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Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) and is curative in ∼60% of patients. Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody that targets programmed death–ligand 1 and has previously shown antitumor activity in several tumor types. In a phase 1b/2 trial (NCT02596971), we evaluated the safety and efficacy of atezolizumab in combination with R-CHOP (atezo–R-CHOP; for 6-8 cycles) in patients with previously untreated DLBCL. Patients achieving a complete response (CR) at the end of induction received consolidation therapy with atezolizumab on day 1 of each 21-day cycle for an additional 17 cycles. Overall, 42 patients with DLBCL were included in this analysis. The primary endpoint, CR rate at the end of induction, as assessed by an independent review committee (modified Lugano 2014 criteria), was 77.5% (95% confidence interval [CI], 64.0-87.7; n = 40). Investigator-assessed progression-free survival and overall survival at 3 years were 77.4% (95% CI, 59.7-88.0) and 87.2% (95% CI, 71.9-94.5), respectively. All treated patients experienced ≥1 adverse event (AE; 32 patients [76.2%] had grade 3-4 AE). One patient had a fatal AE (unconfirmed progressive multifocal leukoencephalopathy) that was considered related to atezolizumab and rituximab, and 17 patients (40.5%) experienced atezolizumab-related AEs of special interest. In previously untreated patients with DLBCL, atezo–R-CHOP demonstrated encouraging clinical efficacy and a safety profile consistent with the known toxicities of the individual drugs. This trial was registered at www.clinicaltrials.gov as #NCT02596971.

Although advanced‑stage follicular lymphoma (FL) is considered incurable, survival has improved with the introduction of the anti-CD20 antibodies, rituximab (R) and obinutuzumab (G). However, FL can undergo histological transformation (HT) to a more aggressive disease, and a validated model for predicting HT risk is not yet available.We assessed HT incidence, risk factors and outcomes in the phase III, GALLIUM study evaluating R- or G-chemotherapy in patients with previously untreated, advanced-stage FL (ClinicalTrials.gov NCT01332968). HT rates were assessed by repeat tumour biopsy at disease progression or relapse, at the investigator's discretion.Of 1202 patients enrolled, 315 (26.2%) experienced progressive disease; 46 (14.6%) had a biopsy at first progression, 40 of whom had biopsy-confirmed HT. HT risk factors were male sex (subdistribution hazard ratio [sHR], 2.21; 95% confidence interval [CI], 1.16-4.20), elevated baseline serum lactate dehydrogenase (sHR, 3.97; 95% CI, 2.03-7.76), and elevated baseline serum βHT was a low-frequency event associated with poor survival outcomes in the GALLIUM study. Male sex and elevated baseline levels of serum LDH and B2M were significant risk factors for HT. Further research is required to develop validated prognostic indices for HT risk and guide treatment decisions.

Obinutuzumab (G) chemoimmunotherapy demonstrated improved progression-free survival (PFS) vs rituximab-based chemoimmunotherapy in patients with previously untreated follicular lymphoma (FL) in the GALLIUM trial. Atezolizumab (atezo) is a programmed death-ligand 1 inhibitor with a complementary mechanism of action to G by restoring cytotoxic T-cell function. We evaluated the safety and efficacy of atezo-G-bendamustine in patients with previously untreated FL in a phase Ib/II trial (#NCT02596971). A safety run-in phase was followed by an expansion phase with atezo-G-bendamustine induction and atezo-G maintenance for ≤24 months. Forty patients with previously untreated FL were enrolled and treated with atezo-G-bendamustine. The primary endpoint, complete response (CR) rate, assessed by an independent review committee (IRC; modified Lugano 2014 criteria) was 75.0% (95% confidence interval [CI], 61.3% to 85.8%). Three-year investigator-assessed PFS and overall survival rates were 80.9% (95% CI, 63.9% to 90.5%) and 89.3% (95% CI, 73.9% to 95.9%), respectively. At baseline, 21/40 patients had circulating lymphoma-specific clonotypes and underwent repeat testing at end of induction; all were minimal residual disease negative (10−5 sensitivity), with 16 (76.2%) CRs, 3 (14.3%) partial responses, and 2 (9.5%) with stable disease (IRC assessed). Grade 5 (fatal) adverse events (AEs) were reported in 5 patients. The efficacy of atezo-G-bendamustine in previously untreated FL did not appear superior to G-bendamustine efficacy as seen in the GALLIUM trial, and the addition of atezo to G-bendamustine was associated with an increased risk of AEs. Particularly due to the unfavorable safety profile, this regimen cannot be recommended in patients with previously untreated FL. This trial was registered at www.clinicaltrials.gov as #NCT02596971.

