Therapeutic cancer vaccines

The clinical benefit of therapeutic cancer vaccines has been established. Whereas regression of lesions was shown for premalignant lesions caused by HPV, clinical benefit in cancer patients was mostly noted as prolonged survival. Suboptimal vaccine design and an immunosuppressive cancer microenvironment are the root causes of the lack of cancer eradication. Effective cancer vaccines deliver concentrated antigen to both HLA class I and II molecules of DCs, promoting both CD4 and CD8 T cell responses. Optimal vaccine platforms include DNA and RNA vaccines and synthetic long peptides. Antigens of choice include mutant sequences, selected cancer testis antigens, and viral antigens. Drugs or physical treatments can mitigate the immunosuppressive cancer microenvironment and include chemotherapeutics, radiation, indoleamine 2,3-dioxygenase (IDO) inhibitors, inhibitors of T cell checkpoints, agonists of selected TNF receptor family members, and inhibitors of undesirable cytokines. The specificity of therapeutic vaccination combined with such immunomodulation offers an attractive avenue for the development of future cancer therapies.     

Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients: a prospective phase II study

Thalidomide is an effective agent for patients with refractory multiple myeloma (MM) with a response rate of 30–40% at doses of 200–800 mg but with considerable side effects. We questioned whether lower doses of thalidomide in combination with a daily dose of cyclophosphamide might be an effective regimen with fewer side effects. We included 38 patients with relapsed or refractory MM. The median doses of thalidomide and cyclophosphamide were 100 and 95 mg/day, respectively. Side effects were observed in all patients, with neurotoxicity as the most troublesome. With a median follow-up of 14 months 84% of the patients responded, including 64% partial responses. The median time of progression-free survival was 30 months and the median overall survival time was 20 months. In conclusion, the results demonstrate that the combination of low-dose thalidomide with a daily dose of cyclophosphamide is an effective regimen with a high overall response rate and manageable side effects.This work is financially supported by research funding from the KWF (Dutch Cancer Society)Conflict of interest: There are no financial and personal relationsships with other people or organisations that could inappropriately influence (bias) our work.     

The Influence of Overweight/Obesity on Patient-Perceived Physical Functioning and Health-Related Quality of Life After Primary Total Hip Arthroplasty

Background  

Overweight/obesity in patients after total hip arthroplasty (THA) is a growing problem and is associated with postoperative complications and a negative effect on functional outcome. The objective of this study is to determine to what extent overweight/obesity is associated with physical functioning and health-related quality of life 1 year after primary THA.     

Seven‐year safety and efficacy of the unrestricted use of drug‐eluting stents in saphenous vein bypass grafts

Objectives : The aim was to investigate the 7‐year clinical outcomes of patients treated with either drug‐eluting stents (DES) or bare‐metal stents (BMS) for saphenous vein graft disease (SVG). Background : Atherosclerotic disease in SVG has several peculiarities which make it difficult to extrapolate outcomes of the use of DES as compared to BMS, from outcomes observed in native coronary arteries. To date no long‐term safety and efficacy results for DES in SVG have been published. Methods : Between January, 2000 and December, 2005 a total of 250 consecutive patients with saphenous vein graft disease were sequentially treated with DES (either sirolimus‐ or paclitaxel‐eluting stents) or with BMS. Yearly follow‐up was performed. Results : At 87 months (7.25 years), a total of 101 patients died (58 [46%] in the BMS group and 43 [42%] in the DES group, P‐value= 0.4). There was no significant difference in the combined endpoint mortality or myocardial infarction. Cumulative target vessel revascularisation (TVR) was higher in the BMS group compared to the DES group (41% vs. 29%, respectively; adjusted hazard ratio [HR] 0.63, 95% confidence interval [CI]: 0.39–1.0). The cumulative incidence of major adverse cardiac events was 73% vs. 68% in the BMS and DES groups, respectively (adjusted HR 0.93, 95% CI: 0.67–1.3). Conclusions : In the present study, the unrestricted use of DES for SVG lesions appeared safe and effective up to 7.25 years‐ and the use of DES resulted in a clinically relevant lower rate of TVR. © 2011 Wiley Periodicals, Inc.     

Different subsets of tumor-infiltrating lymphocytes correlate with macrophage influx and monosomy 3 in uveal melanoma

Purpose. In contrast to many other malignancies, in uveal melanoma (UM) the presence of an immune infiltrate is associated with a bad prognosis. An analysis of the different functional phenotypes of tumor-infiltrating leukocytes (TIL) and a comparison with the genetic background of the tumors may help to explain this apparent anomaly. Methods. We performed a comprehensive immunohistochemical study by evaluating the density of CD8(+) and CD4(+) T lymphocytes, forkhead box p3 (Foxp3(+)) regulatory T cells (Tregs), and CD68(+) and CD68(+)CD163(+) macrophages in 43 cases of UM in relation to tumor characteristics. Expression of the chemokines CCL2, CCL17, and CCL22 in cultured human UM cells and peripheral blood monocytes was analyzed by quantitative PCR (qPCR). Results. The presence of TILs was highly variable between tumors and was dominated by CD8(+) T cells with fewer CD4(+) T cells and Tregs. When tumors were infiltrated by immune cells, the infiltrate generally comprised all different subsets of lymphocytes (P < 0.001) and M2 macrophages (P < 0.001). Different T-cell ratios did not influence clinical outcome. In addition, the presence of TIL correlated with the loss of one chromosome 3 (P < 0.04). UM cells express CCL2 and CCL22, two chemokines known to mediate trafficking of immune cells to the tumor. Conclusions. All studied subtypes of tumor-infiltrating immune cells were collectively increased and showed an association with monosomy of chromosome 3 suggesting that tumor intrinsic factors control the leukocyte influx, possibly through local chemokine secretion.     

