Long-Term Survival in HIV Positive Patients with up to 15 Years of Antiretroviral Therapy

Background

Life expectancy has increased for newly diagnosed HIV patients since the inception of combination antiretroviral treatment (cART), but there remains a need to better understand the characteristics of long-term survival in HIV-positive patients. We examined long-term survival in HIV-positive patients receiving cART in the Australian HIV Observational Database (AHOD), to describe changes in mortality compared to the general population and to develop longer-term survival models.

Methods

Data were examined from 2,675 HIV-positive participants in AHOD who started cART. Standardised mortality ratios (SMR) were calculated by age, sex and calendar year across prognostic characteristics using Australian Bureau of Statistics national data as reference. SMRs were examined by years of duration of cART by CD4 and similarly by viral load. Survival was analysed using Cox-proportional hazards and parametric survival models.

Results

The overall SMR for all-cause mortality was 3.5 (95% CI: 3.0–4.0). SMRs by CD4 count were 8.6 (95% CI: 7.2–10.2) for CD4<350 cells/µl; 2.1 (95% CI: 1.5–2.9) for CD4 = 350–499 cells/µl; and 1.5 (95% CI: 1.1–2.0) for CD4≥500 cells/µl. SMRs for patients with CD4 counts <350 cells/µL were much higher than for patients with higher CD4 counts across all durations of cART. SMRs for patients with viral loads greater than 400 copies/ml were much higher across all durations of cART. Multivariate models demonstrated improved survival associated with increased recent CD4, reduced recent viral load, younger patients, absence of HBVsAg-positive ever, year of HIV diagnosis and incidence of ADI. Parametric models showed a fairly constant mortality risk by year of cART up to 15 years of treatment.

Conclusion

Observed mortality remained fairly constant by duration of cART and was modelled accurately by accepted prognostic factors. These rates did not vary much by duration of treatment. Changes in mortality with age were similar to those in the Australian general population.     

Does Tumor Size Improve the Accuracy of Prognostic Predictions in Node-Negative Gastric Cancer (pT1-4aN0M0 Stage)?

Background

The prognostic importance of tumor size in gastric cancer is unclear. This study investigated whether the inclusion of tumor size could improve prognostic accuracy in node-negative gastric cancer.

Methods

Clinical and pathological data of 492 patients with node-negative gastric cancer who underwent radical surgery in our department from January 1995 to December 2008 were analyzed. The prognostic accuracy of T stage was compared with that of T stage plus tumor size. The ability of tumor size to improve the 95% confidence interval (CI) of postoperative 5-year survival rate in gastric cancer patients was assessed. Different T stages plus tumor size were further analyzed to assess improvements in prognosis.

Results

Mean tumor size was 3.79±1.98 cm with a normal distribution. Multivariate analysis showed that tumor size and T stage were independent prognostic factors. Postoperative 5-year survival rate tended to decrease as tumor size increased in 1 cm increments. The addition of tumor size to T stage improved accuracy in predicting 5-year survival by 4.2% (P<0.05), as well as improving the 95% CI of postoperative 5-year survival rate by 3.2–5.1%. The addition of tumor size improved the predictive accuracy of postoperative 5-year survival rate by 3.9% (95% CI 70.4%–91.1%, P = 0.033) in patients with stage T3N0M0 tumors and by 6.5% (95% CI 68.7%–88.4%, P = 0.014) in patients with stage T4aN0M0 tumors.

Conclusions

Tumor size is an independent prognostic factor for survival in patients with node-negative gastric cancer, as well as improving prognostic accuracy in stage T3/4aN0M0 tumors.     

Non-Invasive Detection of Coronary Endothelial Response to Sequential Handgrip Exercise in Coronary Artery Disease Patients and Healthy Adults

Objectives

Our objective is to test the hypothesis that coronary endothelial function (CorEndoFx) does not change with repeated isometric handgrip (IHG) stress in CAD patients or healthy subjects.

Background

Coronary responses to endothelial-dependent stressors are important measures of vascular risk that can change in response to environmental stimuli or pharmacologic interventions. The evaluation of the effect of an acute intervention on endothelial response is only valid if the measurement does not change significantly in the short term under normal conditions. Using 3.0 Tesla (T) MRI, we non-invasively compared two coronary artery endothelial function measurements separated by a ten minute interval in healthy subjects and patients with coronary artery disease (CAD).

