Cytotoxic effects of chemokine receptor 4 inhibition by AMD3100 in biliary tract cancer cells: Potential drug synergism with gemcitabine.

Biliary tract cancer (BTC) remains one of the most life-threatening types of cancer due to the lack of efficient therapies. Advanced tumour stages at the point of diagnosis and high chemoresistance are two of the predominant reasons for a 5-year survival rate of only ~5%. The present study investigated the effect of the chemokine receptor 4 (CXCR4) inhibitor AMD3100 (Plerixafor), alone and in combination with standard gemcitabine chemotherapy, on the proliferation of BTC cells. The expression of CXCR4 was analysed by reverse transcription-quantitative polymerase chain reaction in eight heterogeneously differentiated BTC cell lines. The effects of treatment with the CXCR4 antagonist, AMD3100, on cell viability and anchorage-independent growth, and the possible synergistic cytotoxic effects of AMD3100 with standard chemotherapeutics were assessed. The expression of CXCR4 was observed to a variable extent in all eight BTC cell lines, with SkChA-1 cells exhibiting the highest expression levels. Treatment with AMD3100 led to a marginal decrease in cell viability in the cell lines, with the exception of the CCSW-1 cells, and a significant reduction in the GBC, MzChA-1, SkChA.-1 and TFK-1 cell lines. The combined treatment of the SkChA-1 cells with varying concentrations of AMD3100 and standard gemcitabine chemotherapy revealed a more marked overall cytotoxicity, indicating a potential synergistic effect. In addition, AMD3100 significantly reduced anchorage-independent growth in the SkChA-1 cells. Overall, the results of the present study suggest that the inhibition of CXCR4 by AMD3100, in combination with gemcitabine, may be a suitable strategy for the future therapy of BTC.

The CXCR4 and adhesion molecule expression of CD34+ hematopoietic cells mobilized by "on-demand" addition of plerixafor to granulocyte-colony-stimulating factor.

BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) is routinely used for mobilization of hematopoietic stem and progenitor cells preceding autologous transplantation after high-dose chemotherapy in hematologic malignancies. However, due to high mobilization failure rates, alternative mobilization strategies are required. STUDY DESIGN AND METHODS: Patients who poorly mobilized CD34+ hematopoietic cells (HCs) with G-CSF additionally received the CXCR4 antagonist plerixafor. The phenotype of CD34+ HCs collected after this plerixafor-induced "rescue" mobilization, in regard to adhesion molecule and CD133, CD34, and CD38 expression in comparison to CD34+ HCs collected after traditional G-CSF administration in good mobilizers, was analyzed flow cytometrically. To confirm previous studies in our patient cohort, the efficiency of mobilization and subsequent engraftment after this "on-demand" plerixafor mobilization were analyzed. RESULTS: Pronounced mobilization occurred after plerixafor administration in poor mobilizers, resulting in similar CD34+ cell yields as obtained by G-CSF in good mobilizers, whereby plerixafor increased the content of primitive CD133+/CD34+/CD38- cells. The surface expression profiles of the marrow homing and retention receptors CXCR4, VLA-4, LFA-1, and CD44 on mobilized CD34+ cells and hematopoietic recovery after transplantation were similar in patients receiving G-CSF plus plerixafor or G-CSF. Unexpectedly, the expression levels of respective adhesion receptors were not related to mobilization efficiency or engraftment. CONCLUSION: The results show that CD34+ HCs collected by plerixafor-induced rescue mobilization are qualitatively equivalent to CD34+ HCs collected after traditional G-CSF mobilization in good mobilizers, in regard to their adhesive phenotype and engraftment potential. Thereby, plerixafor facilitates the treatment of poor mobilizers with autologous HC transplantation after high-dose chemotherapy.

Plerixafor and granulocyte-colony-stimulating factor (G-CSF) in patients with lymphoma and multiple myeloma previously failing mobilization with G-CSF with or without chemotherapy for autologous hematopoietic stem cell mobilization: the Austrian experience on a named patient program.

