25 years of HIV research on virology, virus restriction, immunopathogenesis, genes and vaccines

From 19 to 21 May 2008 an important meeting was held at the Pasteur Institute in Paris to mark the 25th Anniversary of the discovery of HIV as the aetiological agent of AIDS. This review summarizes the historical findings, recent work and future directions presented at this meeting.     

Evaluation framework for carotid bifurcation lumen segmentation and stenosis grading

This paper describes an evaluation framework that allows a standardized and objective quantitative comparison of carotid artery lumen segmentation and stenosis grading algorithms. We describe the data repository comprising 56 multi-center, multi-vendor CTA datasets, their acquisition, the creation of the reference standard and the evaluation measures. This framework has been introduced at the MICCAI 2009 workshop 3D Segmentation in the Clinic: A Grand Challenge III, and we compare the results of eight teams that participated. These results show that automated segmentation of the vessel lumen is possible with a precision that is comparable to manual annotation. The framework is open for new submissions through the website http://cls2009.bigr.nl.     

How reliable are 40 MHz IVUS and 64-slice MDCT in characterizing coronary plaque composition? An ex vivo study with histopathological comparison

The present study investigated whether IVUS could serve as a reliable reference in validating MDCT characterization of coronary plaque against a histological gold standard. Twenty-one specimens were postmortem human coronary arteries. Coronary cross-sections were imaged by 40 MHz IVUS and by 64-slice MDCT and characterized histologically as presenting calcified, fibrous or lipid-rich plaques. Plaque composition was analyzed visually and intra-plaque MDCT attenuation was measured in Hounsfield Units (HU). 83 atherosclerotic plaques were identified. IVUS failed to characterize calcified plaque accurately, with a positive predictive value (ppv) of 75% versus 100% for MDCT. Lipid-rich plaque was even less accurately characterized, with ppv of 60 and 68% for IVUS and MDCT respectively. Mean MDCT attenuation was 966 ± 473 HU for calcified plaque, 83 ± 35 HU for fibrous plaque and 70.92 HU ± 41 HU for lipid-rich plaque. No significant difference in mean MDCT attenuation was found between fibrous and lipid-rich plaques (P = 0.276). In vivo validation of MDCT against an IVUS reference thus appears to be an unsuitable and unreliable approach: 40 MHz IVUS suffers from acoustic ambiguities in plaque characterization, and 64-slice MDCT fails to analyze plaque morphology and components accurately.     

CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract

The mechanisms underlying CD4(+) T cell depletion in human immunodeficiency virus (HIV) infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. Here, we studied the effect of HIV infection on the activation and depletion of defined subsets of CD4(+) and CD8(+) T cells in the blood, gastrointestinal (GI) tract, and lymph node (LN). We also measured HIV-specific T cell frequencies in LNs and blood, and LN collagen deposition to define architectural changes associated with chronic inflammation. The major findings to emerge are the following: the GI tract has the most substantial CD4(+) T cell depletion at all stages of HIV disease; this depletion occurs preferentially within CCR5(+) CD4(+) T cells; HIV-associated immune activation results in abnormal accumulation of effector-type T cells within LNs; HIV-specific T cells in LNs do not account for all effector T cells; and T cell activation in LNs is associated with abnormal collagen deposition. Taken together, these findings define the nature and extent of CD4(+) T cell depletion in lymphoid tissue and point to mechanisms of profound depletion of specific T cell subsets related to elimination of CCR5(+) CD4(+) T cell targets and disruption of T cell homeostasis that accompanies chronic immune activation.     

Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8(+) T cell responses

Vaccinia virus immunization provides lifelong protection against smallpox, but the mechanisms of this exquisite protection are unknown. We used polychromatic flow cytometry to characterize the functional and phenotypic profile of CD8(+) T cells induced by vaccinia virus immunization in a comparative vaccine trial of modified vaccinia virus Ankara (MVA) versus Dryvax immunization in which protection was assessed against subsequent Dryvax challenge. Vaccinia virus-specific CD8(+) T cells induced by both MVA and Dryvax were highly polyfunctional; they degranulated and produced interferon gamma, interleukin 2, macrophage inflammatory protein 1beta, and tumor necrosis factor alpha after antigenic stimulation. Responding CD8(+) T cells exhibited an unusual phenotype (CD45RO(-)CD27(intermediate)). The unique phenotype and high degree of polyfunctionality induced by vaccinia virus also extended to inserted HIV gene products of recombinant NYVAC. This quality of the CD8(+) T cell response may be at least partially responsible for the profound efficacy of these vaccines in protection against smallpox and serves as a benchmark against which other vaccines can be evaluated.     

