Dynamic Contrast-Enhanced MRI in Abdominal Aortic Aneurysms as a Potential Marker for Disease Progression.

BACKGROUND: Abdominal aortic aneurysms (AAAs) may rupture before reaching maximum diameter (Dmax ) thresholds for repair. Aortic wall microvasculature has been associated with elastin content and rupture sites in specimens, but its relation to progression is unknown. PURPOSE: To investigate whether dynamic contrast-enhanced (DCE) MRI of AAA is associated with Dmax or growth. STUDY TYPE: Prospective. POPULATION: A total of 27 male patients with infrarenal AAA (mean age ± standard deviation = 75 ± 5 years) under surveillance with DCE MRI and 2 years of prior follow-up intervals with computed tomography (CT) or MRI. FIELD STRENGTH/SEQUENCE: A 3-T, dynamic three-dimensional (3D) fast gradient-echo stack-of-stars volumetric interpolated breath-hold examination (Star-VIBE). ASSESSMENT: Wall voxels were manually segmented in two consecutive slices at the level of Dmax . We measured slope to 1-minute and area under the curve (AUC) to 1 minute and 4 minutes of the signal intensity change postcontrast relative to that precontrast arrival, and, Ktrans , a measure of microvascular permeability, using the Patlak model. These were averaged over all wall voxels for association to Dmax and growth rate, and, over left/right and anterior/posterior quadrants for testing circumferential homogeneity. Dmax was measured orthogonal to the aortic centerline and growth rate was calculated by linear fit of Dmax measurements. STATISTICAL TESTS: Pearson correlation and linear mixed effects models. A P value <0.05 was considered statistically significant. RESULTS: In 44 DCE MRIs, mean Dmax was 45 ± 7 mm and growth rate in 1.5 ± 0.4 years of prior follow-up was 1.7 ± 1.2 mm per year. DCE measurements correlated with each other (Pearson r = 0.39-0.99) and significantly differed between anterior/posterior versus left/right quadrants. DCE measurements were not significantly associated with Dmax (P = 0.084, 0.289, 0.054 and 0.255 for slope, AUC at 1 minute and 4 minutes, and Ktrans , respectively). Slope and 4 minutes AUC significantly associated with growth rate after controlling for Dmax . CONCLUSION: Contrast uptake may be increased in lateral aspects of the AAA. Contrast enhancement 1-minute slope and 4-minutes AUC may be associated with a period of recent AAA growth that is independent of Dmax . EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Contrast-enhanced CT radiomics improves the prediction of abdominal aortic aneurysm progression.

OBJECTIVES: To determine if three-dimensional (3D) radiomic features of contrast-enhanced CT (CECT) images improve prediction of rapid abdominal aortic aneurysm (AAA) growth. METHODS: This longitudinal cohort study retrospectively analyzed 195 consecutive patients (mean age, 72.4 years ± 9.1) with a baseline CECT and a subsequent CT or MR at least 6 months later. 3D radiomic features were measured for 3 regions of the AAA, viz. the vessel lumen only; the intraluminal thrombus (ILT) and aortic wall only; and the entire AAA sac (lumen, ILT, and wall). Multiple machine learning (ML) models to predict rapid growth, defined as the upper tercile of observed growth (> 0.25 cm/year), were developed using data from 60% of the patients. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic curve (AUC) in the remaining 40% of patients. RESULTS: The median AAA maximum diameter was 3.9 cm (interquartile range [IQR], 3.3-4.4 cm) at baseline and 4.4 cm (IQR, 3.7-5.4 cm) at the mean follow-up time of 3.2 ± 2.4 years (range, 0.5-9 years). A logistic regression model using 7 radiomic features of the ILT and wall had the highest AUC (0.83; 95% confidence interval [CI], 0.73-0.88) in the development cohort. In the independent test cohort, this model had a statistically significantly higher AUC than a model including maximum diameter, AAA volume, and relevant clinical factors (AUC = 0.78, 95% CI, 0.67-0.87 vs AUC = 0.69, 95% CI, 0.57-0.79; p = 0.04). CONCLUSION: A radiomics-based method focused on the ILT and wall improved prediction of rapid AAA growth from CECT imaging. KEY POINTS: • Radiomic analysis of 195 abdominal CECT revealed that an ML-based model that included textural features of intraluminal thrombus (if present) and aortic wall improved prediction of rapid AAA progression compared to maximum diameter. • Predictive accuracy was higher when radiomic features were obtained from the thrombus and wall as opposed to the entire AAA sac (including lumen), or the lumen alone. • Logistic regression of selected radiomic features yielded similar accuracy to predict rapid AAA progression as random forests or support vector machines.