Methods

Twenty healthy adult subjects and 12 CAD patients were studied on a commercial 3.0 T whole-body MR imaging system. Coronary cross-sectional area (CSA), peak diastolic coronary flow velocity (PDFV) and blood-flow were quantified before and during continuous IHG stress, an endothelial-dependent stressor. The IHG exercise with imaging was repeated after a 10 minute recovery period.

Results

In healthy adults, coronary artery CSA changes and blood-flow increases did not differ between the first and second stresses (mean % change ±SEM, first vs. second stress CSA: 14.8%±3.3% vs. 17.8%±3.6%, p = 0.24; PDFV: 27.5%±4.9% vs. 24.2%±4.5%, p = 0.54; blood-flow: 44.3%±8.3 vs. 44.8%±8.1, p = 0.84). The coronary vasoreactive responses in the CAD patients also did not differ between the first and second stresses (mean % change ±SEM, first stress vs. second stress: CSA: −6.4%±2.0% vs. −5.0%±2.4%, p = 0.22; PDFV: −4.0%±4.6% vs. −4.2%±5.3%, p = 0.83; blood-flow: −9.7%±5.1% vs. −8.7%±6.3%, p = 0.38).

Conclusion

MRI measures of CorEndoFx are unchanged during repeated isometric handgrip exercise tests in CAD patients and healthy adults. These findings demonstrate the repeatability of noninvasive 3T MRI assessment of CorEndoFx and support its use in future studies designed to determine the effects of acute interventions on coronary vasoreactivity.     

Effects of a Seven Day Overload-Period of High-Intensity Training on Performance and Physiology of Competitive Cyclists

Objectives

Competitive endurance athletes commonly undertake periods of overload training in the weeks prior to major competitions. This investigation examined the effects of two seven-day high-intensity overload training regimes (HIT) on performance and physiological characteristics of competitive cyclists.

Design

The study was a matched groups, controlled trial.

Methods

Twenty-eight male cyclists (mean ± SD, Age: 33±10 years, Mass 74±7 kg, VO₂ peak 4.7±0.5 L·min⁻¹) were assigned to a control group or one of two training groups for seven consecutive days of HIT. Before and after training cyclists completed an ergometer based incremental exercise test and a 20-km time-trial. The HIT sessions were ∼120 minutes in duration and consisted of matched volumes of 5, 10 and 20 second (short) or 15, 30 and 45 second (long) maximal intensity efforts.

Results

Both the short and long HIT regimes led to significant (p<0.05) gains in time trial performance compared to the control group. Relative to the control group, the mean changes (±90% confidence limits) in time-trial power were 8.2%±3.8% and 10.4%±4.3% for the short and long HIT regimes respectively; corresponding increases in peak power in the incremental test were 5.5%±2.7% and 9.5%±2.5%. Both HIT (short vs long) interventions led to non-significant (p>0.05) increases (mean ± SD) in VO₂ peak (2.3%±4.7% vs 3.5%±6.2%), lactate threshold power (3.6%±3.5% vs 2.9%±5.3%) and gross efficiency (3.2%±2.4% vs 5.1%±3.9%) with only small differences between HIT regimes.

Conclusions

Seven days of overload HIT induces substantial enhancements in time-trial performance despite non-significant increases in physiological measures with competitive cyclists.     

Near-Infrared Transillumination Back Scattering Sounding—New Method to Assess Brain Microcirculation in Patients with Chronic Carotid Artery Stenosis

Purpose

The purpose of the study was to assess the responses of pial artery pulsation (cc-TQ) and subarachnoid width (sas-TQ) to acetazolamide challenge in patients with chronic carotid artery stenosis and relate these responses to changes in peak systolic velocity (PSV), cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and time to peak response (TTP).

Methods

Fifteen patients with carotid artery stenosis ≥90% on the ipsilateral side and <50% on the contralateral side were enrolled into the study. PSV was assessed using colour-coded duplex sonography, CBF, CBV, MTT and TTP with perfusion computed tomography, cc-TQ and sas-TQ with near-infrared transillumination/backscattering sounding (NIR-T/BSS).

Results

Based on the ipsilateral/contralateral cc-TQ ratio after acetazolamide challenge two groups of patients were distinguished: the first group with a ratio ≥1 and the second with a ratio <1. In the second group increases in CBF and CBV after the acetazolamide test were significantly higher in both hemispheres (ipsilateral: +33.0%±8.1% vs. +15.3%±4.4% and +26.3%±6.6% vs. +14.3%±5.1%; contralateral: +26.8%±7.0% vs. +17.6%±5.6% and +20.0%±7.3% vs. +10.0%±3.7%, respectively), cc-TQ was significantly higher only on the ipsilateral side (+37.3%±9.3% vs. +26.6%±8.6%) and the decrease in sas-TQ was less pronounced on the ipsilateral side (−0.7%±1.5% vs. −10.2%±1.5%), in comparison with the first group. The changes in sas-TQ following the acetazolamide test were consistent with the changes in TTP.

