Regulated expression of the inhibitory receptor LAIR-1 on human peripheral T cells during T cell activation and differentiation

The leukocyte-associated Ig-like receptor-1 (LAIR-1) is capable of inhibiting immune cell function through interaction with collagens. LAIR is expressed on the majority of peripheral blood mononuclear cells. The abundant expression of both receptor and ligand calls for regulatory mechanisms to relieve the continuous interaction between collagens and LAIR-1. This regulation may occur at the expression level of the receptor. Here, we report that LAIR-1 is indeed differentially expressed during human T cell differentiation. Naive CD4(+) and CD8(+) T cells as well as CD8(+) T cells of the effector phenotype express higher levels of LAIR-1 compared to memory T cells. In vitro stimulation revealed a decrease in LAIR-1 expression upon activation, and the lower LAIR-1 expression on CD127(-) T cells suggests that activation-induced down-modulation of LAIR-1 may also occur in vivo. Furthermore, crosslinking of LAIR-1 on primary T cells results in an inhibition of T cell function. Our data suggest that regulated expression of LAIR-1 and the subsequent change in the threshold for activation may be a mechanism to modulate inhibition of the immune system.     

Detection of radiotherapy-induced myocardial changes by ultrasound tissue characterisation in patients with breast cancer

Radiotherapy (RT) in the thoracic region is associated with an increased risk of late cardiovascular morbidity and mortality. Ultrasonic tissue characterisation (UTC) is a non-invasive method of identifying changes in myocardial tissue, such as increased fibrosis. The aim of this study was to assess whether UTC can detect early RT-induced myocardial alterations. Seventy-eight eligible patients with early stage breast cancer were evaluated before and immediately after RT. Twenty patients had right-sided and 58 left-sided breast cancer. None received chemotherapy. A comprehensive echocardiographic examination included 3D measurements and UTC of the right ventricular (RV) free wall, ventricular septum and left ventricular (LV) posterior wall. Integrated backscatter calibration was done for the pericardium (cpIBS) and LV cavity (ccIBS). RT for left-sided breast cancer was associated with increased echodensity in the UTC analysis. RV free wall and ventricular septum cpIBS increased from ?15.0 ± 7.3 to ?13.7 ± 7.9 dB (p = 0.079) and from ?18.2 ± 5.1 to -16.0 ± 6.4 dB (p = 0.002), respectively. Likewise, ccIBS in the RV free wall increased from 20.4 ± 5.9 to 22.1 ± 5.6 dB (p = 0.046), and in the LV septum from 17.3 ± 5.2 to 19.8 ± 5.5 dB (p < 0.001). In 3D echocardiography, LV mass increased from 102 ± 18 to 107 ± 18 g (p = 0.005). Patients receiving RT for right-sided breast cancer did not display these changes. Left-sided RT increased myocardial echodensity, particularly in the structures receiving the highest radiation dose. Considering the progressive nature of the RT induced damage, these early changes may help us with individual risk stratification and serve as a tool for screening.     

Effect of a vigorous aerobic regimen on physical performance in breast cancer patients - a randomized controlled pilot trial

This randomized, controlled pilot trial was carried out to assess the feasibility and efficacy of an aerobic exercise in enhancing physical performance of breast cancer patients after adjuvant treatments. The potential of the training regimen to prevent accompanying bone loss was also assessed. Thirty patients, 41-65 years of age, were randomly assigned into training or control groups shortly after adjuvant chemo- or radiotherapy. The 12-week training included a guided aerobic exercise session once a week (the effective part being either step aerobic- or circuit-training in alternate weeks) and similar home exercise sessions twice a week. Adherence to the guided sessions was 78%, while home training was performed an average 2.1 times per week. Agility assessed with figure-8 running test and peak jumping power showed significant between-group treatment-effects (∼5% and ∼10%, respectively). Judged from the accelerometer data, reaction forces up to six times body weight occurred during the training, which implies that the training could also have potential to affect bone mass. The present exercise regimen turned out to be feasible and effective among breast cancer patients in terms of physical performance. Large controlled trials are necessary to confirm these findings.     