A spotlight on avoidance coping to manage fear of recurrence among breast cancer survivors in an eHealth intervention.

BACKGROUND: Fear of recurrence (FoR) is prevalent among breast cancer survivors (BCS) and may be exacerbated by avoidance coping. This study examined BCS with avoidance coping and their engagement in a FoR eHealth intervention (FoRtitude). METHODS: BCS (N = 196) with elevated FoR participated in FoRtitude. Patient-reported measures assessed avoidance coping with FoR and baseline emotional and behavioral health. Intervention engagement was measured quantitatively (e.g., website logins, telecoaching attendance) and qualitatively (i.e., telecoaching notes). RESULTS: 38 BCS (19%) endorsed avoidance coping, which was associated with more severe post-traumatic anxiety-related symptoms and worse global mental health (ps < .05), but not anxiety (p = .19), depression (p = .11), physical health (p = .12), alcohol consumption (p = .85), or physical activity (p = .39). Avoidance coping was not associated with engagement levels (ps > .05) but did characterize engagement-related motivators and barriers. CONCLUSIONS: Avoidance coping was not a barrier to FoRtitude engagement. eHealth delivery is a promising modality for engaging survivors with avoidance coping in FoR interventions.

Intraluminal Thrombus Predicts Rapid Growth of Abdominal Aortic Aneurysms.

Background Intraluminal thrombus (ILT) within abdominal aortic aneurysms (AAAs) may be a potential marker for subsequent aneurysm growth. Purpose To investigate the role of ILT in AAA progression as assessed with CT and MRI. Materials and Methods This was a retrospective study, with patient data included from January 2004 to December 2018 at a Veteran Affairs medical center. Male patients with AAA who underwent contrast material-enhanced CT at baseline and CT or black-blood MRI at follow-up (minimal follow-up duration of 6 months) were included. The maximal AAA diameter was measured with multiplanar reconstruction, and the annual growth rate of aneurysms was calculated. Uni- and multivariable linear regression analyses were used to determine the relationship between demographic and imaging factors and aneurysm growth. Results A total of 225 patients (mean age, 72 years ± 9 [standard deviation]) were followed for a mean of 3.3 years ± 2.5. A total of 207 patients were followed up with CT, and 18 were followed up with MRI. At baseline, the median size of the AAA was 3.8 cm (interquartile range [IQR], 3.3-4.3 cm); 127 of 225 patients (54.7%) had ILT. When compared with AAAs without ILT, AAAs with ILT had larger baseline diameters (median, 4.1 cm [IQR, 3.6-4.8 cm] vs 3.4 cm [IQR, 3.2-3.9 cm]; P < .001) and faster growth rates (median, 2.0 mm/y [IQR, 1.3-3.2 mm/y] vs 1.0 mm/y [IQR, 0.4-1.8 mm/y]; P < .001). Small AAAs (size range, 3-4 cm) with ILT grew 1.9-fold faster than did those without ILT (median, 1.5 mm/y [IQR, 0.9-2.7 mm/y] vs 0.8 mm/y [IQR, 0.3-1.5 mm/y]; P < .001). Medium AAAs (size range, 4-5 cm) with ILT had 1.2-fold faster growth than did those without ILT (median growth, 2.1 mm/y [IQR, 1.4, 3.7 mm/y] vs 1.8 mm/y [IQR, 0.9, 2.0 mm/y]; P = .06). In multivariable analysis, baseline diameter and ILT were independently positively related to aneurysm growth rate (standardized regression coefficient, 0.43 [P < .001] and 0.15 [P = .02], respectively). Conclusion Both maximal cross-sectional aneurysm diameter and the presence of intraluminal thrombus are independent predictors of abdominal aortic aneurysm growth. © RSNA, 2020 Online supplemental material is available for this article.

