Radiation Therapy for Local Cutaneous Melanoma.

While primary treatment for melanoma consists of surgical resection and chemotherapeutics, radiation can be used as either definitive or adjuvant therapy in certain clinical scenarios. This chapter aims to explore the indications for primary definitive radiotherapy as well as adjuvant treatment following resection. Delivery, dose, fractionation, and toxicity of radiation treatment will be discussed. As our understanding of melanoma tumor biology increases, the role of radiotherapy may expand for more effective treatment of oligometastatic disease.

The influence of ethnicity and length of time since immigration on physical activity.

OBJECTIVE: This study investigates whether ethnicity and length of time since immigration influence levels of leisure-time physical activity in Sweden. DESIGN/SETTING/PARTICIPANTS: This cross-sectional study analyses data from the Swedish Survey of Living Conditions from the years 1996, 1997 and 1999, which is conducted annually and is a simple, random sample drawn from the register of the total population in Sweden. The total sample was 14,485 men and women aged 20-74 years, who were categorised according to country of origin: born in Sweden, Western Europe, Finland, Southern Europe, Eastern Europe or all other countries. The multivariate analysis was performed using a logistic regression model in order to investigate the effects of possible confounding factors on physical activity. MAIN RESULTS: The risk of reporting low levels of physical activity was significantly higher for men born in Finland, Southern Europe and in the category 'all other countries', and also for women born in Southern Europe, Eastern Europe and 'all other countries', compared with men and women born in Sweden. After the inclusion of the variables education, smoking, body mass index and longstanding illness or disability into the model, the relationship between ethnicity and low levels of physical activity decreased to non-significance for men born in Finland and Southern Europe, but remained significant for men born in the category 'all other countries'. The differences in risk for women observed in the crude model remained significant even after inclusion of all other variables in the multivariate model. A positive gradient was observed between the length of time since immigration to Sweden and low levels of physical activity in women but no relationship was observed in men. CONCLUSIONS: There are significant differences in levels of leisure-time physical activity between different ethnic groups living in Sweden, which could not all be explained by the confounding factors age, education, smoking, body mass index or long-term illness or disability. In women, but not in men, levels of leisure-time physical activity increased with increasing time since immigration to Sweden.

FLT3 ligand administration after hematopoietic cell transplantation increases circulating dendritic cell precursors that can be activated by CpG oligodeoxynucleotides to enhance T-cell and natural killer cell function.

Dendritic cells (DCs) are key effectors in innate immunity and play critical roles in triggering adaptive immune responses. FLT3 ligand (FLT3-L) is essential for DC development from hematopoietic progenitors. In a phase I clinical trial, we demonstrated that immunotherapy with subcutaneous injection of FLT3-L is safe and well tolerated in cancer patients recovering from autologous hematopoietic cell transplantation (HCT). FLT3-L administration significantly increased the frequency and absolute number of blood DC precursors without affecting other mature cell lineages during the 6-week course of FLT3-L therapy. After 14 days of FLT3-L administration, the number of blood CD11c + DCs, plasmacytoid DCs (PDCs), and CD14 + monocytes increased by 5.3-, 2.9-, 3.8-fold, respectively, and was maintained at increased levels throughout FLT3-L therapy. FLT3-L-increased blood DCs in HCT patients were immature and had modest enhancing effects on in vitro T-cell proliferation to antigens and natural killer (NK) cell function. The addition of type B CpG oligodeoxynucleotides (ODNs) to peripheral blood mononuclear cells obtained from HCT patients receiving FLT3-L therapy induced rapid maturation of both CD11c + DCs and PDCs and enhanced T-cell proliferative responses. In addition, CpG ODN induced potent activation of NK cells from FLT3-L-treated patients with increased surface CD69 expression and augmented cytotoxicity. CpG ODN-induced activation of NK cells was primarily via an indirect mechanism through PDCs. These findings suggest that FLT3-L mobilization of DC precursors followed by a specific DC stimulus such as CpG ODN may provide a novel strategy to manipulate antitumor immunity in patients after HCT.

Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells.

Plasmacytoid dendritic cells (PDCs) are key effectors in host innate immunity and orchestrate adaptive immune responses. CpG oligodeoxynucleotides (ODN) have potent immunostimulatory effects on PDCs through TLR9 recognition and signaling. Little is known about the effects of CpG ODN on human PDC-mediated T cell priming. Here we show that type B CpG ODN effectively promotes PDCs to prime allogeneic naive CD4(+)CD25(-) T cells to differentiate into CD4(+)CD25(+) regulatory T (Treg) cells. The CD4(+)CD25(+) T cells induced by CpG ODN-activated PDCs express forkhead transcription factor 3 and produce IL-10, TGF-beta, IFN-gamma, and IL-6, but low IL-2 and IL-4. These CD4(+)CD25(+) T cells are hyporesponsive to secondary alloantigen stimulation and strongly inhibit proliferation of autologous or allogeneic naive CD4(+) T cells in an Ag-nonspecific manner. CpG ODN-activated PDCs require direct contact with T cells to induce CD4(+)CD25(+) Treg cells. Interestingly, IL-10 and TGF-beta were undetectable in the supernatants of CpG ODN-stimulated PDC cultures. Both CpG-A and CpG-C ODN-activated PDCs similarly induced the generation of CD4(+)CD25(+) Treg cells with strong immune suppressive function. This study demonstrates that TLR9 stimulation can promote PDC-mediated generation of CD4(+)CD25(+) Treg cells and suggests PDCs may play an important role in the maintenance of immunological tolerance.

Surfactant protein D inhibition of human macrophage uptake of Mycobacterium tuberculosis is independent of bacterial agglutination.

The innate immune system in the lung is essential for controlling infections due to inhaled pathogens. Mycobacterium tuberculosis (M.tb) encounters components of the innate immune system when inhaled into the lung, but the consequences of these interactions are poorly understood. Surfactant protein D (SP-D) binds to and agglutinates M.tb bacilli, and reduces the uptake of the bacteria by human macrophages. In the current studies, we utilized a recombinant SP-D variant (CDM) that lacks the collagen domain to further characterize the interaction of SP-D with M.tb, and determine the effects of agglutination on bacterial uptake by human monocyte-derived macrophages. These studies demonstrate that the binding of SP-D and CDM to M.tb is saturable and inhibited by carbohydrate competition and Ca(2+) chelation, implicating the carbohydrate recognition domain in the interaction. Fluorescence microscopy reveals that dodecameric SP-D leads to agglutination of the bacilli, whereas the trimeric CDM does not, demonstrating that the multivalent nature of SP-D is essential for agglutination of M.tb. However, preincubation of M.tb with increasing concentrations of SP-D or CDM leads to a concentration-dependent reduction in the uptake of the bacteria by macrophages, indicating that agglutination does not play a direct role in this observation. Finally, the reduced uptake of M.tb by SP-D is associated with reduced growth of M.tb in monocyte-derived macrophages. These studies provide direct evidence that the inhibition of phagocytosis of M.tb effected by SP-D occurs independently of the aggregation process.