BACKGROUND: Plerixafor in combination with granulocyte-colony-stimulating factor (G-CSF) has been shown to enhance stem cell mobilization in patients with multiple myeloma, non-Hodgkin's lymphoma, and Hodgkin's disease who demonstrated with previous mobilization failure. In this named patient program we report the Austrian experience in insufficiently mobilizing patients. STUDY DESIGN AND METHODS: Twenty-seven patients from eight Austrian centers with a median (range) age of 58 (19-70) years (18 female, nine male) were included in the study. Plerixafor was limited to patients with previous stem cell mobilization failure and was given in the evening of Day 4 of G-CSF application. RESULTS: A median increase of circulating CD34+ cells within 10 to 11 hours from administration of plerixafor by a factor of 4.7 over baseline was noted. Overall, 20 (74%) patients reached more than 10 × 10(6) CD34+ cells/L in the peripheral blood, resulting in 17 (63%) patients collecting at least 2 × 10(6) CD34+ cells/kg body weight (b.w.; median, 2.6 × 10(6) CD34+ cells/kg b.w.; range, 0.08 × 10(6) -8.07 × 10(6) ). Adverse events of plerixafor were mild to moderate and consisted of gastrointestinal side effects and local reactions at the injection site. Thirteen (48%) patients underwent autologous transplantation receiving a median of 2.93 × 10(6) CD34+ cells/kg (range, 1.46 × 10(6) -5.6 × 10(6) ) and showed a trilinear engraftment with a median neutrophil recovery on Day 12 and a platelet recovery on Day 14. CONCLUSION: Our study confirms previous investigations showing that plerixafor in combination with G-CSF is an effective and well-tolerated mobilization regimen with the potential of successful stem cell collection in patients with previous mobilization failure.

An uncommon cause of anaemia: Sheehan's syndrome.

Ischemic pituitary necrosis due to severe postpartum haemorrhage called Sheehan's syndrome is a rare cause of hypopituitarism in the western world, but much more common in developing countries. A 45-year-old female patient being a war refugee from Chechnya with severe anaemia and fatigue was diagnosed at our outpatient department with Sheehan's syndrome after severe postpartum haemorrhage and emergency hysterectomy 15 years ago. Panhypopituitarism was adequately treated with substitution of hydrocortisone, thyroxine and transdermal oestrogen which resulted in haemoglobin increase to nearly normal levels and symptoms improved immediately. Severe anaemia caused by panhypopituitarism shows the importance of the hormonal system for erythropoiesis. Clinical and basic scientific evidence indicates thyroidal hormones to be the main cause.

Vincristine, idarubicin, dexamethasone and thalidomide in scleromyxoedema.

Scleromyxoedema is a rare disease of unknown aetiology that is characterized by progressive cutaneous mucinosis and paraproteinaemia. A variety of systemic (e.g. gastro intestinal, neurological, pulmonary, cardiac and renal) complications may lead to significant morbidity and mortality necessitating therapeutic intervention. The latter remains challenging. Numerous treatment modalities have been reported in the literature, often, however, with inconsistent responses, frequent relapses and potentially serious side-effects. Moreover, the rarity of scleromyxoedema has prevented the execution of controlled therapeutic trials. This paper discusses current proposed therapeutic strategies and reports the case of a 64-year-old male patient with progressive scleromyxoedema associated with IgG-lambda paraproteinaemia in whom monthly administrations of vincristine, idarubicin and dexamethasone in addition to daily oral thalidomide led to clinical and laboratory remission within 12 weeks.

Fulvestrant ('Faslodex') in heavily pretreated postmenopausal patients with advanced breast cancer: single centre clinical experience from the compassionate use programme.

BACKGROUND: Fulvestrant (Faslodex) is an oestrogen receptor (ER) antagonist with demonstrated efficacy in patients with advanced and pretreated breast cancer. PATIENTS AND METHODS: We present a single-centre experience with fulvestrant administered under the compassionate use programme (CUP) to a total of 54 postmenopausal women with metastatic breast cancer progressing on multiple endocrine and cytotoxic therapies. Patients received 250 mg fulvestrant i.m. once monthly as second- (n = 8), third- (n = 30), fourth- (n = 14) and fifth-line (n = 2) hormonal treatment. The median number of previous endocrine therapies was 2 (range 1-4). Most of the patients also had multiple palliative chemotherapies with a median of 1.7 (range 0-6) prior therapies. The median duration of fulvestrant treatment was 6.3 months (range 1-39 months) and the median duration of follow-up was 19.4 months (range 1-63 months). RESULTS: Objective response was achieved by five patients (9.3%): one complete remission (CR) (1.9%) and four partial remissions (PR) (7.4%). Stable disease (SD) lasting > or =6 months was achieved by 16 patients (29.6%). Thus in all, fulvestrant conferred clinical benefit (CB) on 21 women (38.9%). The median time to progression (TTP) was 6.4 months. In all patients with CR and PR, tumour cells were positive for both ER and progesterone receptor (PgR), but lacked HER2/neu overexpression; one patient with PR had an unknown HER2/neu status. Overall, the drug was well tolerated. No grade 3/4 toxicities were reported. CONCLUSIONS: Fulvestrant appears to be an efficient and well-tolerated drug even in women with advanced breast cancer progressing after multiple endocrine and/or cytotoxic treatments.