Introduction A good response to initial therapy is key to maximizing survival in patients with diffuse large B-cell lymphoma (DLBCL), but patients with chemorefractory disease and early progression have poor outcomes. Patients and Methods Data from the GOYA study in patients with DLBCL who received first-line rituximab or obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were analyzed. Positron emission tomography/computed tomography (PET/CT)-derived characteristics associated with total metabolic tumor volume (TMTV) and clinical risk factors for primary chemorefractory disease and disease progression within 12 months (POD12) were explored. Results Of those patients fulfilling the criteria for analysis, 108/1126 (10%) were primary chemorefractory and 147/1106 (13%) had POD12. Primary chemorefractory and POD12 status were strongly associated with reduced overall survival. After multivariable analysis of clinical and imaging-based risk factors by backward elimination, only very high TMTV (quartile [Q] 1 vs. Q4 odds ratio [OR]: 0.45; P = .006) and serum albumin levels (low vs. normal OR of 1.86; P = .004) were associated with primary chemorefractoriness. After additionally accounting for BCL2/MYC translocation in a subset of patients, TMTV and BCL2/MYC double-hit status remained as significant predictors of primary chemorefractoriness (Q1 vs. Q4 OR: 0.32, P = .01 and double-hit vs. no-hit OR of 4.47, P = .02, respectively). Risk factors including very high TMTV, high sum of the product of the longest diameters (SPD), geographic region (Asia), short time since diagnosis, extranodal involvement and low serum albumin were retained for POD12. Conclusion PET-derived TMTV has prognostic value in identifying patients at risk of early treatment failure.

PURPOSE Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) represents the standard of care for first-line treatment of diffuse large B-cell lymphoma (DLBCL). However, many patients are unable to tolerate R-CHOP and have inferior outcomes. This study aimed to develop a practical tool to help physicians identify patients with newly diagnosed DLBCL unlikely to tolerate a full course of R-CHOP. METHODS We developed a predictive model (Tolerability of R-CHOP in Aggressive Lymphoma [TRAIL]) on the basis of a training data set from the phase III GOYA trial (obinutuzumab with CHOP v R-CHOP in 1L DLBCL) using a composite binary end point, identifying patients who prematurely stopped or required reductions of R-CHOP. Candidate predictive variables were selected on the basis of known baseline characteristics that contribute to patient frailty, comorbidity, and/or chemotherapy toxicity. TRAIL was developed using an iterative trial-and-error modeling process to fit a logistic regression model. The final model was evaluated for robustness using a GOYA holdout data set and the phase III MAIN (R-CHOP with or without bevacizumab in 1L DLBCL) R-CHOP-21 data set as external validation. RESULTS TRAIL includes four simple predictors available in the routine clinical setting: Charlson Comorbidity Index, presence of cardiovascular disease or diabetes, serum albumin, and creatinine clearance. Model generalization performance estimated by the area under the curve was around or above 0.70 across GOYA training, GOYA holdout, and MAIN data sets. Classifying patients into low-, intermediate- and high-risk categories, the proportion of patients experiencing a tolerability event was 3.3%, 12.4%, and 32.9%, respectively, in GOYA holdout, and 9.7%, 9.7%, and 34.2%, respectively, in MAIN. CONCLUSION TRAIL may be useful as a clinical decision support tool for treatment decisions in patients with DLBCL who may not tolerate standard chemoimmunotherapies.

Image texture analysis (radiomics) uses radiographic images to quantify characteristics that may identify tumour heterogeneity and associated patient outcomes. Using fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT)-derived data, including quantitative metrics, image texture analysis and other clinical risk factors, we aimed to develop a prognostic model that predicts survival in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) from GOYA (NCT01287741). Image texture features and clinical risk factors were combined into a random forest model and compared with the international prognostic index (IPI) for DLBCL based on progression-free survival (PFS) and overall survival (OS) predictions. Baseline FDG-PET scans were available for 1263 patients, 832 patients of these were cell-of-origin (COO)-evaluable. Patients were stratified by IPI or radiomics features plus clinical risk factors into low-, intermediate- and high-risk groups. The random forest model with COO subgroups identified a clearer high-risk population (45% 2-year PFS [95% confidence interval (CI) 40%-52%]; 65% 2-year OS [95% CI 59%-71%]) than the IPI (58% 2-year PFS [95% CI 50%-67%]; 69% 2-year OS [95% CI 62%-77%]). This study confirms that standard clinical risk factors can be combined with PET-derived image texture features to provide an improved prognostic model predicting survival in untreated DLBCL.