Long-Term Serial Follow-Up of Pulmonary Artery Size and Wall Shear Stress in Fontan Patients

Pulmonary arterial (PA) flow is abnormal after the Fontan operation and is marked by a lack of pulsatility. We assessed the effects of this abnormal flow on the size and function of the PA’s in Fontan patients in long-term serial follow-up. Twenty-three Fontan patients with serial follow-up were included. Median age was 11.1 (9.5–16.0) years at baseline and 15.5 (12.5–22.7) years at follow-up. Median follow-up duration was 4.4 (4.0–5.8) years. Flow and size of the left pulmonary artery were determined using phase-contrast MRI. From this wall shear stress (WSS), distensibility and pulsatility were determined. A group of healthy peers was included for reference. Flow and pulsatility were significantly lower in patients than in controls (p < 0.001). Mean area was comparable in patients and controls, but distensibility was significantly higher in controls (p < 0.001). Mean and peak WSS were significantly lower in Fontan patients (p < 0.001). Between baseline and follow-up, there was a significant increase in normalized flow (15.1 (14.3–19.1) to 18.7 (14.0–22.6) ml/s/m², p = 0.023). Area, pulsatility, distensibility and WSS did not change, but there was a trend toward a lower mean WSS (p = 0.068). Multivariable regression analysis showed that flow, area and age were important predictors for WSS. WSS in Fontan patients is decreased compared to healthy controls and tends to decrease further with age. Pulsatility and distensibility are significantly lower compared to healthy controls. Pulmonary artery size, however, is not significantly different from healthy controls and long-term growth after Fontan operation is proportionate to body size.     

Identification of peptide sequences that potentially trigger HLA-A2.1-restricted cytotoxic T lymphocytes

We used the human processing defective cell line 174CEM.T2 (T2) to identify potential cytotoxic T lymphocyte (CTL) epitopes of human proteins. Exogenously added peptides can increase the number of properly folded HLA-A2.1 molecules on the cell surface of T2 cells, as shown by immunofluorescence measurements using the mouse monoclonal antibody BB7.2 (anti-HLA-A2.1) and fluorescein isothiocyanate-labeled goat anti-mouse F(ab')2 antibody. The peptides were selected on the basis of a computer score derived from the recently described HLA-A2.1 specific motif. Analysis of the influenza matrix protein showed that 15 out of 35 high-scoring peptides up-regulate the expression of HLA-A2.1 molecules on theT2 cell surface. The combination of the computer scoring program and an immunofluorescence-based peptide binding assay allows rapid detection of potential CTL target peptides.     

Air pollution exposure during pregnancy, ultrasound measures of fetal growth, and adverse birth outcomes: a prospective cohort study

Background: Air pollution exposure during pregnancy might have trimester-specific effects on fetal growth.Objective: We prospectively evaluated the associations of maternal air pollution exposure with fetal growth characteristics and adverse birth outcomes in 7,772 subjects in the Netherlands.Methods: Particulate matter with an aerodynamic diameter < 10 μm (PM₁₀) and nitrogen dioxide (NO₂) levels were estimated using dispersion modeling at the home address. Fetal head circumference, length, and weight were estimated in each trimester by ultrasound. Information on birth outcomes was obtained from medical records.Results: In cross-sectional analyses, NO₂ levels were inversely associated with fetal femur length in the second and third trimester, and PM₁₀ and NO₂ levels both were associated with smaller fetal head circumference in the third trimester [–0.18 mm, 95% confidence interval (CI): –0.24, –0.12 mm; and –0.12 mm, 95% CI: –0.17, –0.06 mm per 1-μg/m³ increase in PM₁₀ and NO₂, respectively]. Average PM₁₀ and NO₂ levels during pregnancy were not associated with head circumference and length at birth or neonatally, but were inversely associated with birth weight (–3.6 g, 95% CI: –6.7, –0.4 g; and –3.4 g, 95% CI: –6.2, –0.6 g, respectively). Longitudinal analyses showed similar patterns for head circumference and weight, but no associations with length. The third and fourth quartiles of PM₁₀ exposure were associated with preterm birth [odds ratio (OR) = 1.40, 95% CI: 1.03, 1.89; and OR = 1.32; 95% CI: 0.96, 1.79, relative to the first quartile]. The third quartile of PM₁₀ exposure, but not the fourth, was associated with small size for gestational age at birth (SGA) (OR = 1.38; 95% CI: 1.00, 1.90). No consistent associations were observed for NO₂ levels and adverse birth outcomes.Conclusions: Results suggest that maternal air pollution exposure is inversely associated with fetal growth during the second and third trimester and with weight at birth. PM₁₀ exposure was positively associated with preterm birth and SGA.