Biomodulatory Treatment of Patients with Castration-Resistant Prostate Cancer: A Phase II Study of Imatinib with Pioglitazone, Etoricoxib, Dexamethasone and Low-Dose Treosulfan.

Therapeutic options for patients with castration-resistant prostate cancer (CRPC) remain limited. In a multicenter, Phase II study, 65 patients with histologically confirmed CRPC received a biomodulatory regimen during the six-month core study. Treatment comprised daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan and dexamethasone. The primary endpoint was prostate-specific antigen (PSA) response. Responders could enter an extension phase until disease progression or intolerable toxicity occurred. Mean PSA was 45.3 ng/mL at baseline, and 77 % of patients had a PSA doubling time <3 months. Of the 61 evaluable patients, 37 patients (60.6 %) responded or had stable disease and 23 of them (37.7 % of 61 patients) were PSA responders. Among the 23 responders mean PSA decreased from 278.9 ± 784.1 ng/mL at baseline to 8.8 ± 11.6 ng/mL at the final visit (week 24). The progression-free survival (PFS) was 467 days in the ITT population. Of the 947 adverse events, 57.6 % were suspected to be drug-related, 13.8 % led to dose adjustment or permanent discontinuation and 40.2 % required concomitant medication. This novel combination approach led to an impressive PSA response rate of 37.7 % in CRPC patients. The good PSA response and PFS rate combined with the manageable toxicity profile suggest an alternative treatment option.

Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study).

BACKGROUND: Initially, unresectable colorectal liver metastases can be resected after response to chemotherapy. While cetuximab has been shown to increase response and resection rates, the survival outcome for this conversion strategy needs further evaluation. PATIENTS AND METHODS: Patients with technically unresectable and/or ≥5 liver metastases were treated with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated with regard to resectability every 2 months. Tumour response and secondary resection data have been reported previously. A final analysis of overall survival (OS) and progression-free survival (PFS) was carried out in December 2012. RESULTS: Between December 2004 and March 2008, 56 patients were randomised to arm A, 55 to arm B. The median OS was 35.7 [95% confidence interval (CI) 27.2-44.2] months [arm A: 35.8 (95% CI 28.1-43.6), arm B: 29.0 (95% CI 16.0-41.9) months, HR 1.03 (95% CI 0.66-1.61), P = 0.9]. The median PFS was 10.8 (95% CI 9.3-12.2) months [arm A: 11.2 (95% CI 7.2-15.3), arm B: 10.5 (95% CI 8.9-12.2) months, HR 1.18 (95% CI 0.79-1.74), P = 0.4]. Patients who underwent R0 resection (n = 36) achieved a better median OS [53.9 (95% CI 35.9-71.9) months] than those who did not [21.9 (95% CI 17.1-26.7) months, P < 0.001]. The median disease-free survival for R0 resected patients was 9.9 (95% CI 5.8-14.0) months, and the 5-year OS rate was 46.2% (95% CI 29.5% to 62.9%). CONCLUSIONS: This study confirms a favourable long-term survival for patients with initially sub-optimal or unresectable colorectal liver metastases who respond to conversion therapy and undergo secondary resection. Both FOLFOX/FOLFIRI plus cetuximab, appear to be appropriate regimens for 'conversion' treatment in patients with K-RAS codon 12/13/61 wild-type tumours. Thus, liver surgery can be considered curative or alternatively as an additional 'line of therapy' in those patients who are not cured. CLINICAL TRIAL NUMBER: NCT00153998, www.clinicaltrials.gov.

Pioglitazone, etoricoxib, interferon-α, and metronomic capecitabine for metastatic renal cell carcinoma: final results of a prospective phase II trial.

