Correlation of pretreatment drug induced apoptosis in ovarian cancer cells with patient survival and clinical response

Background This study was performed to determine if a chemotherapy-induced apoptosis assay (MiCK) could predict the best therapy for patients with ovarian cancer. Methods A prospective, multi-institutional and blinded trial of the assay was conducted in 104 evaluable ovarian cancer patients treated with chemotherapy. The MiCK assay was performed prior to therapy, but treating physicians were not told of the results and selected treatment only on clinical criteria. Outcomes (response, time to relapse, and survival) were compared to the drug-induced apoptosis observed in the assay. Results Overall survival in primary therapy, chemotherapy naïve patients with Stage III or IV disease was longer if patients received a chemotherapy which was best in the MiCK assay, compared to shorter survival in patients who received a chemotherapy that was not the best. (p < 0.01, hazard ratio HR 0.23). Multivariate model risk ratio showed use of the best chemotherapy in the MiCK assay was the strongest predictor of overall survival (p < 0.01) in stage III or IV patients. Standard therapy with carboplatin plus paclitaxel (C + P) was not the best chemotherapy in the MiCK assay in 44% of patients. If patients received C + P and it was the best chemotherapy in the MiCK assay, they had longer survival than those patients receiving C + P when it was not the best chemotherapy in the assay (p = 0.03). Relapse-free interval in primary therapy patients was longer if patients received the best chemotherapy from the MiCK assay (p = 0.03, HR 0.52). Response rates (CR + PR) were higher if physicians used an active chemotherapy based on the MiCK assay (p = 0.03). Conclusion The MiCK assay can predict the chemotherapy associated with better outcomes in ovarian cancer patients. This study quantifies outcome benefits on which a prospective randomized trial can be developed

Understanding atmospheric organic aerosols via factor analysis of aerosol mass spectrometry: a review

Organic species are an important but poorly characterized constituent of airborne particulate matter. A quantitative understanding of the organic fraction of particles (organic aerosol, OA) is necessary to reduce some of the largest uncertainties that confound the assessment of the radiative forcing of climate and air quality management policies. In recent years, aerosol mass spectrometry has been increasingly relied upon for highly time-resolved characterization of OA chemistry and for elucidation of aerosol sources and lifecycle processes. Aerodyne aerosol mass spectrometers (AMS) are particularly widely used, because of their ability to quantitatively characterize the size-resolved composition of submicron particles (PM1). AMS report the bulk composition and temporal variations of OA in the form of ensemble mass spectra (MS) acquired over short time intervals. Because each MS represents the linear superposition of the spectra of individual components weighed by their concentrations, multivariate factor analysis of the MS matrix has proved effective at retrieving OA factors that offer a quantitative and simplified description of the thousands of individual organic species. The sum of the factors accounts for nearly 100% of the OA mass and each individual factor typically corresponds to a large group of OA constituents with similar chemical composition and temporal behavior that are characteristic of different sources and/or atmospheric processes. The application of this technique in aerosol mass spectrometry has grown rapidly in the last six years. Here we review multivariate factor analysis techniques applied to AMS and other aerosol mass spectrometers, and summarize key findings from field observations. Results that provide valuable information about aerosol sources and, in particular, secondary OA evolution on regional and global scales are highlighted. Advanced methods, for example a-priori constraints on factor mass spectra and the application of factor analysis to combined aerosol and gas phase data are discussed. Integrated analysis of worldwide OA factors is used to present a holistic regional and global description of OA. Finally, different ways in which OA factors can constrain global and regional models are discussed

A Four Carbon Organonitrate as a Significant Product of Secondary Isoprene Chemistry

Abstract Oxidation of isoprene by nitrate radicals (NO3) or by hydroxyl radicals (OH) under high NOx conditions forms a substantial amount of organonitrates (ONs). ONs impact NOx concentrations and consequently ozone formation while also contributing to secondary organic aerosol. Here we show that the ONs with the chemical formula C4H7NO5 are a significant fraction of isoprene-derived ONs, based on chamber experiments and ambient measurements from different sites around the globe. From chamber experiments we found that C4H7NO5 isomers contribute 5%?17% of all measured ONs formed during nighttime and constitute more than 40% of the measured ONs after further daytime oxidation. In ambient measurements C4H7NO5 isomers usually dominate both nighttime and daytime, implying a long residence time compared to C5 ONs which are removed more rapidly. We propose potential nighttime sources and secondary formation pathways, and test them using a box model with an updated isoprene oxidation scheme

Feasibility of using the drug-induced apoptosis assay (MiCK assay) in mesothelioma as compared to non-small cell lung cancer (NSCLC).