Introduction: Up to 40% of patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL) fail to achieve remission, or relapse, with standard-of-care rituximab (R) plus CHOP (R-CHOP). Atezolizumab (atezo) is a fully humanized anti-programmed death-ligand 1 (PD-L1) antibody with a complementary mode of action to R. We present updated data from an ongoing Phase I/II study (NCT02596971) evaluating the safety and efficacy of atezo combined with R-CHOP (R-CHOP-atezo) in pts with previously untreated DLBCL. This is an updated analysis performed at the end of consolidation (EOC). Methods: This open-label, multicenter study enrolled adults with previously untreated advanced DLBCL (ECOG performance status 0-2). Pts received induction treatment with R-CHOP-atezo (8 x 21-day cycles of R [375mg/m2 i.v. on Day 1 (Cycles 1-8)] and atezo [1200mg i.v. on Day 1 (Cycles 2−8)], and 6 or 8 cycles of CHOP, as determined by the investigator [INV]). Pts who had a complete response (CR) at end of induction (EOI) received consolidation treatment with atezo 1200mg i.v. on Day 1 of Cycles 9─25, every 21 days for 12 months. Pts are followed for 12 months after EOC. Primary endpoints were safety and efficacy as determined by CR rate at EOI by an independent review committee (IRC) using Lugano 2014 criteria (modified to include required confirmation of CR at EOI by biopsy in cases with bone marrow involvement at baseline, and confirmation of a PET-based partial response [PR] by CT-based CR or PR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: As of May 2019, 42 pts had enrolled and received treatment. Of these, 7 pts discontinued study treatment prior to EOI (protocol violation [n=1], adverse event [AE; n=4], progressive disease [PD; n=1] and withdrawn consent [n=1]); 5 more pts discontinued at EOI (PD [n=2] and PR [n=3]). Of 30 pts initiating consolidation treatment, 15 discontinued (AE [n=9], PD [n=3] and withdrawn consent [n=3]). Median observation time was 21.3 (0.7-29.2) months. Key baseline characteristics included: median age, 65 years; International Prognostic Index (IPI) score ≥3, 69%; cell of origin (COO; Nanostring): ABC (34%), GCB (53%), unclassified (12.5%). Among the 40 pts who received at least one dose of atezo, and were therefore evaluable for efficacy at EOI, 31 (77.5%) had a CR and 4 (10%) had a PR by IRC; PD occurred in 2 (5%) pts; 3 (7.5%) were not evaluable. At 6, 12, 18 (EOC) and 24 months, Kaplan-Meier estimates (95% CI) of INV-assessed PFS were 97.4% (82.8, 99.6), 83.6% (67.0, 92.3), 80.6% (63.5, 90.3) and 74.9% (54.3, 87.2), respectively, and those for OS were 100% (not evaluable), 97.5% (83.6, 99.6), 89.8% (75.1, 96.1) and 86.4% (70.0, 94.2), respectively. Kaplan-Meier survival curves for PFS and OS are shown in the Figure. All 42 pts in the safety population experienced ≥1 AE of any grade, with neutropenia (52.4%), constipation (42.9%) and fatigue (40.5%) the most common. Grade 3-4 AEs occurred in 28/42 (67%) pts during induction and 15/30 (50%) pts during consolidation. Hematologic events were the most common grade 3-4 AEs (Table). One fatal AE (unconfirmed progressive multifocal leukoencephalopathy) was reported during follow-up. Overall, 24% of pts had an AE of special interest (AESI). The most common AESIs during induction were lipase increased (n=1), hyperthyroidism (n=1) and amylase increased (n=1), and those during consolidation were lipase increased (n=2), pancreatitis (n=2) and hepatitis (n=2). These events were generally well managed by atezo discontinuation and steroid treatment, and were largely reversible. AEs led to discontinuation of any treatment in 15 (36%) pts. AEs that led to discontinuation of any treatment in ≥1 pt were neutropenia (n=3), lipase increased (n=3) and amylase increased (n=2). Despite a relatively high number of discontinuations due to AEs during consolidation, events were generally manageable and reversible and all pts maintained response at the time of the analysis. Exploratory biomarker data and minimal residual disease data will be presented. Conclusions: The EOI PET-CR response rate and preliminary PFS with R-CHOP-atezo are encouraging and at least comparable to those previously reported for R-CHOP. The overall safety profile of R-CHOP-atezo appears manageable and as expected, with no new safety signals reported with consolidation and no overall increase in toxicity other than immune-mediated events. Disclosures Younes: BMS: Research Funding; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; Genentech: Research Funding; Syndax: Research Funding; Xynomics: Consultancy; Biopath: Consultancy; Takeda: Honoraria; Abbvie: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Research Funding. Burke:Celgene: Consultancy; Roche/Genentech: Consultancy; Gilead: Consultancy. Cheson:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Diefenbach:Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Trillium: Research Funding. Hahn:Roche: Other: Roche paid airfare and accommodation for attendance at ASH 3 years ago . Hawkes:Takeda: Speakers Bureau; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Astra Zeneca: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mundi pharma: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Khan:Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau. Lossos:NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees. Vitolo:F. Hoffmann-La Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees. Yuen:Seattle Genetics, Inc.: Other: Travel expenses, Research Funding. Raval:Roche: Employment, Equity Ownership. Shivhare:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Sellam:Roche: Employment, Equity Ownership. Sharman:AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Atezolizumab (atezo) is a programmed death-ligand 1 (PD-L1) blocking antibody. In the United States, atezo is approved for treatment of pts with locally advanced or metastatic urothelial carcinoma who are: not eligible for cisplatin-containing chemotherapy (chemo) and whose tumors express PDL-1, or are not eligible for any platinum-containing chemo regardless of PD L1 status; or have disease progression during or following any platinum-containing chemo, or within 12 months of neoadjuvant or adjuvant chemo. Atezo is also approved: in combination with bevacizumab, paclitaxel and carboplatin for first-line treatment of pts with metastatic non-squamous non-small-cell lung carcinoma (NSCLC) with no EGFR or ALK genomic tumor aberrations, and for pts with metastatic NSCLC who have disease progression during or following platinum-containing chemo; in combination with paclitaxel protein-bound for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1; and in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer. Atezo is not approved for treatment of pts with multiple myeloma.

