Tumor-infiltrating lymphocytes predict improved overall survival after post-mastectomy radiotherapy: a study of the randomized DBCG82bc cohort.

BACKGROUND: The predictive value of tumor-infiltrating lymphocytes (TILs) on the benefit from radiotherapy (RT) remains unclear. Our aim was to investigate the association between TILs and post-mastectomy RT (PMRT) regarding the risk of recurrence and survival in a randomized cohort. MATERIAL AND METHODS: Stromal TILs were histologically estimated in 1011 tumors from high-risk breast cancer (BC) patients from the DBCG82bc trial. Patients were diagnosed between 1982 and 90, treated with total mastectomy and partial axillary lymph node dissection, randomized to ± PMRT followed by adjuvant systemic treatment. A competing risk model, Kaplan-Meier analysis and multivariate Cox regression analysis were used for correlating TILs and clinical outcome. RESULTS: 106 of 1011 patients (10.5%) showed high TILs using a 30% cut-off. In multivariate regression analysis, a high level of TILs was an independent factor associated with lower risk of distant metastasis (DM) and improved overall survival (OS), but without association with loco-regional control. High TILs were associated with a significantly greater OS after PMRT at 20 years compared to low TILs (8% improvement for low TILs (23% to 31%) vs. 22% for high TILs (26% to 48%), interaction-test: p = 0.028). The association between TILs and PMRT was more pronounced among estrogen-receptor negative (ER-) tumors, and patients having ER-/low TILs tumors showed no OS benefit from PMRT at 20 years (-4% improvement for low TILs (28% to 24%) vs. 23% for high TILs (20% to 43%). A similar trend in the association between high TILs and reduced risk of DM after PMRT was seen. CONCLUSION: High TILs predict improved OS from PMRT in BC patients, and the association appeared especially strong for ER- tumors. A trend in the association between high TILs and reduced risk of DM after PMRT was seen. These findings may indicate that RT triggers an immune response inducing a systemic effect outside the treatment field.

Renal cryoablation - does deep endophytic ablation affect the renal collecting system?

Objective: To investigate to what extent the urothelium of the renal collecting system is affected when performing deep endophytic cryoablation.Methods: The study was conducted as an in vivo animal model with a total of 15 female pigs. Each animal was subjected to bilateral endophytioc renal cryoablation and randomized to a postoperative follow-up period of either one, two or four weeks. At the end of follow-up all animals had a magnetic resonance imaging (MRI) examination and bilateral nephrectomy was performed. On MRI-imaging the extent of the cryolesions, as well as signs of urinomas or fistulas, were examined. Histopathologic examinations were performed to investigate the effect on the urothelium.Results: All animals tolerated the procedure well without any postoperative complications. MRI examinations found the renal collecting system to be involved in the cryolesions at all three stages of follow-up and revealed no signs of hematomas, urinomas or fistula formations. Epithelial edema was found at all three stages of follow-up while significant parenchymal fibrosis adjacent to the urothelium was most pronounced in the four weeks of follow-up group. The urothelium was significantly affected with luminal hemorrhage as well as hemorrhage in and underneath the urothelium and urothelial dissociation from the underlying renal parenchyma. Despite these impacts on the urothelium, this was found to be intact and vital at all three stages of follow-up, in sharp contrast to the renal parenchyma that underwent fibrotic changes.Conclusions: In this, in vivo non-tumor pig model CA effectively destroyed the renal parenchyma while the impacted renal urothelium remained intact and did not undergo fibrotic changes, nor was urinomas or fistulas observed.

Langerhans cell markers CD1a and CD207 are the most rapidly responding genes in lesional psoriatic skin following adalimumab treatment.

TNFα-, IL-23- and IL-17-targeting drugs are highly effective in the treatment of psoriasis. However, the precise molecular mechanism remains unknown. In psoriatic skin, the presence of Langerhans cells (LCs) is reduced, but the role of LC is poorly understood. The purpose of this study was to investigate the impact of TNFα and IL-23/IL-17 on the presence of LC in the skin during treatment. Therefore, psoriatic skin was investigated before and after 4 days of adalimumab or ustekinumab treatment. Furthermore, TNFα and IL-17A stimulation was investigated in an ex vivo model of epidermis and dermis from healthy normal skin kept in cultures at an air-liquid interphase for 4 days. In a gene array analysis, we found that the two LC markers, CD1a and CD207, were among the most up- or downregulated genes in psoriatic skin after anti-TNFα therapy. Validation showed that both mRNA expression and protein level followed the same pattern and became significantly upregulated after 4 days of treatment. No changes were seen after ustekinumab treatment. In the ex vivo skin model, a decrease in the CD1a level was seen after TNFα stimulation and it was caused by LC migration from epidermis. No response in LC migration was seen after IL-17A stimulation. Taken together, we demonstrated that changes in the LC level in epidermis precede the histological and clinical changes during adalimumab treatment in psoriatic skin. Furthermore, TNFα plays a prominent role in orchestrating LC migration in the skin. This seems not to be the true for the IL-23/IL-17A pathway.

