STREPTOCOCCAL ANTIBODY CROSS-REACTIVITY WITH HLA-DR4+VE B-LYMPHOCYTES. BASIS OF THE DR4 ASSOCIATED GENETIC PREDISPOSITION TO RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE?

B-lymphocytes obtained from patients with either rheumatic feveror rheumatic heart disease and from normal subjects were reactedwith serum obtained from rabbits immunized with streptococcalcell wall antigen. The presence of cytotoxicity was sought usingan inverted phase microscope after differential uptake of eosindye. The serum was found to be significantly more cytotoxicto HLA-DR4 containing cells of both patients and normals comparedwith DR4 negative cells (P<0. 0001). KEY WORDS: Streptococcal cell wall antigen, Antiserum, Cytotoxicity     

Interleukin 12 gene transfer into skin distant from the tumor site elicits antimetastatic effects equivalent to local gene transfer

We have reported that particle-mediated interleukin 12 (IL-12) gene transfer into the skin overlying the local tumor inhibits systemic metastases. To further characterize this effect, we compared the antitumor and antimetastatic effects of IL-12 cDNA delivered at the local tumor site versus at a site distant from the primary tumor, in a spontaneous metastasis model of LLC-F5 tumor. Local IL-12 gene delivery into the skin overlying the intradermal tumor (local IL-12 treatment) on days 7, 9, and 11 after tumor implantation resulted in the most suppression of the growth of the primary LLC-F5 tumor, whereas IL-12 gene transfer into the skin distant from the tumor (distant IL-12 treatment) was less effective. In contrast, both local IL-12 and distant IL-12 treatment, followed by tumor excision, inhibited lung metastases to a similar extent, resulting in significantly extended survival of test mice. The results of in vivo studies using depleting anti-asialo GM1 antibody and anti-CD4/anti-CD8 monoclonal antibodies, or neutralizing anti-interferon gamma (IFN-gamma) monoclonal antibody demonstrated that natural killer (NK) cells, CD8(+) T cells, and IFN-gamma contributed to the antimetastatic effects in both treatment groups. Furthermore, the levels of mRNA expression of vascular endothelial growth factor and matrix methalloproteinase 9 at the tumor microenvironment were suppressed after both local and distant IL-12 treatment. These results suggest that the current particle-mediated IL-12 gene delivery in the spontaneous LLC-F5 metastasis model can confer antimetastatic activities, irrespective of the gene transfection site, via a combination of several mechanisms involving CD8(+) T cells, NK cells, IFN-gamma, and antiangiogenesis.     

Differential internalization of hu14.18-IL2 immunocytokine by NK and tumor cell: impact on conjugation, cytotoxicity, and targeting

The hu14.18-IL2 (EMD 273063) IC, consisting of a GD(2)-specific mAb genetically engineered to two molecules of IL-2, is in clinical trials for treatment of GD(2)-expressing tumors. Anti-tumor activity of IC in vivo and in vitro involves NK cells. We studied the kinetics of retention of IC on the surface of human CD25(+)CD16(-) NK cell lines (NKL and RL12) and GD(2)(+) M21 melanoma after IC binding to the cells via IL-2R and GD(2), respectively. For NK cells, ～ 50% of IC was internalized by 3 h and ～ 90% by 24 h of cell culture. The decrease of surface IC levels on NK cells correlated with the loss of their ability to bind to tumor cells and mediate antibody-dependent cellular cytotoxicity in vitro. Unlike NK cells, M21 cells retained ～ 70% of IC on the surface following 24 h of culture and maintained the ability to become conjugated and lysed by NK cells. When NKL cells were injected into M21-bearing SCID mice, IT delivery of IC augmented NK cell migration into the tumor. These studies demonstrate that once IC binds to the tumor, it is present on the tumor surface for a prolonged time, inducing the recruitment of NK cells to the tumor site, followed by tumor cell killing.     