Conclusions

The ipsilateral/contralateral cc-TQ ratio following acetazolamide challenge may be used to distinguish patient groups characterized by different haemodynamic parameters. Further research on a larger group of patients is warranted.     

Differentiation of Central Lung Cancer from Atelectasis: Comparison of Diffusion-Weighted MRI with PET/CT

Objective

Prospectively assess the performance of diffusion-weighted magnetic resonance imaging (DW-MRI) for differentiation of central lung cancer from atelectasis.

Materials and Methods

38 consecutive lung cancer patients (26 males, 12 females; age range: 28–71 years; mean age: 49 years) who were referred for thoracic MR imaging examinations were enrolled. MR examinations were performed using a 1.5-T clinical scanner and scanning sequences of T1WI, T2WI, and DWI. Cancers and atelectasis were measured by mapping of the apparent diffusion coefficients (ADCs) obtained with a b-value of 500 s/mm².

Results

PET/CT and DW-MR allowed differentiation of tumor and atelectasis in all 38 cases, but T2WI did not allow differentiation in 9 cases. Comparison of conventional T2WI and DW-MRI indicated a higher contrast noise ratio of the central lung carcinoma than the atelectasis by DW-MRI. ADC maps indicated significantly lower mean ADC in the central lung carcinoma than in the atelectasis (1.83±0.58 vs. 2.90±0.26 mm²/s, p<0.0001). ADC values of small cell lung carcinoma were significantly greater than those from squamous cell carcinoma and adenocarcinoma (p<0.0001 for both).

Conclusions

DW-MR imaging provides valuable information not obtained by conventional MR and may be useful for differentiation of central lung carcinoma from atelectasis. Future developments may allow DW-MR imaging to be used as an alternative to PET-CT in imaging of patients with lung cancer.     

Treatment Initiation,Program Attrition and Patient Treatment Outcomes Associated with Scale-Up and Decentralization of HIV Care in Rural Malawi

Objective

To describe patient antiretroviral therapy (cART) outcomes associated with intensive decentralization of services in a rural HIV program in Malawi.

Methods

Longitudinal analysis of data from HIV-infected patients starting cART between August 2001 and December 2008 and of a cross-sectional immunovirological assessment conducted 12 (±2) months after therapy start. One-year mortality, lost to follow-up, and attrition (deaths and lost to follow-up) rates were estimated with exact Poisson 95% confidence intervals (CI) by type of care delivery and year of initiation. Association of virological suppression (<50 copies/mL) and immunological success (CD4 gain ≥100 cells/µL), with type of care was investigated using multiple logistic regression.

Results

During the study period, 4322 cART patients received centralized care and 11,090 decentralized care. At therapy start, patients treated in decentralized health facilities had higher median CD4 count levels (167 vs. 130 cell/µL, P<0.0001) than other patients. Two years after cART start, program attrition was lower in decentralized than centralized facilities (9.9 per 100 person-years, 95% CI: 9.5–10.4 vs. 20.8 per 100 person-years, 95% CI: 19.7–22.0). One year after treatment start, differences in immunological success (adjusted OR = 1.23, 95% CI: 0.83–1.83), and viral suppression (adjusted OR = 0.80, 95% CI: 0.56–1.14) between patients followed at centralized and decentralized facilities were not statistically significant.

Conclusions

In rural Malawi, 1- and 2-year program attrition was lower in decentralized than in centralized health facilities and no statistically significant differences in one-year immunovirological outcomes were observed between the two health care levels. Longer follow-up is needed to confirm these results.     

Poor Clinical Outcomes for HIV Infected Children on Antiretroviral Therapy in Rural Mozambique: Need for Program Quality Improvement and Community Engagement

Introduction

Residents of Zambézia Province, Mozambique live from rural subsistence farming and fishing. The 2009 provincial HIV prevalence for adults 15–49 years was 12.6%, higher among women (15.3%) than men (8.9%). We reviewed clinical data to assess outcomes for HIV-infected children on combination antiretroviral therapy (cART) in a highly resource-limited setting.