We enrolled 45 patients with metastatic renal cell carcinoma (RCC) at a progressive disease between March 2003 and April 2008 to assess the impact of an anti-inflammatory treatment regime in combination with metronomic low-dose chemotherapy. 42% of the patients had been systemically pre-treated. Therapy consisted of etoricoxib 60 mg daily plus pioglitazone 60 mg daily, day 1+, low-dose interferon-α 4.5 MU sc three times a week, week 1+ and low-dose capecitabine 1 g/m(2) twice daily orally for 14 days, every 3 weeks, day 1+, until disease progression. Objective response was observed in 35% of the patients (PR 27, CR 9%), which was paralleled by strong CRP decline for all patients with initially elevated CRP levels (n = 32). CRP values decreased from mean 42.3 mg/L (range 9.1-236), to 11.1 mg/L, (range 1.1-35.6), P = 0.006. Median overall survival and progression-free survival for the total cohort were 26.9 and 7.2 months for patients with elevated CRP 24.4 and 11.3 months (95% CI, 22.8-31.0/5.7-16.9) and 13.8-2.6 months (95% CI, 6.5-21.1/0.4-4.8) for the non-elevated CRP group, respectively (P = 0.082/0.017). Median observation time: 26.1 months; Overall survival at 5 years: 18%. Toxicity>WHO grade 3 was reported: Hand-foot syndrome in 16 patients (36%), diarrhea in 4, and pneumonia in 2 patients. Our data allow us to conclude that the control of tumor-associated inflammation is an important therapeutic principle in patients with metastatic RCC.

Detection of Aspergillus species in blood and bronchoalveolar lavage samples from immunocompromised patients by means of 2-step polymerase chain reaction: clinical results.

Bronchoalveolar lavage (BAL) samples from 67 patients who were at high risk for invasive aspergillosis were examined using a recently developed 2-step polymerase chain reaction (PCR) that detects

Dyshematopoiesis in de novo acute myeloid leukemia: cell biological features and prognostic significance.

Dyshematopoiesis was found in 44 (42.3%) of 104 cases of de novo acute myeloid leukemia (AML). Dyshematopoietic AML (dys-AML) and AML without hematopoietic dysplasia (non-dys-AML) were compared with regard to biological, hematological, immunophenotypic, and cytogenetic parameters as well as prognostic criteria. Median age of patients was 55 years in both groups. In dys-AML, the median leukocyte count (p = 0.04), peripheral blast (p = 0.02) and medullary blast cell count (p < 0.001) were significantly decreased, whereas the median platelet count (p - 0.04) was increased. Immunophenotyping demonstrated that leukemic blast cells in dys-AML more frequently expressed the adhesion molcules CD54 (p = 0.05) and CD58 (p = 0.08) than leukemic cells in non-dys-AML. Cytogenetically, we distinguished two karyotypic patterns, one group with a normal karyotype or prognostically favorable single chromosome aberrations ("P(0)-karyotype"), and another one with unfavorable single aberrations or complex aberrations ("P(1)-karyotype"). The incidence of these groups was not significantly different between dys-AML and non-dys-AML. Complete remission rate (CRR) after induction chemotherapy (p = 0.03) and overall survival time (OS; p = 0.03) were significantly lower in dys-AML. In addition, median disease free survival (DFS; p = n.s.) was inferior compared to non-dys-AML. In the dys-AML as well as in the non-dys-AML patient group, CRR, DFS, and OS were decreased in the P(1)-compared to the P(0)-subgroup. We conclude that dyshematopoietic AML is characterized by specific cell biological features and that hematopoietic and cytogenetic status represent complementary prognostic factors in de novo AML.

Differential expression of transglutaminase in human erythroleukemia cells in response to retinoic acid.

Two human erythroleukemia cell lines, HEL and K562, express transglutaminase activity. The enzyme was identified as a tissue transglutaminase following chromatographic purification. All-trans-retinoic acid (10 microM) stimulated differentiation in HEL cells as judged by a 4-fold increase in hemoglobin content and a reduction in cell proliferation. The transglutaminase activity increased 9-fold. This increase in transglutaminase was the result of a pretranslational regulation of the gene as revealed by Northern blot analysis of mRNA. These changes were not a result of cell apoptosis, since parallel DNA degradation catalyzed by a Ca2(+)-dependent endonuclease could not be demonstrated. The K562 cells, in contrast, showed no transglutaminase induction following exposure to retinoic acid and displayed no changes in maturation markers or cell growth.