e18538 Background: The drug-induced apoptosis MiCK assay has been predictive of outcomes in acute myelocytic leukemia, ovarian cancer, and a variety of solid tumors including breast cancer (Cancer Research 2012; 72:3901). We compared MiCK assay results in mesothelioma patients (pts) with NSCLC pts. Methods: Specimens from tissue or effusions were submitted to a central lab, processed to purify neoplastic cells, and a MiCK assay was performed as described (Cancer 2012; 118: 4877). Best chemotherapy regimens are defined as drugs/combinations with highest kinetic units (KU) of apoptosis +/- 1 SD compared to other drugs (this definition was predictive of outcomes in ovarian cancer). Active drugs have results over 1.0 KU of apoptosis. Results: 10 specimens have been submitted and 7 have been successful. Mean age was 69 and mean number of prior lines of therapy were 0.7 in 3 mesothelioma pts and 2.0 in 4 NSCLC pts. Mean number of drugs or combinations assayed successfully were 41 in mesothelioma and 20 in NSCLC. In mesothelioma, best active chemotherapy regimens (&gt;1.0 KU) have been pemetrexed+doxorubicin, epirubicin, idarubicin, cyclophosphamide, ifosfamide, and dactinomycin. In NSCLC, best active regimens have been doxorubicin+cisplatin, irinotecan, and cyclophosphamide+doxorubicin+vincristine. In mesothelioma pts, the assay has been able to identify unexpected significant activity of several drugs: epirubicin, idarubicin, daunorubicin, dactinomycin, bendamustine, melphalan, vincristine, topotecan, azacytidine and bortezomib. Conclusions: Use of the MiCK assay in mesothelioma is at least as successful in the laboratory as it is in NSCLC. Unexpected new leads for innovative therapeutic strategies have been identified by the in vitro results. This feasibility study justifies a prospective controlled trial of the MiCK assay in mesothelioma and NSCLC pts. Clinical trials of drugs with unexpected activity are warranted in mesothelioma pts. Clinical trial information: NCT 01770665. </jats:p

Endometrial carcinoma in vitro chemosensitivity testing of single and combination chemotherapy regimens using the novel microculture kinetic apoptosis assay: implications for endometrial cancer treatment

Objective: The in vitro microculture kinetic (MiCK) apoptosis assay has been used to predict single or combination chemotherapy response in leukemia patients. This feasibility study addressed MiCK in endometrial cancer specimens. Methods: Endometrial cancer specimens from total abdominal hysterectomies were processed at a central laboratory. Single cell suspensions of viable endometrial cancer cells were plated in individual wells. Single and combination regimens were tested: combinations of doxorubicin, cisplatin, and paclitaxel and carboplatin and paclitaxel (Gynecologic Oncology Group [GOG] 209 endometrial cancer phase III trial arms) as well as single agent testing with paclitaxel, carboplatin, doxorubicin, cisplatin, ifosfamide, and vincristine (active agents in GOG trials). Apoptosis was measured continuously over 48 hours. Results: Fifteen of nineteen patients had successful assays. The highest mean chemo sensitivity was noted in the combination of cisplatin, doxorubicin, and paclitaxel with lower mean chemosensitivity for carboplatin and paclitaxel. Combination chemotherapy had higher chemosensitivity than single drug chemotherapy. However, in 25% of patients a single drug had higher chemosensitivity than combination chemotherapy. As single agents, ifosfamide, cisplatin, and paclitaxel had the highest kinetic unit values. Conclusion: Using a panel of agents simulating clinical dose regimens, the MiCK assay was feasible in evaluating in vitro chemosensitivity of endometrial cancer. MiCK assay results correlated with GOG clinical trial results. However, 25% of patients might be best treated with single agent chemotherapy selected by MiCK. Ifosfamide, cisplatin, and paclitaxel appear to have high activity as single agents. MiCK may be useful in future new drug testing and individualizing endometrial cancer patient’s chemotherapy management. Originally published Journal of Gynecologic Oncology, Vol. 21, No. 1, Mar 201

Clinical outcomes and alternative chemotherapy (CT) options in patients (pts) with de novo carboplatin (carbo)-resistant stage III or IV ovarian cancer (CA) based on the drug-induced apoptosis (MiCK) assay.

e16525 Background: In order to understand platinum-resistant ovarian CA better, we evaluated the outcomes of pts with in vitro carbo resistance and CT alternatives based on the MiCK assay. Methods: 77 pts with primary stage III or IV ovarian CA previously untreated with CT had a MiCK assay prior to therapy. The MiCK assay was performed as described (J Trans Med 2012; 10:162). Physicians did not receive the results of the assay prior to CT. The time to recurrence in pts treated with standard carbo+paclitaxel CT who had in vitro de novo carbo resistance (carbo KU&lt;1 in the MiCK assay) was compared to time to recurrence in pts treated with carbo+paclitaxel with no in vitro resistance (carbo KU&gt;1) using the log-rank test. The pattern of assay sensitivity to other drugs was analyzed. Results: In pts with de novo carbo resistance in the MiCK assay who were treated with carbo+paclitaxel, the median time to recurrence was only 5.0 months compared to 16 months in pts with carbo sensitivity (p = 0.01). In patients with de novo carbo resistance, 63% of pts were still sensitive (KU&gt;1) to cisplatin in the MiCK assay. For those pts resistant to carbo in the MiCK assay, alternative active CTs were cisplatin 63%, docetaxel 50%, cisplatin+gemcitabine 60%, topotecan 25%, liposomal doxorubicin 20%, etoposide 50%, gemcitabine 17% and cyclophosphamide 50%. The MiCK assay was able to rank individual drugs and combinations with highest drug induced apoptosis for individual patients. Conclusions: Pts with de novo in vitro carbo resistance have more rapid relapse, and can be prospectively rapidly identified before initial CT (time required for MiCK assay 48 hours). Alternative drugs or combinations with in vitro activity (still using drugs within national evidence based treatment guidelines) can be identified with the MiCK assay. This suggests that for pts with relapsing disease with clinically apparent carbo resistance, the MiCK assay can identify individualized CT for such pts. This study gives the framework for a prospective randomized phase III trial of assay-directed CT versus standard CT in platinum-resistant ovarian CA. Clinical trial information: NCT 00443196. </jats:p