Methods

We studied rates of 2-year mortality and loss to follow-up (LTFU) for children <15 years of age initiating cART between June 2006–July 2011 in 10 rural districts. National guidelines define LTFU as >60 days following last-scheduled medication pickup. Kaplan-Meier estimates to compute mortality assumed non-informative censoring. Cumulative LTFU incidence calculations treated death as a competing risk.

Results

Of 753 children, 29.0% (95% CI: 24.5, 33.2) were confirmed dead by 2 years and 39.0% (95% CI: 34.8, 42.9) were LTFU with unknown clinical outcomes. The cohort mortality rate was 8.4% (95% CI: 6.3, 10.4) after 90 days on cART and 19.2% (95% CI: 16.0, 22.3) after 365 days. Higher hemoglobin at cART initiation was associated with being alive and on cART at 2 years (alive: 9.3 g/dL vs. dead or LTFU: 8.3–8.4 g/dL, p<0.01). Cotrimoxazole use within 90 days of ART initiation was associated with improved 2-year outcomes Treatment was initiated late (WHO stage III/IV) among 48% of the children with WHO stage recorded in their records. Marked heterogeneity in outcomes by district was noted (p<0.001).

Conclusions

We found poor clinical and programmatic outcomes among children taking cART in rural Mozambique. Expanded testing, early infant diagnosis, counseling/support services, case finding, and outreach are insufficiently implemented. Our quality improvement efforts seek to better link pregnancy and HIV services, expand coverage and timeliness of infant diagnosis and treatment, and increase follow-up and adherence.     

Monitoring Early Response to Anti-Angiogenic Therapy: Diffusion-Weighted Magnetic Resonance Imaging and Volume Measurements in Colon Carcinoma Xenografts

Objectives

To evaluate the use of diffusion-weighted MRI (DW-MRI) and volume measurements for early monitoring of antiangiogenic therapy in an experimental tumor model.

Materials and Methods

23 athymic nude rats, bearing human colon carcinoma xenografts (HT-29) were examined before and after 6 days of treatment with regorafenib (n = 12) or placebo (n = 11) in a clinical 3-Tesla MRI. For DW-MRI, a single-shot EPI sequence with 9 b-values (10–800 s/mm²) was used. The apparent diffusion coefficient (ADC) was calculated voxelwise and its median value over a region of interest, covering the entire tumor, was defined as the tumor ADC. Tumor volume was determined using T2-weighted images. ADC and volume changes between first and second measurement were evaluated as classifiers by a receiver-operator-characteristic (ROC) analysis individually and combined using Fisher''s linear discriminant analysis (FLDA).

Results

All ADCs and volumes are stated as median±standard deviation. Tumor ADC increased significantly in the therapy group (0.76±0.09×10⁻³ mm²/s to 0.90±0.12×10⁻³ mm²/s; p<0.001), with significantly higher changes of tumor ADC than in the control group (0.10±0.11×10⁻³ mm²/s vs. 0.03±0.09×10⁻³ mm²/s; p = 0.027). Tumor volume increased significantly in both groups (therapy: 347.8±449.1 to 405.3±823.6 mm³; p = 0.034; control: 219.7±79.5 to 443.7±141.5 mm³; p<0.001), however, the therapy group showed significantly reduced tumor growth (33.30±47.30% vs. 96.43±31.66%; p<0.001). Area under the curve and accuracy of the ADC-based ROC analysis were 0.773 and 78.3%; and for the volume change 0.886 and 82.6%. The FLDA approach yielded an AUC of 0.985 and an accuracy of 95.7%.

Conclusions

Regorafenib therapy significantly increased tumor ADC after 6 days of treatment and also significantly reduced tumor growth. However, ROC analyses using each parameter individually revealed a lack of accuracy in discriminating between therapy and control group. The combination of both parameters using FLDA substantially improved diagnostic accuracy, thus highlighting the potential of multi-parameter MRI as an imaging biomarker for non-invasive early tumor therapy monitoring.     

Virtual Touch Tissue Quantification of Acoustic Radiation Force Impulse: A New Ultrasound Elastic Imaging in the Diagnosis of Thyroid Nodules

Objective

Virtual touch tissue quantification (VTQ) of acoustic radiation force impulse (ARFI) is a new quantitative technique to measure tissue stiffness. The study was aimed to assess the usefulness of VTQ in the diagnosis of thyroid nodules.