Introduction: Throughout the world, trauma is a leading cause of morbidity and mortality in the young and most active group of society. While specialist trauma centers play a critical role in the survival after severe trauma, the assessment of trauma-related costs, budgeting for adequate trauma capacity, and determining the cost-effectiveness of interventions in critical care are fraught with difficulties. Through a systematic review of the European literature on severe trauma, we aimed to identify the key elements that drive the costs of acute trauma care. Methods: A PubMed/MEDLINE search for articles relating the costs and economics of trauma was performed for the period January 1995 to July 2007. One hundred and seventy-three European publications were identified. Twelve publications were retrieved for complete review that provided original cost data, a breakdown of costs according to the different elements of trauma care, and focused on severe adult polytrauma. The identified publications presented studies from the UK (3), Germany (6), Italy (2), and Switzerland (1). Results: In all publications reviewed, length of stay in the intensive care unit (ICU; 60%) and requirements for surgical interventions (£ 25%) were the key drivers of hospital costs. The cost of transfusion during the initial rescue therapy can also be substantial, and in fact represented a significant portion of the overall cost of emergency and ICU care. Multiple injuries often require multiple surgical interventions, and prolonged ICU and hospital stay, and across all studies a clear relationship was observed between the severity of polytrauma injuries observed and overall treatment costs. While significant differences existed in the absolute costs of trauma care across countries, the key drivers of costs were remarkably similar. Conclusions: Irrespective of the idiosyncrasies of the national healthcare systems in Europe, severity of injury, length of stay in ICU, surgical interventions and transfusion requirements represent the key drivers of acute trauma care for severe injury.