Diffusion-weighted MRI in early chemotherapy response evaluation of patients with diffuse large B-cell lymphoma--a pilot study: comparison with 2-deoxy-2-fluoro- D-glucose-positron emission tomography/computed tomography

To determine the feasibility of diffusion‐weighted MRI (DWI) in the evaluation of the early chemotherapeutic response in patients with aggressive non‐Hodgkin's lymphoma (NHL), eight patients with histologically proven diffuse large B‐cell lymphoma were imaged by MRI, including DWI, and positron emission tomography/computed tomography (PET/CT) before treatment (E1), and after 1 week (E2) and two cycles (E3) of chemotherapy. In all patients, whole‐body screening using T₁‐ and T₂‐weighted images in the coronal plane was performed. To quantitatively evaluate the chemotherapeutic response, axial images including DWI were acquired. Apparent diffusion coefficient (ADC) maps were reconstructed, and the ADC value of the tumor was measured. In addition, the tumor volume was estimated on axial T₂‐weighted images. The maximum standardized uptake value (SUV_max) and active tumor volume were measured on fused PET/CT images. Lymphomas showed high signal intensity on DW images and low signal intensity on ADC maps, except for necrotic foci. The mean pre‐therapy ADC was 0.71 × 10^?3 mm²/s; it increased by 77% at E2 (p < 0.05) and 24% more at E3 (insignificant); the total increase was 106% (p < 0.05). The mean tumor volume by MRI was 276 mL at baseline; it decreased by 58% at E2 (p < 0.05) and 65% more at E3 (p < 0.05), giving a total decrease of 84% (p < 0.05). All the imaged pre‐therapy tumors were strongly positive on PET/CT, with a mean SUV_max of 20. The SUV_max decreased by 60% at E2 (p < 0.05) and 59% more at E3 (p < 0.05), giving a total decrease of 83% (p < 0.05). The active tumor burden decreased by 66% at E2 (p < 0.05). At baseline, both central and peripheral tumor ADC values correlated inversely with SUV_max (p < 0.05), and also correlated inversely with active tumor burden on PET/CT and with tumor volume on MRI at E2 (p < 0.05). In conclusion, the results of DWI in combination with whole‐body MRI were comparable with those of integrated PET/CT. Copyright © 2011 John Wiley & Sons, Ltd.     

Prostate-specific antigen in the follow-up of prostatic adenocarcinoma treated with external beam radiation.

Prostate-specific antigen (PSA) has been shown to be a more sensitive tumor marker than prostatic acid phosphatase (PAP) in prostatic adenocarcinoma: PSA was positive in 54 of our 117 patients (46%) and PAP was positive in 24 (21%). In order to compare the usefulness of these markers during and after radiotherapy serum samples from 24 patients treated with external beam irradiation were analyzed. PAP was only slightly positive in 1 patient (4%) after radiotherapy. His PSA level was highly elevated and he died of progressive disease. In the other 23 patients the cancer was in local control. However, the serum PSA level remained positive in 5 of these patients indicating vital cancer cells may still have been present. An alternative possibility is that metaplastic prostatic cells which secrete PSA were left after radiotherapy, as has been shown to be the case in prostatic hyperplasia. Before radiotherapy increased PSA levels were measured in 3 patients. In 2 of them the level declined to normal within 6 months after radiotherapy. The PAP levels were normal. It is concluded that PSA (positive in 25% of patients after radiotherapy) might be more sensitive than PAP (positive in 4%) in monitoring the effect of radiotherapy in prostatic cancer patients.     