Methods

173 pathologically proven thyroid nodules in 142 patients were included and all were examined by conventional ultrasound (US), conventional elasticity imaging (EI) and VTQ of ARFI. The tissue stiffness for VTQ was expressed as shear wave velocity (SWV) (m/s). Receiver-operating characteristic curve (ROC) analyses were performed to assess the diagnostic performance. Intra- and inter-observer reproducibility of VTQ measurement was assessed.

Results

The SWVs of benign and malignant thyroid nodules were 2.34±1.17 m/s (range: 0.61–9.00 m/s) and 4.82±2.53 m/s (range: 2.32–9.00 m/s) respectively (P<0.001). The mean SWV ratios between each nodule and the adjacent thyroid tissue were 1.19±0.67 (range: 0.31–6.87) for benign and 2.50±1.54 (range: 0.85–6.69) for malignant nodules (P<0.001). ROC analyses indicated that the area under the curve was 0.861 (95% CI : 0.804, 0.918) (P<0.001) for SWV and 0.831(95% CI : 0.761, 0.900)(P<0.001) for the SWV ratio. The cutoff points for the differential diagnosis were 2.87 m/s for SWV and 1.59 for SWV ratio. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for EI were 65.9%, 66.7%, 66.5%, 40.3%, and 85.1%, respectively, and were 63.6%–75%, 82.2%–88.4%, 80.3%–82.1%, 58.9%–65.1%, and 87.7%–90.5%, respectively, for VTQ. The diagnostic value of VTQ is the highest for nodules >20 mm and lowest for those ≤10 mm. The correlation coefficients were 0.904 for intraobserver measurement and 0.864 for interobserver measurement.

Conclusions

VTQ of ARFI provides quantitative and reproducible information about the tissue stiffness, which is useful for the differentiation between benign and malignant thyroid nodules. The diagnostic performance of VTQ is higher than that of conventional EI.     

Increased Platelet Reactivity in Idiopathic Pulmonary Fibrosis Is Mediated by a Plasma Factor

Introduction

Idiopathic Pulmonary Fibrosis (IPF) is a progressive, incurable fibrotic interstitial lung disease with a prognosis worse than many cancers. Its pathogenesis is poorly understood. Activated platelets can release pro-fibrotic mediators that have the potential to contribute to lung fibrosis. We determine platelet reactivity in subjects with IPF compared to age-matched controls.

Methods

Whole blood flow cytometry was used to measure platelet-monocyte aggregate formation, platelet P-selectin expression and platelet fibrinogen binding at basal levels and following stimulation with platelet agonists. A plasma swap approach was used to assess the effect of IPF plasma on control platelets.

Results

Subjects with IPF showed greater platelet reactivity than controls. Platelet P-selectin expression was significantly greater in IPF patients than controls following stimulation with 0.1 µM ADP (1.9% positive ±0.5 (mean ± SEM) versus 0.7%±0.1; p = 0.03), 1 µM ADP (9.8%±1.3 versus 3.3%±0.8; p<0.01) and 10 µM ADP (41.3%±4.2 versus 22.5%±2.6; p<0.01). Platelet fibrinogen binding was also increased, and platelet activation resulted in increased platelet-monocyte aggregate formation in IPF patients. Re-suspension of control platelets in plasma taken from subjects with IPF resulted in increased platelet activation compared to control plasma.

Conclusions

IPF patients exhibit increased platelet reactivity compared with controls. This hyperactivity may result from the plasma environment since control platelets exhibit increased activation when exposed to IPF plasma.     

Pretreatment CD4 Cell Slope and Progression to AIDS or Death in HIV-Infected Patients Initiating Antiretroviral Therapy—The CASCADE Collaboration: A Collaboration of 23 Cohort Studies

Background

CD4 cell count is a strong predictor of the subsequent risk of AIDS or death in HIV-infected patients initiating combination antiretroviral therapy (cART). It is not known whether the rate of CD4 cell decline prior to therapy is related to prognosis and should, therefore, influence the decision on when to initiate cART.