The aim of this study was to assess the results of surgical and endovascular treatment of failing or failed infrainguinal vein bypasses. Eight hundred seventy-five patients with peripheral vein bypasses performed during a 5-year period were followed up prospectively by ankle blood pressure measurements and/or duplex scanning at 3, 6, 9, 12, 18, 24, 36, and 48 months. A total of 59 (7%) grafts required revision during the study period. Fifty-six juxtaanastomotic or intragraft stenoses in 46 failing but patent bypasses were electively revised. Thirty-one predominantly proximal and midgraft lesions in 28 grafts were treated surgically by patch angioplasty (n= 17), interposition/jump grafting (n= 10), or thromboendarterectomy (n= 4). Twenty-five predominantly distal stenoses in 18 grafts were treated by percutaneous transluminal balloon angioplasty (PTA). With this approach, surgery yielded a higher 12-month “primary” bypass patency after revision (72% vs 37%, P=0.02), a higher secondary patency (81% vs 48%, P=0.05) and a better limb survival (96% vs 64%, P=0.03) than PTA. Following thrombectomy (n=12) or thrombolysis (n= 1) of 13 occluded bypasses, a 6-month “primary” patency after revision of 31%, a secondary patency of 38%, and a limb survival of 61% were achieved. In conclusion surgical repair appears to be the most durable procedure in the management of threatened infrainguinal vein bypasses. PTA of distal vein graft lesions was associated with a high risk of restenosis and graft failure.

Previous research has indicated that intraplaque hemorrhage is a significant pathogenetic factor in carotid artery disease. The present study was undertaken to evaluate whether the clinical presentation of patients with carotid artery disease could be correlated to quantitative histologic analysis of surgically removed carotid specimens. Two-hundred-seventy patients undergoing carotid endarterectomy comprised the material. Symptomatology was assessed preoperatively. After removal, the carotid plaques were analyzed histologically for relative volume content of hemorrhage, fatty tissue, fibrous tissue, and calcification. There was no difference between asymptomatic and symptomatic patients. However, when the time interval between onset of symptoms and surgery was considered, plaques from patients with recent symptoms contained more hemorrhage compared with plaques from asymptomatic patients (p = 0.0045). The paper supports the theory of intraplaque hemorrhage being related to clinical events in carotid artery disease.

Purpose: The purpose of this study was to assess the impact of arteriovenous fistulas combined with varying degrees of stenosis on distal bypass hemodynamics and Doppler spectral parameters. Methods: In an in vitro flow model bypass stenoses causing 30%, 55%, and 70% diameter reduction were induced 10 cm upstream of a fistula with low outflow resistance. Flow and intraluminal pressure were measured proximal to the stenosis and downstream of the fistula. The waveform parameters peak systolic velocity, end-diastolic velocity, pulsatility index, and pulse rise time were determined from midstream Doppler spectra obtained 10 cm downstream of the fistula. All measurements were carried out with open and clamped fistula. Results: At 30% diameter reducing stenosis opening of the fistula induced a 12% systolic pressure drop across the stenosis but had no adverse effect on the Doppler waveform parameters. At 55% stenosis the pressure drop increased from 16% to 31% after fistula opening. This increased pressure drop was associated with a further reduction in peak systolic velocity, a decrease in pulsatility index, and an enhanced pulse rise time prolongation. Fistula opening at 70% stenosis increased the systolic pressure drop from 31% to 48% and had significant impact on all waveform parameters. Conclusions: Distal arteriovenous fistulas enhance pressure loss across stenoses and affect downstream velocity waveform configuration. The presence of a combined fistula and a stenosis mimics the distal hemodynamic conditions of a more severe stenosis. Assessment of the hemodynamic impact of fistulas must be undertaken in the evaluation of in situ vein bypass stenoses. (J Vasc Surg 1996;24;1043-9.)

Background and Purpose Echolucent carotid atherosclerotic plaques are associated with an increased risk of neurological symptoms. Elevated plasma triglycerides is a risk factor for cerebral and coronary infarction. This study examined these individual pathogenetic risk factors to determine whether they were related. Methods We included 85 symptomatic patients with at least 40% carotid artery stenosis. Plaque morphology of the relevant artery was evaluated by high-resolution B-mode ultrasonography as echolucent, echo-rich, or intermediate. Fasting and postprandial lipids and lipoproteins were measured before and at hourly intervals for 4 hours after a fatty meal (1 g cream fat per kilogram body weight). Results When we compared patients with echolucent plaques to patients with echo-rich or intermediate plaques, the former had higher fasting and postprandial plasma triglycerides ( P ≤.006), higher chylomicron remnants/VLDL cholesterol ( P =.02) and triglycerides ( P ≤.004), a larger area under the plasma triglyceride curve 0 to 4 hours after a fatty meal, with (AUC TG−TG 0h ) or without (AUC TG ) subtraction of fasting levels ( P =.007 and P =.003), a larger body mass index ( P =.03), and were younger ( P =.01). Multiple logistic regression analysis found that when age and body mass index were taken into account, fasting plasma and VLDL triglycerides, postprandial chylomicron remnants/VLDL triglycerides, AUC TG−TG 0h and AUC TG with odds ratios of 4.1, 3.8, 3.0, 2.7, and 4.3, respectively, were independent predictors of an echolucent plaque. Conclusions Echolucent carotid artery plaques are associated with elevated levels of triglyceride-rich lipoproteins in the fasting or postprandial state.

