Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers.

BACKGROUND: This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based therapy. PATIENTS AND METHODS: Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control. RESULTS: Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin, and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD. CONCLUSIONS: Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance.

Spatiotemporal antiphase dynamics in coupled extended optical media.

Experimental evidence of spatiotemporal antiphase dynamics is given for an extended system made of two liquid crystal slices that are optically coupled by two equal amplitude counterpropagating pumping beams. Theory and experiments carried out in a transverse one-dimensional configuration show that roll patterns are generated in each slice. These rolls are spatially in-phase or antiphase for a focusing or a defocusing nonlinearity type, respectively. These in-phase or antiphase dynamics remain robust even for complex spatiotemporal regimes such as dislocation regimes.

Average patterns and coherent phenomena in wide aperture lasers.

Using a realistic model of wide aperture, weakly astigmatic lasers we develop a framework to analyze experimental average intensity patterns. We use the model to explain the appearance of patterns in terms of the modes of the cavity and to show that the breaking of the symmetry of the average intensity patterns is caused by overlaps in the frequency spectra of nonvanishing of modes with different parity. This result can be used even in systems with very fast dynamics to detect experimentally overlaps of frequency spectra of modes.

Secondary transverse instabilities in optical parametric oscillators.

We investigate the effect of coupling between diffraction and walk-off on secondary instabilities in nondegenerate optical parametric oscillators. We show that traveling waves that propagate in the walk-off direction, which are generated at the onset of absolute instability, experience Eckhaus and zigzag phase instabilities. Each of these secondary instabilities splits into absolute and convective instabilities that modify the Eckhaus and zigzag instability boundaries. As a consequence, the stability domain of modulated traveling waves is enlarged and may coexist with uniform steady states. The predictions are consistent with the numerical solutions of the optical parametric oscillator model.

Multi-center study of two dose levels of paclitaxel with carboplatin in locally advanced and metastatic non-small cell lung cancer (NSCLC).

BACKGROUND: The efficacy and toxicity of the combination of two cytotoxic compounds that are active as single agents in non-small cell lung cancer (NSCLC), paclitaxel (Taxol) and carboplatin (Paraplatin) was investigated in a multicenter, community-based setting. MATERIALS AND METHODS: Two consecutive cohorts of chemonaive patients with stages IIIA/B and IV NSCLC received two dose levels of paclitaxel. The first cohort received 200 mg/m2 over 3 hours (HD) and the second cohort 175 mg/m2 over 3 hours (LD) in combination with a fixed dose of carboplatin. The dose of carboplatin was calculated according to the Calvert formula with an area under the concentration versus time curve (AUC) value of 6 mg/ml/minute. The carboplatin clearance, calculated by the Chatelut formula rather than the glomerulation filtration rate (GFR) +25, was introduced into the Calvert formula. The eligibility criteria were identical for both cohorts throughout the study. Treatment was administered every three weeks. The study endpoints were response rate (RR), toxicity, time to progression (TTP) and survival (S). RESULTS: One hundred and thirty consecutive eligible patients from 36 Belgian institutions were fully evaluable for all study parameters (99 in the HD and 31 in the LD cohort). Myelosuppression was the most prominent side-effect of treatment with comparable results for both cohorts. The worst grade 3-4 leucopenia and neutropenia per patient in the HD versus LD cohort was 34.4 vs 19.3% and 59.2 vs 51.6%, respectively. 10.4% of patients in the HD cohort required hospitalisation for febrile neutropenia (6.2% with and 4.2% without documented bacterial infection), while in the LD cohort the respective figures were 13.7, 10.3 and 3.4%. The most prominent non-hematologic toxicities were alopecia and polyneuropathy, with no major difference between the HD and LD cohort (grade 2 alopecia in 78.1 vs. 83.9% and grade 3 neuropathy in 14.3 vs. 9.7%, respectively). The overall best clinical RR was 31 out of 130 (23.8%) with one complete (CR) and 30 partial responses (PR). The respective RR in the HD and LD cohort was 23.2 and 25.8%. Median TTP and S for all patients was 120 and 248 days, with no apparent difference between the HD and the LD cohort (119 and 254 versus 128 and 222, respectively). The one year survival was 34% in the HD cohort. The 95% confidence intervals for efficacy and toxicity parameters overlapped in both cohorts. CONCLUSION: In this multicenter study, the combination of paclitaxel and carboplatin produced a moderate RR of 23.8% in stages IIIA/B & IV NSCLC. The therapy was generally well tolerated at both doses of paclitaxel. Myelosuppression, neurotoxicity and alopecia were the major therapy-related side-effects. The differences between the two paclitaxel dose cohorts with respect to activity and toxicity were minimal. The use of the Chatelut formula to calculate the carboplatin clearance is feasible, but might have lead to the apparent excess in myelotoxicity in our study compared to other studies which used other methods for estimating renal function.

Influence of walkoff on pattern formation in nondegenerate optical parametric oscillators.

Convective and absolute nature of instabilities in nondegenerate optical parametric oscillators with large transverse section, for negative detunings and in the presence of walkoff, is examined. The asymptotic response of the signal and idler fields to a transverse localized two-dimensional perturbation is evaluated. The presence of walkoff breaks the rotational symmetry in the transverse plane, and the system, at the absolute instability threshold, selects traveling waves propagating in the walkoff direction among an infinity of unstable spatiotemporal modes. We show that in optical parametric oscillators (OPO's) with negative detunings, contrary to the case of positive detunings, the walkoff shrinks the region of convective instabilities, and even may suppress the convective/absolute transition. Hence, in a certain range of parameters, signal field envelopes in the form of wave packets of zero group velocity are found where the instability is absolute at the onset, although the walkoff is present. We also show that nonlinear pattern selection is ruled by the cross-coupling terms appearing in the asymmetric coupled Ginzburg-Landau equations derived near-threshold of the signal and idler generation. The numerical solutions of the original OPO equations confirm the analytical predictions for the values of the instability thresholds and the corresponding selected patterns.

A single course of 2-chloro-deoxyadenosine does not eradicate leukemic cells in hairy cell leukemia patients in complete remission.

The nucleoside analog 2-chlorodeoxyadenosine (2-CdA) has recently emerged as a most promising treatment for hair-cell leukemia (HCL). The response rates are high regardless of prior therapy, and the duration of complete responses (CR) after a single course of treatment is longer than with any other therapeutic agent. We investigated the presence of minimal residual disease (MRD) in ten HCL patients treated in our institution with 2-CdA. The presence of residual leukemic cells was investigated in patients in CR following one course of treatment, using the polymerase chain reaction (PCR) and heavy-chain immunoglobulin genes (IgH), or TCR delta derived clonospecific probes. Eight patients achieved a complete remission after a single course of treatment, as evaluated at 6 months. Among these patients, seven are still in CR with a median follow-up of 12 months (range, 6-20 months) and one has relapsed after 15 months. Using PCR, all the evaluable patients remaining in CR showed persistent evidence of detectable MRD with no sign of decrease over the observation period. From this small series, we conclude that a single course of 2-CdA does not eradicate HCL and that persistence of residual leukemic cells appears to be common in patients in complete morphologic remission. Whether persistence of MRD will have an impact on long-term outcome, or whether HCL patients in morphologic CR with persistent MRD will remain so, is a matter of longer follow-up.