GM-CSF, IL-3 and G-CSF receptors on acute myeloid leukemia cells : function, regulation of expression, and ligand binding characteristics

IL-3, GM-CSF and G-CSF stimulate proliferation of human acute myeloid leukemia in vitro, but patterns of response among clinical cases are diverse. As described in Chapters 2 and 3, numbers and affinity of IL-3, GM-CSF and G-CSF receptors on cells of patients with AML were assessed and correlated with the proliferative response of the cells to IL-3, GM-CSF and G-CSF. In 13 of 15 cases of primary AML high affinity receptors for IL-3 were demonstrable on the cells. The average numbers of IL-3 receptors ranged from 21-145 receptors per cell. Normal white blood cells showed IL-3 receptors on their surface at similar densities. IL-3 receptor positivity often correlated with GM-CSF receptor positivity of AML, GMCSF receptors were demonstrated on the cells of 11 of 15 cases although average numbers of GM-CSF receptors were 10 times greater. The binding of G-CSF to normal and human AML cells was investigated in a series of 14 cases of primary AML. In all 14 cases specific receptors for G-CSF were demonstrated on purified blast cells. The average numbers of G-CSF receptors ranged from very low (specific binding scarcely detectable) to 428 receptors per cell. Normal granulocytes showed G-CSF binding sites on their surface at higher densities (703 to 1,296 sites/cell). GCSF receptors appeared of a single affinity type with a dissociation constant (Kct) ranging between 214 to 378 pM for AML blasts and 405 to 648 pM for normal peripheral blood granulocytes. The in vitro response of the cells to exogenous IL-3, GM-CSF or G-CSF was examined by measuring thymidine uptake. IL-3 and GM-CSF were potent inducers of DNA synthesis in vitro. In 12 of 14 cases including those with relatively low specific binding, G-CSF was a potent inducer of DNA synthesis of blasts in vitro; apparently relatively few receptors permit activation of AML cell growth. In a minority of cases however, the cells were unable to respond to IL-3 (4 of 15 cases), GM-CSF (4 of 15 cases) or G-CSF (2 of 14 cases) in spite of normal receptor availability on the cell surface. The inability of the cells to respond to stimulation might be caused by the inability of the receptors to transduce a secondary signal into the cells. The results from these experiments taken together did not provide evidence for overexpression or gross changes in receptor affinity as an explanation for AML growt

Validation of Six Nomograms for Predicting Non-sentinel Lymph Node Metastases in a Dutch Breast Cancer Population

Background: The usefulness of axillary lymph node dissection (ALND) in patients with positive sentinel nodes (SN) is still an ongoing debate. Several nomograms have been developed for predicting non-sentinel lymph node metastases (NSLNM). We validated six nomograms using data from 10 years of breast cancer surgery in our hospital. Methods: We retrospectively analyzed all patients with a proven breast malignancy and a SN procedure between 2001 and 2011 in our hospital. Results: Data from 1084 patients were reviewed; 260 (24 %) had a positive SN. No patients with isolated tumor cells, 6 patients (8 %) with micrometastases, and 65 patients (41 %) with macrometastases had additional axillary NSLNM. In 2 patients (3 %) with micrometastases, the ALND influenced postoperative treatment. In the group of patients with macrometastases tumor size >2 cm, extranodal growth and having no negative SNs were predictors of NSLNM. The revised MD Anderson Cancer Center and Helsinki nomograms performed the best, with an area under the curve value of 0.78. Conclusions: ALND could probably be safely omitted in most patients with micrometastases but is still indicated in patients with macrometastases, especially in patients with tumor size >2 cm, extranodal growth, and no negative SNs. The revised MD Anderson Cancer Center and Helsinki nomograms were the most predictive in our patient group

Intraoperative assessment and reporting of radical prostatectomy specimens to guide nerve-sparing surgery in prostate cancer patients (NeuroSAFE)

AIMS: Radical prostatectomy for prostate cancer is frequently complicated by urinary incontinence and erectile dysfunction. Nerve-sparing surgery reduces the risk of post-operative complications and can be optimized using intraoperative frozen sections of the adjacent neurovascular structure (NeuroSAFE). The aim of t

Inter-observer variability of cribriform architecture and percent Gleason pattern 4 in prostate cancer: relation to clinical outcome

The Grade group is an important parameter for clinical decision-making in prostate cancer. Recently, percent Gleason pattern 4 and presence of invasive cribriform and/or intraductal carcinoma (CR/IDC) have been recognized for their independent predictive value for prostate cancer outcome. There is sparse data on the inter-observer agreement for these pathologic features in practice. Our objectives were to investigate inter-observer variability of percent Gleason pattern and CR/IDC and to relate individual tumour scores to clinical outcome. Our cohort included 80 consecutive radical prostatectomies with a median follow-up 87.1 months (interquartile range 43.3–119.2), of which the slide with largest tumour volume was scored by six pathologists for Grade group (four tiers: 1, 2, 3 and 4/5), percent Gleason pattern 4 (four tiers: 0–25%, 26–50%, 51–75% and 76–100%) and presence of CR/IDC (two tiers: absent, present). The individual assignments were related to post-operative biochemical recurrence (20/80). Inter-observer agreement was substantial (Krippendorff’s α 0.626) for assessment of Grade group and moderate for CR/IDC (α 0.507) and percent Gleason pattern 4 (α 0.551). For each individual pathologist, biochemical recurrence rates incremented by Grade group and presence of CR/IDC, although such relation was less clear for percent Gleason pattern 4. In conclusion, inter-observer agreement for CR/IDC and percent Gleason pattern 4 is lower than for Grade groups, indicating awareness of these features needs further improvement. Grade group and CR/IDC, but not percent Gleason pattern 4 was related to biochemical recurrence for each pathologist, indicating overall validity of individual grade assignments despite inter-observer variability