area analysis if analysed for complete ischemic region. CBV parameter had the highest accuracy and there was a trend for the mean PS values for midline shift prediction.

Identification of penumbra and infarct in acute ischemic stroke using computed tomography perfusion-derived blood flow and blood volume measurements.

BACKGROUND AND PURPOSE: We investigated whether computed tomography (CT) perfusion-derived cerebral blood flow (CBF) and cerebral blood volume (CBV) could be used to differentiate between penumbra and infarcted gray matter in a limited, exploratory sample of acute stroke patients. METHODS: Thirty patients underwent a noncontrast CT (NCCT), CT angiography (CTA), and CT perfusion (CTP) scan within 7 hours of stroke onset, NCCT and CTA at 24 hours, and NCCT at 5 to 7 days. Twenty-five patients met the criteria for inclusion and were subsequently divided into 2 groups: those with recanalization at 24 hours (n=16) and those without (n=9). Penumbra was operationally defined as tissue with an admission CBF <25 mL x 100 g(-1) x min(-1) that was not infarcted on the 5- to 7-day NCCT. Logistic regression was applied to differentiate between infarct and penumbra data points. RESULTS: For recanalized patients, CBF was significantly lower (P<0.05) for infarct (13.3+/-3.75 mL x 100 g(-1) x min(-1)) than penumbra (25.0+/-3.82 mL x 100 g(-1) x min(-1)). CBV in the penumbra (2.15+/-0.43 mL x 100 g(-1)) was significantly higher than contralateral (1.78+/-0.30 mL x 100 g(-1)) and infarcted tissue (1.12+/-0.37 mL x 100 g(-1)). Logistic regression using an interaction term (CBFxCBV) resulted in sensitivity, specificity, and accuracy of 97.0%, 97.2%, and 97.1%, respectively. The interaction term resulted in a significantly better (P<0.05) fit than CBF or CBV alone, suggesting that the CBV threshold for infarction varies with CBF. For patients without recanalization, CBF and CBV for infarcted regions were 15.1+/-5.67 mL x 100 g(-1) x min(-1) and 1.17+/-0.41 mL x 100 g(-1), respectively. CONCLUSIONS: We have shown in a limited sample of patients that CBF and CBV obtained from CTP can be sensitive and specific for infarction and should be investigated further in a prospective trial to assess their utility for differentiating between infarct and penumbra.

Dynamic CT perfusion imaging in subarachnoid hemorrhage-related vasospasm.

BACKGROUND AND PURPOSE: Nimodipine is a therapy that reduces morbidity and mortality in patients with subarachnoid hemorrhage (SAH), though the mechanisms by which it does so are not well understood. In a rabbit model of SAH, we studied the effects of nimodipine by using functional CT imaging. We hypothesized that the nimodipine treatment group would have (1) increased mean basilar artery diameter, (2) less diminished cerebral blood flow (CBF) following vasospasm, and (3) better neurologic outcomes. METHODS: SAH was induced in 26 New Zealand White rabbits randomized to 2 groups: treated (nimodipine) or control (no treatment). CT perfusion and CT angiography were used to measure CBF and basilar artery diameter at baseline, 10, 30, and 60 minutes after SAH, and on days 3, 5, 7, 9, and 16. Neurologic assessments were performed on each day of scanning. RESULTS: Basilar artery diameter in the treated group was greater than in the control group post-SAH (P < .05). When vasospasm was >15%, CBF in the nimodipine group was significantly greater than in the control group in the brain stem, cerebellum, parieto-occipital cerebrum, and deep gray matter (P < .05). Neurologic scores in the nimodipine group were significantly better than in the control group on days 5 and 9 (P < .05). CONCLUSION: Animals treated with nimodipine showed (1) increased mean basilar artery diameter, (2) improved neurologic outcome, and (3) increased mean CBF despite no significant difference in the incidence and severity of delayed vasospasm. These data provide a basis for future studies comparing the efficacy of new treatments for SAH to that of nimodipine.