Results of treatment in irradiated testicular seminoma patients

Excellent treatment results have been achieved historically with postoperative radiotherapy in testicular seminoma. In this retrospective study the treatment results of 211 patients with Stage I-II testicular seminoma treated in Finland during the years 1970-1983 were evaluated. 176 (84%) patients received postoperative radiotherapy alone. In addition to radiotherapy, 26 (12%) patients received chemotherapy during the primary treatment. There were 129 Stage I (61%), 66 Stage IIA-B (31%) and 16 Stage IIC (8%) tumors. The 5-year survival rate was 95% in Stage I, 87% in Stage IIA-B and 73% in Stage IIC. In Stage I, seven relapses (relapse rate 6%) occurred after irradiation; three of them were cured with second-line therapies. None of the relapses occurred within the radiotherapy field. In Stage IIA-B, 31 patients had only parailiacic + aortic irradiation, 25 patients received both parailiacic + aortic and mediastinal irradiation. With both radiotherapy techniques there was no significant difference in the number of relapses (seven and three) and in the remission rate (94% and 96%). Radiotherapy alone was used on four Stage IIC patients and one of them died during the primary treatment. Two of them relapsed, but could be cured with chemotherapy. These results correspond to those reported in the literature and they suggest that prophylactic mediastinal irradiation is unnecessary in Stage IIA-B patients. Stage IIC patients should receive chemotherapy initially.     

High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma.

PURPOSE: Matrix metalloproteinases (MMP) are proteolytic enzymes that play an important role in various aspects of cancer progression. In the present work, we have studied the prognostic significance of serum levels of gelatinase B (MMP-9), collagenase-1 (MMP-1), and collagenase-3 (MMP-13) in patients with advanced melanoma. EXPERIMENTAL DESIGN: Total pretreatment serum levels of MMP-9 in 71 patients and MMP-1 and MMP-13 in 48 patients were determined by an assay system based on ELISA. Total MMP levels were also assessed in eight healthy controls. The active and latent forms of MMPs were defined by using Western blot analysis and gelatin zymography. RESULTS: Patients with high serum levels of MMP-9 (> or = 376.6 ng/mL; n = 19) had significantly poorer overall survival (OS) than patients with lower serum MMP-9 levels (n = 52; median OS, 29.1 versus 45.2 months; P = 0.033). High MMP-9 levels were also associated with visceral or bone metastasis (P = 0.027), elevated serum alkaline phosphatase level (P = 0.0009), and presence of liver metastases (P = 0.032). Serum levels of MMP-1 and MMP-13 did not correlate with OS. MMP-1 and MMP-9 were found mainly in latent forms in serum, whereas the majority of MMP-13 in serum was active (48 kDa) form. MMP-13 was found more often in active form in patients (mean, 99% of the total MMP-13 level) than in controls (mean, 84% of the total MMP-13 level; P < 0.0001). After initiating the therapy, patients with elevated levels of MMP-1 (> or = 29.8 ng/mL, n = 10) progressed more rapidly than patients with lower levels (median, 1.9 versus 3.5 months; P = 0.023). Serum levels of MMP-9 and MMP-13 did not correlate with the time to progression (TTP). In multivariate analysis with age and gender, MMP-9 or MMP-1 turned out to be independent prognostic factors for OS [P = 0.039; hazard ratio (HR), 1.8; 95% confidence interval (95% CI), 1.03-3.3] or TTP (P = 0.023; HR, 2.7; 95% CI, 1.15-6.4), respectively. CONCLUSIONS: Our findings provide evidence that MMP-1, MMP-9, and MMP-13 play important roles at different phases of metastatic melanoma spread and that serum MMP-9, in particular, could have clinical value in identifying patients at high risk for melanoma progression.     