Objective:To correlate B-mode ultrasound findings to carotid plaque histology.Design:European multicentre study (nine centres).Material and Methods:Clinical presentation and risk factors were recorded and preoperative ultrasound Duplex scanning with special emphasis on B-mode imaging studies was performed in 270 patients undergoing carotid endarterectomy. Perioperatively, macroscopic plaque features were evaluated and the removed specimens were analysed histologically for fibrous tissue, calcification and ‘soft tissue’ (primarily haemorrhage and lipid).Results:Males had more soft tissue than females (p = 0.0006), hypertensive patients less soft tissue than normotensive (p = 0.01) and patients with recent symptoms more soft tissue than patients with earlier symptoms (p = 0.004). There was no correlation between surface description on ultrasound images compared to the surface judged intraoperatively by the surgeon. Echogenicity on B-mode images was inversely related to soft tissue (p = 0.005) and calcification was directly related to echogenicity (p < 0.0001). Heterogeneous plaques contained more calcification than homogeneous (p = 0.003), however, there was no difference in content of soft tissue.Conclusion:Ultrasound B-mode characteristics are related to the histological composition of carotid artery plaques and to patient's history. These results may imply that patients with distant symptoms may be regarded and treated as asymptomatic patients whereas asymptomatic patients with echolucent plaques should be considered for carotid endarterectomy.

With the aim of assessing the velocity profile of femoropopliteal and femorocrural vein bypasses, 128 patients undergoing infrainguinal vein bypass surgery entered a postoperative Duplex surveillance protocol, which included clinical assessment and Duplex scanning, using Doppler spectral analysis. Doppler spectra were obtained at three sites in each graft and the following waveform parameters recorded: maximum systolic velocity, minimum diastolic velocity and resistance index. In patent reconstructions systolic velocity decreased by 30% during the first 6 months after surgery. In the absence of arteriovenous fistulas the initially antegrade diastolic velocity was replaced by a retrograde flow within 3 months, whereas a forward flow in diastole was sustained in grafts with patent fistulas. Abnormal Duplex findings in 31 patients led to angiography and revision in 13 cases. Four revised grafts failed, while nine remained patent at follow-up 1-12 months later. Ten (56%) of 18 non-revised bypasses with abnormal Duplex findings failed within 9 months compared to 1 (1%) of 76 bypasses with a normal velocity profile (p0.00001). In conclusion, Ultrasound Duplex scanning with spectral analysis provides valuable information concerning haemodynamics of infrainguinal vein bypasses and identifies grafts at risk of thrombosis. Inclusion of low resistance index (0.75) as an additional criteria for detection of stenoses appears to improve the sensitivity of Duplex scanning.

In trauma patients with significant hemorrhage, it is hypothesized that failure to normalize prothrombin time (PT) after recombinant activated factor VII (rFVIIa) treatment predicts poor clinical outcomes and potentially indicates a need for additional therapeutic interventions.To assess the value of PT to predict outcomes after rFVIIa or placebo therapy, we performed a post hoc analysis of data from 169 severely injured, critically bleeding trauma patients who had 1-hour postdose PT measurements from two randomized clinical trials. Baseline characteristics and outcome parameters were compared between subjects with 1-hour postdose PTor=18 seconds and PT18 seconds.In rFVIIa-treated subjects, prolonged postdose PT valuesor=18 seconds were associated with significantly higher 24-hour mortality (60% vs. 3%; p0.001) and 30-day mortality, increased incidence of massive transfusion, and fewer intensive care unit-free days compared with postdose PT values18 seconds. Recombinant rFVIIa-treated subjects with postdose PTor=18 seconds had significantly lower baseline hemoglobin levels, fibrinogen levels, and platelet counts than subjects with postdose PT values18 seconds even though they received similar amounts of blood products before rFVIIa dosing. Placebo-treated subjects with postdose PTor=18 seconds had significantly increased incidence of massive transfusion, significantly decreased intensive care unit-free days, and significantly lower levels of fibrinogen and platelets at baseline compared with subjects with postdose PT values18 seconds.The presence of prolonged PT after rFVIIa or placebo therapy was associated with poor clinical outcomes. Because subjects with postdosing PTor=18 seconds had low levels of hemoglobin, fibrinogen, and platelets, this group may benefit from additional blood component therapy.