Meta-analysis of tumour burden in pre-operative axillary ultrasound positive and negative breast cancer patients

Purpose

Radiotherapy (RT) after breast-conserving surgery for early-stage breast cancer patients has similar survival benefits with whole breast RT (WBRT) or accelerated partial breast irradiation (APBI). However, the impact of RT type and side-effects severity on change in quality of life (QOL) is unknown. We examined changes in RT side-effects severity and QOL by RT type.

Methods

We analyzed data from a cohort of 285 newly diagnosed early-stage breast cancer patients with tumor size ≤3.0 cm and lymph node-negative disease. Patients (93 [32.6%] stage 0; 49 [17.2%] non-white; mean age = 59.3 years) completed four interviews (6 weeks, 6, 12, and 24 months) after definitive surgical treatment. We measured severity of RT side effects, fatigue and skin irritation, using a 5-point scale (1 “not at all” to 5 “all the time”) and measured QOL using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and RAND 36-item Health Survey Vitality subscale. Repeated-measures analysis of covariance of each outcome controlled for demographic, clinical/treatment, and psychosocial factors.

Results

Patients initiated RT by 6 months (113 received APBI; 172 received WBRT) and completed RT by 12 months. Patients receiving WBRT (vs. APBI) reported greater increase in fatigue and skin irritation severity from 6-week to 6-month interviews (each P < 0.001). Improvement in neither total FACT-B nor Vitality differed significantly by RT type over 2-year follow-up.

Conclusions

Findings suggest that early-stage breast cancer patients can benefit from less-severe, short-term side effects of APBI with no differential impact on QOL change within 2-year follow-up.

     

Targeted intraoperative radiotherapy (TARGIT) yields very low recurrence rates when given as a boost

PURPOSE: Patients undergoing breast-conserving surgery were offered boost radiotherapy with targeted intraoperative radiotherapy (TARGIT) using the Intrabeam system to test the feasibility, safety, and efficacy of the new approach. METHODS AND MATERIALS: We treated 302 cancers in 301 unselected patients. This was not a low-risk group. One-third of patients (98/301) were younger than 51 years of age. More than half of the tumors (172, 57%) were between 1 cm and 2 cm, and one-fifth (62, 21%) were >2 cm; 29% (86) had a Grade 3 tumor and, in 29% (87), axillary lymph nodes contained metastasis. After primary surgery, 20 Gy was delivered intraoperatively to the surface of the tumor bed, followed by external-beam radiotherapy (EBRT), but excluding the usual boost. RESULTS: The treatment was well tolerated. The follow-up ranged from 3 to 80 months (164 and 90 patients completed 2 and 3 years follow-up, respectively). Four patients (1.3%) had local recurrence. The Kaplan-Meier estimate of local recurrence is 2.6% (SE = 1.7) at 5 years. This compares favorably with the 4.3% recurrence rate in boosted patients from the EORTC boost study, in which only 8.1% patients were node-positive, as opposed to 29% in our series. CONCLUSION: Targeted intraoperative radiotherapy combined with EBRT results in a low local recurrence rate. This could be attributed to both accurate targeting and timeliness of the treatment. These data support the need for a randomized trial to test whether the TARGIT boost is superior to conventional external boost, especially in high-risk women.     

Why should breast surgeons use ultrasound?

Portable ultrasound is now used in a variety of clinical settings by specialties outside of radiology. Despite increased accessibility to ultrasound, the overall performance of ultrasound by breast surgeons is consistently low. We discuss the reasons why this is unacceptable for future patient care and answer the question, ‘Why should breast surgeons use ultrasound?’ We reviewed the literature for evidence assessing the outcomes of breast surgeon-performed ultrasound both intra-operatively and in the outpatient department. Intra-operative ultrasound performed by surgeons reduces re-excision rates in breast-conserving surgery. Outpatient-based ultrasound performed by surgeons frees up the resources of radiology departments, allowing them to focus upon patients requiring more complex diagnostic and interventional procedures. For surgeons to competently perform intra-operative and outpatient-based ultrasound, a period of formal ultrasound training is necessary to acquire knowledge of ultrasound skills and techniques. This should be followed by a period of mentorship and supervised training with an experienced breast radiologist. Breast surgeon-performed ultrasound is beneficial to the multi-disciplinary care of breast cancer patients. To further improve multidisciplinary care, breast surgeons and radiologists should work more collaboratively to optimise imaging applications both in the operating theatre and outpatient department. Current advances in therapeutic percutaneous techniques are of interest to both surgeons and radiologists. In future, a hybrid specialisation should be considered to incorporate accreditation in both specialties for breast interventional procedures.