Methods and Findings

We carried out survival analyses of patients from the 23 cohorts of the CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) collaboration with a known date of HIV seroconversion and with at least two CD4 measurements prior to initiating cART. For each patient, a pre-cART CD4 slope was estimated using a linear mixed effects model. Our primary outcome was time from initiating cART to a first new AIDS event or death. We included 2,820 treatment-naïve patients initiating cART with a median (interquartile range) pre-cART CD4 cell decline of 61 (46–81) cells/µl per year; 255 patients subsequently experienced a new AIDS event or death and 125 patients died. In an analysis adjusted for established risk factors, the hazard ratio for AIDS or death was 1.01 (95% confidence interval 0.97–1.04) for each 10 cells/µl per year reduction in pre-cART CD4 cell decline. There was also no association between pre-cART CD4 cell slope and survival. Alternative estimates of CD4 cell slope gave similar results. In 1,731 AIDS-free patients with >350 CD4 cells/µl from the pre-cART era, the rate of CD4 cell decline was also not significantly associated with progression to AIDS or death (hazard ratio 0.99, 95% confidence interval 0.94–1.03, for each 10 cells/µl per year reduction in CD4 cell decline).

Conclusions

The CD4 cell slope does not improve the prediction of clinical outcome in patients with a CD4 cell count above 350 cells/µl. Knowledge of the current CD4 cell count is sufficient when deciding whether to initiate cART in asymptomatic patients. Please see later in the article for the Editors'' Summary     

Direct Transformation of Lung Microenvironment by Interferon-α Treatment Counteracts Growth of Lung Metastasis of Hepatocellular Carcinoma

Background

Interferon (IFN)-α is effective in inhibiting tumor growth and metastasis of hepatocellular carcinoma (HCC). However, the biologic mechanisms of IFN-α treatment in lung metastasis are not yet clear.

Methods

The effect of IFN-α treatment was studied by using an orthotopic xenograft model and measuring tumor size and lung metastasis. Pretreatment with IFN-α before implantation of tumor was done to explore the effect of IFN-α on lung tissues. Cytokines and macrophages were measured by immunohistochemistry and/or PCR assay, using human origin or mouse origin primers to differentiate the sources. Circulating tumor cells (CTCs) were also assayed by flow cytometry.

Results

IFN-α treatment did not decrease the number of CTCs (0.075%±0.020% versus 0.063%±0.018%, P = 0.574, IFN-α–treated versus control groups), but did decrease the number and size of lung metastasis (number: 1.75±1.0 versus 28.0±6.3, P = 0.008; size [pixels]: 116.8±72.2 versus 5226.4±1355.7, P = 0.020), and inhibited macrophage infiltration (0.20%±0.04% versus 1.36%±0.21%, P = 0.0058) and alteration of matrix metalloproteinase (MMP)-9 expression (mean integrated optical density (IOD): 5.1±1.7 versus 21.9±0.4, P<0.000) in the lung, which was independent of the primary tumor.

Conclusion

IFN-α inhibited lung metastasis by directly modulating the lung microenvironment.     

Radioimmunoimaging of Liver Metastases with PET Using a 64Cu-Labeled CEA Antibody in Transgenic Mice

Purpose

Colorectal cancer is one of the most common forms of cancer, and the development of novel tools for detection and efficient treatment of metastases is needed. One promising approach is the use of radiolabeled antibodies for positron emission tomography (PET) imaging and radioimmunotherapy. Since carcinoembryonic antigen (CEA) is an important target in colorectal cancer, the CEA-specific M5A antibody has been extensively studied in subcutaneous xenograft models; however, the M5A antibody has not yet been tested in advanced models of liver metastases. The aim of this study was to investigate the ⁶⁴Cu-DOTA-labeled M5A antibody using PET in mice bearing CEA-positive liver metastases.

Procedures

Mice were injected intrasplenically with CEA-positive C15A.3 or CEA-negative MC38 cells and underwent micro-computed tomography (micro-CT) to monitor the development of liver metastases. After metastases were detected, PET/MRI scans were performed with ⁶⁴Cu-DOTA-labeled M5A antibodies. H&E staining, immunohistology, and autoradiography were performed to confirm the micro-CT and PET/MRI findings.

Results

PET/MRI showed that M5A uptake was highest in CEA-positive metastases. The %ID/cm³ (16.5%±6.3%) was significantly increased compared to healthy liver tissue (8.6%±0.9%) and to CEA-negative metastases (5.5%±0.6%). The tumor-to-liver ratio of C15A.3 metastases and healthy liver tissue was 1.9±0.7. Autoradiography and immunostaining confirmed the micro-CT and PET/MRI findings.

Conclusion

We show here that the ⁶⁴Cu-DOTA-labeled M5A antibody imaged by PET can detect CEA positive liver metastases and is therefore a potential tool for staging cancer, stratifying the patients or radioimmunotherapy.     