Not all coronary angiograms can be acquired through the femoral route. The transradial catheterisation procedure in patients with occlusive atherosclerotic iliofemoral disease is described. Transfemoral left-sided cardiac catheterisation was performed in approximately 99.5% of patients referred for coronary angiography, while out of 48 patients in whom transfemoral access was impossible, transradial coronary angiography was successful in 37. With the exception of one, all patients with coronary artery disease had lesions of the right coronary artery, more than 70% had multivessel disease and 14% had stenosis of the left main coronary artery. Ten patients had angioplasty performed during the same procedure. Complications occurred in 5 out of 39 cases, 2 (5%) of these were severe. Although the femoral route was used in more than 99% of an unselected population referred for coronary angiography, it was found that transradial angiography and angioplasty can be performed in patients with occlusive atherosclerotic iliofemoral disease with considerable success and an acceptable complication rate.

Summary Background Penetrating trauma injury is generally associated with higher short-term mortality than blunt trauma, and results in substantial societal costs given the young age of those typically injured. Little information exists on the patient and treatment characteristics for penetrating trauma in England and Wales, and the acute outcomes and costs of care have not been documented and analysed in detail. Methods Using the Trauma Audit Research Network (TARN) database, we examined patient records for persons aged 18+ years hospitalised for penetrating trauma injury between January 2000 and December 2005. Patients were stratified by injury severity score (ISS). Results 1365 patients were identified; 16% with ISS 1–8, 50% ISS 9–15, 15% ISS 16–24, 16% ISS 25–34, and 4% with ISS 35–75. The median age was 30 years and 91% of patients were men. Over 90% of the injuries occurred in alleged assaults. Stabbings were the most common cause of injury (73%), followed by shootings (19%). Forty-seven percent were admitted to critical care for a median length of stay of 2 days; median total hospital length of stay was 7 days. Sixty-nine percent of patients underwent at least one surgical procedure. Eight percent of the patients died before discharge, with a mean time to death of 1.6 days (S.D. 4.0). Mortality ranged from 0% among patients with ISS 1–8 to 55% in patients with ISS > 34. The mean hospital cost per patient was £7983, ranging from £6035 in patients with ISS 9–15 to £16,438 among patients with ISS > 34. Costs varied significantly by ISS, hospital mortality, cause and body region of injury. Conclusion The acute treatment costs of penetrating trauma injury in England and Wales vary by patient, injury and treatment characteristics. Measures designed to reduce the incidence and severity of penetrating trauma may result in significant hospital cost savings.

AIMS To review the pharmacokinetics of rFVIIa in various patient populations, and to discuss the differences observed between groups. METHODS Based on a registry of Novo Nordisk studies, 14 studies evaluating rFVIIa pharmacokinetics following single and multiple bolus administration in healthy volunteers, adult and paediatric patients with congenital haemophilia and inhibitors, patients undergoing liver surgery and in patients with cirrhosis, inherited FVII deficiency, upper gastrointestinal bleeding or severe trauma were identified. Data on rFVIIa PK, analyzed with noncompartmental and population pharmacokinetic methods, were extracted. RESULTS Plasma clearance was a more robust parameter than half-life for comparing rFVIIa pharmacokinetics between groups. In healthy volunteers and patients with no or low-level bleeding (e.g. adults with haemophilia, nonbleeding patients with cirrhosis), plasma clearance was relatively low (30–40 ml kg−1 h−1). In children with haemophilia and adults with high-level bleeding (e.g. cirrhotic patients undergoing orthotopic liver transplantation or resection) and patients with congenital FVII deficiency, plasma clearance was relatively higher (60–90 ml kg−1 h−1). CONCLUSIONS Comparison of plasma clearance rates in different patient populations suggested that subjects fall into two distinct groups. These differences may have clinical implications in terms of how to adapt the rFVIIa dosing regimen, depending on the expected bleeding rate/blood loss and underlying disease.