Single-agent gemcitabine: an active and better tolerated alternative to standard cisplatin-based chemotherapy in locally advanced or metastatic non-small cell lung cancer

This randomized study was designed to determine the response rates, survival and toxicities of single-agent gemcitabine (GEMZAR) and a combination of cisplatin/etoposide in chemonaive patients with non-resectable, locally advanced or metastatic non-small cell lung cancer (NSCLC). Gemcitabine 1000 mg/m2 was given as a 30-min intravenous infusion on days 1, 8, 15 of a 28-day cycle, cisplatin 100 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 (following cisplatin), 2 and 3. Major eligibility criteria included histologically confirmed non-small cell lung cancer, measurable disease, Zubrod performance status 0-2, no prior chemotherapy, no prior radiation of the measured lesion, and no CNS metastases. One hundred and forty-seven patients were enrolled, 72 in the gemcitabine and 75 in the cisplatin/etoposide arm. Patient characteristics were well-matched across both arms. Sixty-seven gemcitabine and 72 cisplatin/etoposide patients were qualified for efficacy analysis. There were no complete responses, but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response rates of 17.9% (95%, CI: 9.6-29.2%,) and 15.3% (95% CI: 7.9-25.7%,), respectively. Median survival times were 6.6 months (95% CI: 4.9-7.3 months) for gemcitabine and 7.6 months (95% CI: 5.4-9.3 months) for cisplatin/etoposide. The 1-year survival probability estimate was 26% for gemcitabine and 24% for cisplatin/etoposide. There were no statistically significant between-group differences in time-to-event measures, but patients in the gemcitabine arm had a greater probability of achieving a tumour response after 2 months (probability estimate: 8 vs. 0%,) and of the response lasting at least 6 months (73 vs. 45%,). Clinical and haematologic toxicity was more pronounced in the cisplatin/etoposide arm. Quality-of-life measures indicated a significant worsening of symptomatology in the cisplatin/etoposide arm for hair loss, nausea and vomiting, and appetite loss. This randomized study provides further evidence that single-agent gemcitabine is an active and effective therapy for patients with non-resectable. locally advanced or metastatic NSCLC and good performance status, and that it is better tolerated than the combination cisplatin/ etoposide.     

Docetaxel 100 versus 80 mg/m2 as adjuvant treatments of early breast cancer: an exploratory analysis of a randomised trial

Docetaxel-containing regimens are widely used as adjuvant treatmentof early breast cancer, and the dose 100 mg/m² is often selectedas the starting dose. Yet the optimal starting dose is unknown,since different docetaxel doses have never been compared ina randomised trial in the adjuvant setting. In metastatic breastcancer, three doses of     

Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer.

PURPOSE: The combination of interferon alfa-2a (IFNalpha2a) plus vinblastine (VLB) induces objective tumor responses in patients with advanced renal cell cancer. However, no prospective randomized trial has shown that this treatment prolongs overall survival. We compared overall survival after treatment with IFNalpha2a plus VLB versus VLB alone in patients with advanced renal cell cancer. PATIENTS AND METHODS: We prospectively randomized 160 patients with locally advanced or metastatic renal cell cancer to receive either VLB alone or IFNalpha2a plus VLB for 12 months or until progression of disease. In both groups, VLB was administered intravenously at 0.1 mg/kg every 3 weeks, and in the combination group IFNalpha2a was administered subcutaneously at 3 million units three times a week for 1 week, and 18 million units three times a week thereafter for the second and subsequent weeks. For patients unable totolerate IFNalpha2a at 18 million units per injection, the dose was reduced to 9 million units. RESULTS: Median survival was 67.6 weeks for the 79 patients receiving IFNalpha2a plus VLB and 37.8 weeks for the 81 patients treated with VLB (P =.0049). Overall response rates were 16. 5% for patients treated with IFNalpha2a plus VLB and 2.5% for patients treated with VLB alone (P =.0025). Treatment with the combination was associated with constitutional symptoms and abnormalities in laboratory parameters, but no toxic deaths were reported. CONCLUSION: The combination of IFNalpha2a plus VLB is superior to VLB alone in the treatment of patients with locally advanced or metastatic renal cell carcinoma. This is the first study to demonstrate that survival can be prolonged by using IFNalpha2a for these patients.