TRIM21 is important in the early phase of inflammation in the imiquimod-induced psoriasis-like skin inflammation mouse model.

Tripartite motif-containing protein 21 (TRIM21) regulates pro-inflammatory cytokines and type I interferons and acts as an autoantigen in certain autoimmune diseases, but TRIM21 has not been investigated in psoriasis. It has been suggested that TRIM21 may have a dual function; in the early phase of inflammation, it may function as a stimulator; but upon immune stimulation, its ubiquitinating mode of action may shift from stabilization to degradation of IRF3 causing inhibition of the immune responses. The imiquimod (IMQ)-induced psoriasis-like mouse model displays features similar to those of human psoriasis. However, chronicity is lacking in this model. We investigated whether the role of TRIM21 in psoriasis was pro-inflammatory or anti-inflammatory. We hypothesized that a shift of the TRIM21-ubiquitinating mode of action may explain the lack of chronicity in the IMQ-induced psoriasis-like mouse model. We showed that TRIM21 expression is increased in lesional psoriatic skin and in the early phase of IMQ-induced inflammation both in vitro and in vivo. Surprisingly, inflammation was significantly less pronounced in TRIM21 knockout mice than in wild-type mice as shown by ear thickness measured at days 8, 9 and 10 after treatment start, by spleen weight as a marker of systemic effect of IMQ at 10 days after treatment start and by expression of IL-12p40 at days 3 and 10 after treatment start and IL-17A at day 3 after treatment start. Therefore, induction of TRIM21 expression cannot explain the lack of chronicity in the IMQ-induced psoriasis-like skin inflammation mouse model.

IκBζ is a key driver in the development of psoriasis.

Psoriasis is a common immune-mediated, chronic, inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although TNFα- and IL-17A-targeting drugs have recently proven to be highly effective, the molecular mechanism underlying the pathogenesis of psoriasis remains poorly understood. We found that expression of the atypical IκB member IκB (inhibitor of NF-κB) ζ, a selective coactivator of particular NF-κB target genes, was strongly increased in skin of patients with psoriasis. Moreover, in human keratinocytes IκBζ was identified as a direct transcriptional activator of TNFα/IL-17A-inducible psoriasis-associated proteins. Using genetically modified mice, we found that imiquimod-induced psoriasis-like skin inflammation was completely absent in IκBζ-deficient mice, whereas skin inflammation was still inducible in IL-17A- and TNFα-deficient mice. IκBζ deficiency also conferred resistance against IL-23-induced psoriasis. In addition, local abrogation of IκBζ function by intradermal injection of IκBζ siRNA abolished psoriasis-like skin inflammation. Taken together, we identify IκBζ as a hitherto unknown key regulator of IL-17A-driven effects in psoriasis. Thus, targeting IκBζ could be a future strategy for treatment of psoriasis, and other inflammatory diseases for which IL-17 antagonists are currently tested in clinical trials.

[Legionella pneumonia in patients treated with infliximab]. / Legionella pneumoni hos patienter, der er i behandling med infliximab.

Therapy with tumour necrosis factor-alfa inhibitors is widely used in various inflammatory disorders, but adverse events from severe infections with intracellular pathogens may occur. We describe two cases of severe pulmonary legionellosis in patients treated with infliximab for Crohn's disease and psoriasis, respectively. We conclude that legionella infections are probably more frequent in patients receiving immunosuppressive therapy with tumour necrosis factor-alfa inhibitors than in the background population.

[Prevention of vertical transmission of HIV in Denmark]. / Forebyggelse af vertikal transmission af human immundefektvirus i Danmark.

INTRODUCTION: Human immunodeficiency virus (HIV) is a RNA virus that can be transmitted parenterally, sexually or vertically. An effective prevention strategy has been implemented in industrialised countries, thereby reducing vertical transmission from 15-25% to < 1%. The aim of this study was to describe vertical transmission of HIV in Denmark after the introduction of ART. MATERIALS AND METHODS: The study was a retrospective study of all HIV-infected women who gave birth in Denmark between 1 January 2000 and 31 May 2005 and their children. RESULTS: 83 HIV-infected women gave birth to 96 children during the study period. In 79% of the cases, the woman knew her HIV status at the beginning of her pregnancy. The median CD4 count before delivery was 447 x 10(6)/l, and in 76% of the cases the HIV-RNA was < 20 copies/ml. 88% of the women delivered by Caesarean section. None of the children were breastfed. None of the children were infected during pregnancy, delivery or after birth. During the same period of time, 8 children were diagnosed with HIV in Denmark; they were born to mothers whose HIV infection was not diagnosed during pregnancy or delivery and therefore preventive treatment was not initiated. CONCLUSION: As long as preventive treatment strategies are followed, there is no transmission of HIV from mother to child, neither during pregnancy nor during or after birth.