A series of 124 patients had their greater saphenous vein assessed with duplex ultrasound scanning prior to planned infrainguinal bypass procedures. 33 (27%) bypass procedures thrombosed within the first year. A naturally occurring optimal vein diameter was discovered: 5.0-6.5 mm at mid-thigh level and 1.0-1.5 mm less at mid-calf level. It was significantly correlated with higher one year patency: thrombosis occured in 8% of the cases in veins with this optimal diameter combination and in 31 % of the cases in all other combinations (P < 0.001).

Objective: To relate the histological composition of carotid artery plaques with morphology as evaluated by B-mode ultrasound. Design: Prospective study. Material and Methods: Seventy-eight symptomatic patients underwent carotid end-arterectomy after preoperative ultrasound Duplex scanning evaluating plaque morphology. Morphometric analysis of the removed specimen was performed in order to quantify content of lipid, haemorrhage, calcification and fibrous tissue. Results: Echolucent plaques contained more lipid ( p = 0.01) and less calcification ( p = 0.01) and fibrous tissue ( p = 0.03) than echo-rich plaques. Intraplaque haemorrhage was directly related to lipid content ( p = 0.004) and inversely related to amount of fibrous tissue in the plaque ( p = 0.02). Conclusion: The intensity of the reflected B-mode ultrasound signal appears related to the histological composition of the plaque. The association between intraplaque haemorrhage and a high lipid content may support the theory of the lipid-rich plaque being more prone to rupture.

Objectives: To assess the association between antibodies to cardiolipin and infrainguinal vein graft patency. Materials and Methods: Plasma levels of antibodies to cardiolipin, haemostatic factors, lipids and the smoking marker carboxyhaemoglobin were determined preoperatively and 6 weeks postoperatively in 80 patients undergoing infrainguinal vein bypass surgery. Bypass patency was assessed by ankle blood pressure measurements and ultrasound duplex scanning at 1 week, 6 weeks, 3, 6, 9 and 12 months. A localised increase in the graft peak systolic velocity by a factor of 2.5 or more was considered to indicate a significant stenosis. Results: Antibodies to cardiolipin were identified in seven (9%) patients preoperatively. In four of these seven patients the bypasses thrombosed within 3 months after surgery and another two developed stenoses. At 6 months the primary bypass patency, i.e. patency without stenosis, was 14% (95% confidence interval (CI) 0–33%) in patients with antibodies to cardiolipin, as opposed to 57% (95% CI 45–69%) in patients without these antibodies (log rank test: p = 0.03). Diabetes mellitus was also associated with a reduced 6 months' primary bypass patency (38% (95% CI 16–60%) vs. 58% (95% CI 45–71%), p = 0.006). A Cox regression analysis showed that both the presence of antibodies to cardiolipin and diabetes independently contributed towards predicting the overall risk of bypass failure. Conclusion: Antibodies to cardiolipin were identified in 9% of patients undergoing infrainguinal vein bypass surgery and appeared to be associated with increased risk of bypass failure.

Objectives:To determine the incidence of postoperative neurological complications following carotid endarterectomy in patients with severely compromised cerebral circulation.Design:Prospective open clinical study.Setting:Department of Vascular Surgery, University Hospital.Materials and Methods:We determined the incidence of postendarterectomy seizures related to haemodynamic impairment in terms of intraoperatively measured perfusion pressure in 151 patients undergoing 153 carotid endarterectomies.Main Results:Cerebral perfusion pressure index (ICA/CCA pressure ratio) was significantly reduced (25% or more) in 47% (55/118) of patients with 70–99% stenosis compared to 6% (2/35) of patients with 30–69% stenosis (p < 0.00005). Among the 57 haemodynamically compromised patients five developed seizures considered due to cerebral hyperperfusion five to seven days after surgery. The seizures were associated with headache in two, focal neurological deficits in four and hypertensive episodes in all cases. The symptoms remitted within 2 weeks and no patients suffered cerebral haemorrhage.Conclusions:Seizures following correction of high grade stenoses causing severe pressure reduction may be more common than previously assumed. Patients at risk should be identified and postoperative blood pressure controlled meticulously.