Contribution of the Vertebral Posterior Elements in Anterior–Posterior DXA Spine Scans in Young Subjects

Because DXA is a projection technique, anterior–posterior (AP) measurements of the spine include the posterior elements and the vertebral body. This may be a disadvantage because the posterior elements likely contribute little to vertebral fracture resistance. This study used QCT to quantify the impact of the posterior elements in DXA AP spine measures. We examined 574 subjects (294 females and 280 males), age 6–25 yr, with DXA and QCT. QCT measures were calculated for the cancellous bone region and for the vertebral body including and excluding the posterior elements. DXA data were analyzed for the entire L₃ vertebra and for a 10‐mm slice corresponding to the QCT scan region. BMC and BMD were determined and compared using Pearson's correlation. The posterior elements accounted for 51.4 ± 4.2% of the total BMC, with a significant difference between males (49.9 ± 4.0%) and females (52.8 ± 3.9%, p < 0.001). This percentage increased with age in younger subjects of both sexes (p < 0.001) but was relatively consistent after age 17 for males and 16 for females (p > 0.10). DXA areal BMD and QCT volumetric BMD correlated strongly for the whole vertebra including the posterior elements (R = 0.83), with BMC measures showing a stronger relationship (R = 0.93). Relationships were weaker when excluding the posterior elements. We conclude that DXA BMC provides a measure of bone that is most consistent with QCT and that the contribution of the posterior elements is consistent in young subjects after sexual maturity.     

A word of caution: Early failure of Magmaris® bioresorbable stent after pulmonary artery stenting

Bioresorbable scaffolds (BRS) have been advocated as the fourth revolution in interventional cardiology medical devices with promising technology to improve the treatment of coronary artery disease with an event-free future. We describe the first reported use and early collapse of the Magmaris® Resorbable Magnesium Scaffold (RMS) stent (BIOTRONIK AG, Switzerland) to relieve left pulmonary artery severe stenosis in a newborn after the Norwood procedure. The stent collapse was detected 2 weeks after implantation and urgently treated with a balloon-expandable stent. This complication raises the alarm about the need to keep implanted RMS under scrutiny. The possibility of faster scaffold resorption in small babies or lack of sufficient radial force of RMS to resist acute vessel recoil has led to ineffective relief of branch pulmonary artery stenosis and failure to enable a safe short-term bridge to Stage II palliation.     

The prognostic value of intraepithelial and stromal CD3‐, CD117‐ and CD138‐positive cells in non‐small cell lung carcinoma

Al‐Shibli K, Al‐Saad S, Andersen S, Donnem T, Bremnes RM, Busund L‐T. The prognostic value of intraepithelial and stromal CD3‐, CD117‐ and CD138‐positive cells in non‐small cell lung carcinoma. APMIS 2010; 118: 371–82. The major value of prognostic markers in potentially curable non‐small cell lung carcinoma (NSCLC) should be to guide therapy after surgical treatment. Although tumor‐infiltrating T lymphocytes and plasma cells have been documented in NSCLC, a clear association with clinical outcome, especially for the stromal component, has not been well established. The aim of this study was to elucidate the prognostic significance of these cells/markers in the epithelial and stromal compartments of NSCLC. Tissue microarrays from 335 resected, stage I‐IIIA, NSCLC were constructed by duplicate cores from viable neoplastic epithelial and stromal areas. Immunohistochemistry was used to evaluate the infiltration of CD3⁺, CD117⁺ as well as CD138⁺ cells in epithelial and stromal areas. In univariate analyses, increasing numbers of stromal CD3⁺ (p = 0.001) and epithelial CD3⁺ cells (p = 0.004) correlated significantly with an improved disease‐specific survival. No such relation was noted with CD3⁺ or CD117⁺ cells. In the multivariate analysis, stromal CD3⁺ cells was an independent prognostic factor for disease‐specific survival (HR 1.925, CI 1.21–3.04, p = 0.005). Increased presence of the pan T‐cell marker, CD3, which is an independent factor, correlates with improved clinical outcome in NSCLC. This prognostic impact of T cells is clearer in the tumor stroma. Neither plasma cells nor mast cells were prognostic indicators in our cohort.