Differentiation between Primary Cerebral Lymphoma and Glioblastoma Using the Apparent Diffusion Coefficient: Comparison of Three Different ROI Methods

Objective

Apparent diffusion coefficients (ADC) can help differentiate between central nervous system (CNS) lymphoma and Glioblastoma (GBM). However, overlap between ADCs for GBM and lymphoma have been reported because of various region of interest (ROI) methods. Our aim is to explore ROI method to provide the most reproducible results for differentiation.

Materials and Methods

We studied 25 CNS lymphomas and 62 GBMs with three ROI methods: (1) ROI₁, whole tumor volume; (2) ROI₂, multiple ROIs; and (3) ROI₃, a single ROI. Interobserver variability of two readers for each method was analyzed by intraclass correlation(ICC). ADCs were compared between GBM and lymphoma, using two-sample t-test. The discriminative ability was determined by ROC analysis.

Results

ADCs from ROI₁ showed most reproducible results (ICC >0.9). For ROI₁, ADC_mean for lymphoma showed significantly lower values than GBM (p = 0.03). The optimal cut-off value was 0.98×10⁻³ mm²/s with 85% sensitivity and 90% specificity. For ROI₂, ADC_min for lymphoma was significantly lower than GBM (p = 0.02). The cut-off value was 0.69×10⁻³ mm²/s with 87% sensitivity and 88% specificity.

Conclusion

ADC values were significantly dependent on ROI method. ADCs from the whole tumor volume had the most reproducible results. ADC_mean from the whole tumor volume may aid in differentiating between lymphoma and GBM. However, multi-modal imaging approaches are recommended than ADC alone for differentiation.     

Moderate/Severe Hyponatremia Increases the Risk of Death among Hospitalized Chinese Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Patients

Objectives

To evaluate whether the serum sodium concentration is associated with the progression and long-term prognosis of Chinese HIV/AIDS patients.

Methods

Three hundred and eighty seven hospitalized patients were recruited into this retrospective cohort study. The strata of serum sodium concentration were moderate/severe hyponatremia, mild hyponatremia and normonatremia. Disease progression was estimated using CD4 counts and the WHO clinical stage. Correlation analysis was used to evaluate the serum sodium concentration with disease progression. The Kaplan-Meier method and the Cox proportional hazards model were used to analyze the effect of different serum sodium levels on survival.

Results

In this study 206 patients (53.2%) had hyponatremia, including 10.6% patients with moderate/severe hyponatremia and 42.6% with mild hyponatremia. The serum sodium concentration was significantly correlated with the HIV/AIDS progression (P<0.001). During the follow-up, 100 patients (25.6%) died. The cumulative survival rates of HIV/AIDS patients were 47.8%±8.5% in patients with moderate/severe hyponatremia, 59.8%±5.0% with mild hyponatremia and 79.9%±3.4% with normonatremia (log-rank P<0.001). After adjusting for sex, age, WHO stage, CD4 count, hemoglobin and albumin, the relative hazard was 3.5 (95% CI: 1.9–6.5) for patients with moderate/severe hyponatremia (P<0.001), and 1.5 (95% CI: 0.9–2.4) for those with mild hyponatremia (P = 0.161), compared with normonatremic patients.

Conclusions

The serum sodium level is closely correlated with the severity of patients. Only moderate/severe hyponatremia affects the prognosis of Chinese HIV/AIDS patients. Earlier intensive medical managements(including HAART)are necessary to increase the survival rates of Chinese HIV/AIDS patients with moderate/severe hyponatremia.     

Effectiveness of early antiretroviral therapy initiation to improve survival among HIV-infected adults with tuberculosis: a retrospective cohort study

Background

Randomized clinical trials examining the optimal time to initiate combination antiretroviral therapy (cART) in HIV-infected adults with sputum smear-positive tuberculosis (TB) disease have demonstrated improved survival among those who initiate cART earlier during TB treatment. Since these trials incorporated rigorous diagnostic criteria, it is unclear whether these results are generalizable to the vast majority of HIV-infected patients with TB, for whom standard diagnostic tools are unavailable. We aimed to examine whether early cART initiation improved survival among HIV-infected adults who were diagnosed with TB in a clinical setting.