Outcomes for Relapsed and Refractory Peripheral T-Cell Lymphoma Patients after Front-Line Therapy from the COMPLETE Registry.

BACKGROUND: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data. OBJECTIVES: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease. METHODS: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days. RESULTS: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months. CONCLUSIONS: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.

The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study.

BACKGROUND: The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1. METHODS: Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis. RESULTS: Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P = .06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89). CONCLUSIONS: This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.

Evaluation of the distribution and progression of intraluminal thrombus in abdominal aortic aneurysms using high-resolution MRI.

BACKGROUND: Intraluminal thrombus (ILT) signal intensity on MRI has been studied as a potential marker of abdominal aortic aneurysm (AAA) progression. PURPOSE: 1) To characterize the relationship between ILT signal intensity and AAA diameter; 2) to evaluate ILT change over time; and 3) to assess the relationship between ILT features and AAA growth. STUDY TYPE: Prospective. SUBJECTS: Eighty AAA patients were imaged, and a subset (n = 41) were followed with repeated MRI for 16 ± 9 months. FIELD STRENGTH/SEQUENCE: 3D black-blood fast-spin-echo sequence at 3 T. ASSESSMENT: ILT was designated as "bright" if the signal was greater than 1.2 times that of adjacent psoas muscle. AAAs were divided into three groups based on ILT: Type 1: bright ILT; Type 2: isointense ILT; Type 3: no ILT. During follow-up, an active ILT change was defined as new ILT formation or an increase in ILT signal intensity to bright; stable ILT was defined as no change in ILT type or ILT became isointense from bright previously. STATISTICAL TESTS: Shapiro-Wilk test; Mann-Whitney U-test; Fisher's exact test; Kruskal-Wallis test; Spearman's r; intraclass correlation coefficient (ICC), Cohen's kappa. RESULTS: AAAs with Type 1 ILT were larger than those with Types 2 and 3 ILT (5.1 ± 1.1 cm, 4.4 ± 0.9 cm, 4.2 ± 0.8 cm, P = 0.008). The growth rate of AAAs with Type 1 ILT was significantly greater than that of AAAs with Types 2 and 3 ILT (2.6 ± 2.5, 0.6 ± 1.3, 1.5 ± 0.6 mm/year, P = 0.01). During follow-up, AAAs with active ILT changes had a 3-fold increased growth rate compared with AAAs with stable ILT (3.6 ± 3.0 mm/year vs. 1.2 ± 1.5 mm/year, P = 0.008). DATA CONCLUSION: AAAs with bright ILT are larger in diameter and grow faster. Active ILT change is associated with faster AAA growth. Black-blood MRI can characterize ILT features and monitor their change over time, which may provide new insights into AAA risk assessment. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2019;50:994-1001.

On the Relative Impact of Intraluminal Thrombus Heterogeneity on Abdominal Aortic Aneurysm Mechanics.

Intraluminal thrombus (ILT) is present in the majority of abdominal aortic aneurysms (AAA) of a size warranting consideration for surgical or endovascular intervention. The rupture risk of AAAs is thought to be related to the balance of vessel wall strength and the mechanical stress caused by systemic blood pressure. Previous finite element analyses of AAAs have shown that ILT can reduce and homogenize aneurysm wall stress. These works have largely considered ILT to be homogeneous in mechanical character or have idealized a stiffness distribution through the thrombus thickness. In this work, we use magnetic resonance imaging (MRI) to delineate the heterogeneous composition of ILT in 7 AAAs and perform patient-specific finite element analysis under multiple conditions of ILT layer stiffness disparity. We find that explicit incorporation of ILT heterogeneity in the finite element analysis is unlikely to substantially alter major stress analysis predictions regarding aneurysm rupture risk in comparison to models assuming a homogenous thrombus, provided that the maximal ILT stiffness is the same between models. Our results also show that under a homogeneous ILT assumption, the choice of ILT stiffness from values common in the literature can result in significantly larger variations in stress predictions compared to the effects of thrombus heterogeneity.

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.

