Carboplatin and paclitaxel plus ASA404 as first-line chemotherapy for extensive-stage small-cell lung cancer: a multicenter single arm phase II trial (SAKK 15/08)

INTRODUCTION Small-cell lung cancer (SCLC) is a highly vascularized tumor. ASA404 is a tumor vascular disrupting agent. This is the first trial to report the effects of combining chemotherapy with ASA404 in SCLC. METHODS Patients with untreated metastatic SCLC were treated with carboplatin (area under curve, 6) plus paclitaxel (175 mg/m(2)) plus ASA404 (1800 mg/m(2)) on day 1 every 21 days for up to 6 cycles. The primary endpoint was the progression-free survival (PFS) rate at 24 weeks. RESULTS Median age was 61 years; 53% were women, 41% had weight loss; and 96% had a performance status of 0-1. Twelve patients completed all 6 cycles, and most adverse events were related to chemotherapy. Median PFS and time to progression were 7.0 months (95% CI, 5.7-9.4 months) and 7.5 months (95% CI, 5.7-9.4 months), respectively. The progression-free survival (PFS) rate at 24 weeks was 41% (95% CI, 18%-65%). The overall response rate was 94%. The median overall survival time was 14.2 months (95% CI, 8.2-16.0 months) and 1-year survival was 57%. The median follow-up time was 17.7 months. Due to negative results with ASA404 in non-small-cell lung cancer trials, the trial was stopped prematurely after 17 of 56 planned patients were being accrued. CONCLUSIONS This is the first report of a clinical trial with a vascular disrupting agent in SCLC. No unexpected toxicity was observed. PFS was not prolonged with carboplatin and paclitaxel plus ASA404.

Amplified bioproductivity during Transition IV (332 000-342 000 yr ago): evidence from the geochemical record of Lake El'gygytgyn

Abstract. To date, terrestrial archives of long-term climatic change within the Arctic have widely been restricted to ice cores from Greenland and, more recently, sediments from Lake El’gygytgyn in northeast Arctic Russia. Sediments from this lake contain a paleoclimate record of glacialinterglacial cycles during the last three million years. Lowresolution studies at this lake have suggested that changes observed during Transition IV (the transition from marine isotope stage (MIS) 10 to MIS 9) are of greater amplitude than any observed since. In this study, geochemical parameters are used to infer past climatic conditions thus providing the first high-resolution analyses of Transition IV from a terrestrial Arctic setting. These results demonstrate that a significant shift in climate was subsequently followed by a rapid increase in biogenic silica (BSi) production. Following this sharp increase, bioproductivity remained high, but variable, for over a thousand years. This study reveals differences in the timing and magnitude of change within the ratio of silica to titanium (Si/Ti) and BSi records that would not be apparent in lower resolution studies. This has significant implications for the increasingly common use of Si/Ti data as an alternative to traditional BSi measurements.

Influence of hormone replacement therapy on proteomic pattern in serum of postmenopausal women

OBJECTIVES: Proteomics approaches to cardiovascular biology and disease hold the promise of identifying specific proteins and peptides or modification thereof to assist in the identification of novel biomarkers. METHOD: By using surface-enhanced laser desorption and ionization time of flight mass spectroscopy (SELDI-TOF-MS) serum peptide and protein patterns were detected enabling to discriminate between postmenopausal women with and without hormone replacement therapy (HRT). RESULTS: Serum of 13 HRT and 27 control subjects was analyzed and 42 peptides and proteins could be tentatively identified based on their molecular weight and binding characteristics on the chip surface. By using decision tree-based Biomarker Patternstrade mark Software classification and regression analysis a discriminatory function was developed allowing to distinguish between HRT women and controls correctly and, thus, yielding a sensitivity of 100% and a specificity of 100%. The results show that peptide and protein patterns have the potential to deliver novel biomarkers as well as pinpointing targets for improved treatment. The biomarkers obtained represent a promising tool to discriminate between HRT users and non-users. CONCLUSION: According to a tentative identification of the markers by their molecular weight and binding characteristics, most of them appear to be part of the inflammation induced acute-phase response

Treatment with the HIV protease inhibitor Nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: a phase I trial (SAKK 65/08).

Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in Multiple Myeloma.The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. 12 patients with advanced hematological malignancies were treated with nelfinavir (2500 - 5000 mg/d p.o., d 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m2, d 1, 4, 8, 11; 21 day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. Endpoints included dose limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2 x 2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly upregulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for ≥ 2 cycles, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising signals for activity in advanced, bortezomib-refractory MM. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (Trial registration NCT01164709).