Methods and Findings

We retrospectively reviewed charts for 308 HIV-infected adults in Rwanda with a CD4 count≤350 cells/µl and a TB diagnosis. We estimated the effect of cART on survival using marginal structural models and simulated 2-y survival curves for the cohort under different cART strategies:start cART 15, 30, 60, or 180 d after TB treatment or never start cART. We conducted secondary analyses with composite endpoints of (1) death, default, or lost to follow-up and (2) death, hospitalization, or serious opportunistic infection. Early cART initiation led to a survival benefit that was most marked for individuals with low CD4 counts. For individuals with CD4 counts of 50 or 100 cells/µl, cART initiation at day 15 yielded 2-y survival probabilities of 0.82 (95% confidence interval: [0.76, 0.89]) and 0.86 (95% confidence interval: [0.80, 0.92]), respectively. These were significantly higher than the probabilities computed under later start times. Results were similar for the endpoint of death, hospitalization, or serious opportunistic infection. cART initiation at day 15 versus later times was protective against death, default, or loss to follow-up, regardless of CD4 count. As with any observational study, the validity of these findings assumes that biases from residual confounding by unmeasured factors and from model misspecification are small.

Conclusions

Early cART reduced mortality among individuals with low CD4 counts and improved retention in care, regardless of CD4 count. Please see later in the article for the Editors'' Summary     

Hemodynamic Effects of Stent Struts versus Straightening of Vessels in Stent-Assisted Coil Embolization for Sidewall Cerebral Aneurysms

Background

Recent clinical studies have shown that recanalization rates are lower in stent-assisted coil embolization than in coiling alone in the treatment of cerebral aneurysms.

Objective

This study aimed to assess and compare the hemodynamic effect of stent struts and straightening of vessels by stent placement on reducing flow velocity in sidewall aneurysms, with the goal of reducing recanalization rates.

Methods

We evaluated 16 sidewall aneurysms treated with Enterprise stents. We performed computational fluid dynamics simulations using patient-specific geometries before and after treatment, with or without stent struts.

Results

Stent placement straightened vessels by a mean (±standard deviation) of 12.9°±13.1° 6 months after treatment. Placement of stent struts in the initial vessel geometries reduced flow velocity in aneurysms by 23.1%±6.3%. Straightening of vessels without stent struts reduced flow velocity by 9.6%±12.6%. Stent struts had significantly stronger effects on reducing flow velocity than straightening (P = 0.004, Wilcoxon test). Deviation of the effects was larger by straightening than by stent struts (P = 0.01, F-test). The combination of stent struts and straightening reduced flow velocity by 32.6%±12.2%. There was a trend that larger inflow angles produced a larger reduction in flow velocity by straightening of vessels (P = 0.16).

Conclusion

In sidewall aneurysms, stent struts have stronger effects (approximately 2 times) on reduction in flow velocity than straightening of vessels. Hemodynamic effects by straightening vary in each case and can be predicted by inflow angles of pre-operative vessel geometry. These results may be useful to design a treatment strategy for reducing recanalization rates.     

Delay in cART Initiation Results in Persistent Immune Dysregulation and Poor Recovery of T-Cell Phenotype Despite a Decade of Successful HIV Suppression

Background

Successful combination antiretroviral therapy (cART) increases levels of CD4+ T-cells, however this increase may not accurately reflect long-term immune recovery since T-cell dysregulation and loss of T-cell homeostasis often persist. We therefore assessed the impact of a decade of effective cART on immune regulation, T-cell homeostasis, and overall T-cell phenotype.

Methods

We conducted a retrospective study of 288 HIV+ cART-naïve patients initiating therapy. We identified 86 individuals who received cART for at least a decade, of which 44 consistently maintained undetectable plasma HIV-RNA levels throughout therapy. At baseline, participants were classified into three groups according to pre-treatment CD4+ T-cell counts: Group I (CD4<200 cells/mm³); Group II (CD4: 200–350 cells/mm³); Group III (CD4>350 cells/mm³). Outcomes of interest were: (1) CD4+ T-cell count restoration (CD4>532 cells/mm³); (2) normalization of CD4:CD8 T-cell ratio (1.2–3.3); (3) maintenance of CD3+ T-cell homeostasis (CD3: 65%–85% of peripheral lymphocytes); (4) normalization of the complete T-cell phenotype (TCP).

Results

Despite a decade of sustained successful cART, complete T-cell phenotype normalization only occurred in 16% of patients, most of whom had initiated therapy at high CD4+ T-cell counts (>350 cells/mm³). The TCP parameter that was the least restored among patients was the CD4:CD8 T-cell ratio.

Conclusions

Failure to normalize the complete T-cell phenotype was most apparent in patients who initiated cART with a CD4+ T-cell count <200 cells/mm³. The impact of this impaired T-cell phenotype on life-long immune function and potential comorbidities remains to be elucidated.