BACKGROUND: Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. METHODS: We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. FINDINGS: Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months [95% CI 11·8-15·7] vs 9·6 months [8·6-11·2]; hazard ratio [HR] 0·73 [95% CI 0·62-0·87], p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months [95% CI 12·6-18·0] with atezolizumab vs 10·3 months [8·8-12·0] with docetaxel; HR 0·74 [95% CI 0·58-0·93]; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 [95% CI 0·59-0·96]). Overall survival improvement was similar in patients with squamous (HR 0·73 [95% CI 0·54-0·98]; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 [0·60-0·89]; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. INTERPRETATION: To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. FUNDING: F. Hoffmann-La Roche Ltd, Genentech, Inc.

Clinicopathologic analysis of a large series of microinvasive breast cancers.

Clinical management of microinvasive breast cancer (Tmic) remains controversial. Although metastases are infrequent in Tmic carcinoma patients, surgical treatment typically includes lymph node sampling. The objective of this study was to determine the rate and predictors of lymph node metastases, recurrence, and survival in a large series of Tmic breast carcinomas. Consecutive cases of Tmic were identified within our health care system from 2001 to 2015. We reviewed results of lymph node sampling and other pathologic factors including hormone receptor/HER2 status, associated in situ tumor size/grade, margin status, number of invasive foci, surgical/adjuvant therapies, and recurrence/survival outcomes. In this cohort, 294 Tmic cases were identified with mean follow-up of 4.6 years. Of 260 patients who underwent axillary staging, lymph node metastases were identified in 1.5% (all of which were ductal type). All Tmic cases with positive lymph node metastases had associated DCIS with size > 5 cm (5.3-8.5 cm) compared to a median DCIS tumor size of 2.5 cm (0.2-19.0 cm) for the entire cohort. No lymph node metastases were seen with microinvasive lobular carcinoma. During the follow-up period, there were no regional/distant recurrences or breast cancer-associated deaths in a mean follow-up period of 4.6 years. Two patients developed subsequent ipsilateral breast cancer (DCIS) in a different quadrant than the original Tmic. Clinical behavior of microinvasive breast cancer in this series is similar to DCIS. Lymph node metastases are uncommon and were only seen with ductal type microinvasive carcinoma. Our data suggest limited benefit for routine node sampling and support management of Tmic similar to DCIS, particularly for patients with DCIS < 5 cm in size.

Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.

BACKGROUND: Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer. METHODS: In this ongoing, multicentre, open-label, phase 2 trial, we enrolled adults (aged ≥18 years) with histologically confirmed recurrent or metastatic colorectal cancer locally assessed as dMMR/MSI-H from 31 sites (academic centres and hospitals) in eight countries (Australia, Belgium, Canada, France, Ireland, Italy, Spain, and the USA). Eligible patients had progressed on or after, or been intolerant of, at least one previous line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan. Patients were given 3 mg/kg nivolumab every 2 weeks until disease progression, death, unacceptable toxic effects, or withdrawal from study. The primary endpoint was investigator-assessed objective response as per Response Evaluation Criteria in Solid Tumors (version 1.1). All patients who received at least one dose of study drug were included in all analyses. This trial is registered with ClinicalTrials.gov, number NCT02060188. FINDINGS: Of the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, 40 (54%) had received three or more previous treatments. At a median follow-up of 12·0 months (IQR 8·6-18·0), 23 (31·1%, 95% CI 20·8-42·9) of 74 patients achieved an investigator-assessed objective response and 51 (69%, 57-79) patients had disease control for 12 weeks or longer. Median duration of response was not yet reached; all responders were alive, and eight had responses lasting 12 months or longer (Kaplan-Meier 12-month estimate 86%, 95% CI 62-95). The most common grade 3 or 4 drug-related adverse events were increased concentrations of lipase (six [8%]) and amylase (two [3%]). 23 (31%) patients died during the study; none of these deaths were deemed to be treatment related by the investigator. INTERPRETATION: Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic colorectal cancer, and could be a new treatment option for these patients. FUNDING: Bristol-Myers Squibb.

Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial.

BACKGROUND: Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of patients with advanced, platinum-treated non-small-cell lung cancer (NSCLC). METHODS: In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing. FINDINGS: Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (IQR 7·2-11·9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (≥3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8-18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression. INTERPRETATION: Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting. FUNDING: Merck KGaA and Pfizer.

A prospective cohort study of patients with peripheral T-cell lymphoma in the United States.

BACKGROUND: Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States. METHODS: Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided. RESULTS: Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P = .03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P = .09]). CONCLUSIONS: To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2017;123:1174-1183. © 2016 American Cancer Society.

Non-contrast 3D black blood MRI for abdominal aortic aneurysm surveillance: comparison with CT angiography.

OBJECTIVES: Management of abdominal aortic aneurysms (AAAs) is based on diameter. CT angiography (CTA) is commonly used, but requires radiation and iodinated contrast. Non-contrast MRI is an appealing alternative that may allow better characterization of intraluminal thrombus (ILT). This study aims to 1) validate non-contrast MRI for measuring AAA diameter, and 2) to assess ILT with CTA and MRI. METHOD: 28 patients with AAAs (diameter 50.7 ± 12.3 mm) underwent CTA and non-contrast MRI. MRI was acquired at 3 T using 1) a conventional 3D gradient echo (GRE) sequence and 2) a 3D T1-weighted black blood fast-spin-echo sequence. Two radiologists independently measured the AAA diameter. The ratio of signal of ILT and adjacent psoas muscle (ILTr = signalILT/signalMuscle) was quantified. RESULTS: Strong agreement between CTA and non-contrast MRI was shown for AAA diameter (intra-class coefficient > 0.99). Both approaches had excellent inter-observer reproducibility (ICC > 0.99). ILT appeared homogenous on CTA, whereas MRI revealed compositional variations. Patients with AAAs ≥5.5 cm and <5.5 cm had a variety of distributions of old/fresh ILT types. CONCLUSIONS: Non-contrast 3D black blood MRI provides accurate and reproducible AAA diameter measurements as validated by CTA. It also provides unique information about ILT composition, which may be linked with elevated risk for disease progression. KEY POINTS: • Non-contrast MRI is an appealing alternative to CTA for AAA management. • Non-contrast MRI can accurately measure AAA diameters compared to CTA. • MRI affords unique characterization of intraluminal thrombus composition.

Tumor histopathology predicts outcomes after resection of colorectal cancer liver metastases treated with and without pre-operative chemotherapy.

BACKGROUND AND OBJECTIVES: Study objectives, included determination of: (i) associations between radiologic and pathologic responses of colorectal cancer liver metastases (CRCLM) to chemotherapy; and (ii) whether CRCLM histopathology is associated with recurrence free survival (RFS) after resection among patients not treated with pre-operative chemotherapy (untreated). METHODS: Demographics, clinicopathologic characteristics, and outcomes among patients who underwent CRCLM resection from 2007 to 2014 were reviewed. Tumor regression grade (TRG) of 1-2 and 4-5 depict low and high proportions of viable tumor relative to fibrosis, respectively. RESULTS: Of 138 patients, 84 (60.9%) were treated with pre-operative chemotherapy. In these patients, there was no difference in proportions with TRG 1-2 among those with verses without radiologic response (26.9% vs. 18.8%, P = 0.393). TRG 1-2 was associated with superior RFS on univariable (median 15 vs. 6 months, P < 0.001) and multivariable (P = 0.005) analyses. Radiologic response was not associated with RFS. Among untreated patients (n = 54), TRG 4-5 was associated with poor RFS on univariable (median 44 vs. 15 months, P = 0.011) and multivariable (P = 0.012) analyses. CONCLUSIONS: High proportions of CRCLM fibrosis occur in 20% of patients without radiologic response to chemotherapy. Among untreated patients, high proportion of viable tumor relative to fibrosis is associated with poor RFS after resection. J. Surg. Oncol. 2016;113:456-462. © 2016 Wiley Periodicals, Inc.

Clot Through the Heart: Paradoxical Embolism With Thrombus-in-Transit at Multidetector Computed Tomography.

We present the case of a 67-year-old man with concomitant stroke and pulmonary embolism 1 day after radiofrequency catheter ablation for refractory atrial tachycardia. A chest computed tomographic angiogram revealed "thrombus-in-transit" across a patent foramen ovale, confirming the diagnosis of paradoxical embolism. Paradoxical embolism is a rare definitive diagnosis. Our case is a key demonstration of the even rarer instance where such a diagnosis is confirmed at multidetector computed tomography.

A phase 1b study of trebananib in combination with pegylated liposomal doxorubicin or topotecan in women with recurrent platinum-resistant or partially platinum-sensitive ovarian cancer.

OBJECTIVE: To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. METHODS: In this open-label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m(2) (cohorts A1 and A3, respectively) or topotecan 4 mg/m(2) (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary). RESULTS: 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n=1) and sudden death (n=1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug-drug interactions were apparent. CONCLUSIONS: Trebananib 10mg/kg and 15 mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts.

Temporal Evolution of Ascending Aortic Aneurysm Wall Stress Predicts All-Cause Mortality.

OBJECTIVES: Diameter-based risk stratification for elective repair of ascending aortic aneurysm fails to prevent type A dissection in many patients. Aneurysm wall stresses may contribute to risk prediction; however, rates of wall stress change over time are poorly understood. Our objective was to examine aneurysm wall stress changes over three to five years and subsequent all-cause mortality. METHODS: Male veterans with <5.5-cm ascending aortic aneurysms and computed tomography at baseline and 3 to 5-years follow-up underwent three-dimensional aneurysm model construction. Peak circumferential and longitudinal wall stresses at systole were calculated using finite element analysis. Temporal trends were assessed by mixed-effects modelling. Changes in aortic wall stresses, diameter, and length over time were evaluated as predictors of subsequent 3-year all-cause mortality by Cox proportional hazards modelling. RESULTS: Sixty-two male veterans were included in the study. Yearly changes in geometric and biomechanical measures were 0.12 mm/yr (95% CI, 0.04-0.20) for aortic diameter, 0.41 mm/yr (0.12-0.71) for aortic length, 1.19 kPa/yr (-5.94-8.33) for peak circumferential stress, and 0.48 kPa/yr (-3.89-4.84) for peak longitudinal stress. Yearly change in peak circumferential stress was significantly associated with hazard of death-hazard ratio for peak circumferential stress growth per 10 kPa/yr, 1.27 (95% CI, 1.02-1.60; p = 0.037); hazard ratio for peak circumferential stress growth ≥ 32 kPa/yr, 8.47 (95% CI, 2.42-30; p < 0.001). CONCLUSIONS: In this population of nonsurgical aneurysm patients, large temporal changes in peak circumferential stress, but not aortic diameter or length, was associated with all-cause mortality. Biomechanical stress and stress changes over time may be beneficial as additional risk factors for elective surgery in small aneurysms.

Height and body surface area versus wall stress for stratification of mid-term outcomes in ascending aortic aneurysm.

Objectives: Current diameter-based guidelines for ascending thoracic aortic aneurysms (aTAA) do not consistently predict risk of dissection/rupture. ATAA wall stresses may enhance risk stratification independent of diameter. The relation of wall stresses and diameter indexed to height and body surface area (BSA) is unknown. Our objective was to compare aTAA wall stresses with indexed diameters in relation to all-cause mortality at 3.75 years follow-up. Methods: Finite element analyses were performed in a veteran population with aortas ≥ 4.0 cm. Three-dimensional geometries were reconstructed from computed tomography with models accounting for pre-stress geometries. A fiber-embedded hyperelastic material model was applied to obtain wall stress distributions under systolic pressure. Peak wall stresses were compared across guideline thresholds for diameter/BSA and diameter/height. Hazard ratios for all-cause mortality and surgical aneurysm repair were estimated using cause-specific Cox proportional hazards models. Results: Of 253 veterans, 54 (21 %) had aneurysm repair at 3.75 years. Indexed diameter alone would have prompted repair at baseline in 17/253 (6.7 %) patients, including only 4/230 (1.7 %) with diameter < 5.5 cm. Peak wall stresses did not significantly differ across guideline thresholds for diameter/BSA (circumferential: p = 0.15; longitudinal: p = 0.18), but did differ for diameter/height (circumferential: p = 0.003; longitudinal: p = 0.048). All-cause mortality was independently associated with peak longitudinal stresses (p = 0.04). Peak longitudinal stresses were best predicted by diameter (c-statistic = 0.66), followed by diameter/height (c-statistic = 0.59), and diameter/BSA (c-statistic = 0.55). Conclusions: Diameter/height improved stratification of peak wall stresses compared to diameter/BSA. Peak longitudinal stresses predicted all-cause mortality independent of age and indexed diameter and may aid risk stratification for aTAA adverse events.