A combined experimental and theoretical study of the Ti2 + N2O reaction.

The reactivity of diatomic titanium with nitrous oxide has been studied in solid neon. Two molecules with the same Ti2-N2O stoichiometry are identified from concentration, temperature, and irradiation effects. The more stable one is characterized by five fundamental vibrational transitions located below 1000 cm(-1), the high frequency one at 946 cm(-1) corresponding to a pure TiO stretching mode. Its structure, a rhombus OTiNTiN with the extra O atom fixed on one Ti, is confirmed by quantum chemical calculations, at the CCSD(T) level, which predict a Cs structure in the singlet state with a Ti-O bond length close to 1.66 Å, two nonequivalent Ti-N distances close to 1.94 and 1.75 Å, and a OTiTi angle of 119.2°. The second Ti2-N2O molecule, only observed after annealing, is easily converted into the first one upon irradiation above 12 000 cm(-1) and its kinetics of photoconversion allows vibrational transitions to be identified. The strongest one located at 2123.4 cm(-1) characterizes an N-N stretching mode. Corresponding ab initio calculations complete this picture with details on the electronic structure and allow us to identify a most adequate density functional to describe the spectroscopic properties of the studied species in a simpler broken-symmetry open-shell DFT context. The theoretical results predict the existence of a metastable product OTi2N2 and correctly account for the observed spectra of the various isotopic varieties.

Pd(2)N(2), a proteiform molecule: Matrix isolation spectroscopy and density functional theory calculations.

The formation of Pd(2)N(2) from the cocondensation of effusive beams of Pd and N(2) in neon and argon matrices is evidenced by absorptions in the range of 2200-1800 cm(-1). In argon, selective irradiation in the near-infrared and visible ranges leads to interconversions between three structures, distinguished by the stretching frequency of the diatomic N(2): Bridged T-shaped (nu(NN) at 1990 cm(-1)), side on (nu(NN) at 2178 cm(-1)) and parallel (nu(NN) at 1823 cm(-1)). For the first two structures, the nu(NN) mode is also accompanied by another signal below 500 cm(-1). An extra feature close to 490 cm(-1), not sensitive to irradiation at lambda(irr)>400 nm and also assignable to a molecule with the same Pd:N(2) stoichiometry (2:1), corresponds to a centrosymmetrical Pd-N-N-Pd structure with an inactive nu(NN) mode close to 2141 cm(-1), as deduced from the observation of a weak signal close to 2630 cm(-1) associated with this species and assignable to the combination nu(NN)+nu(PdN). All these experimental data and their structural implications are fully supported by theoretical calculations [density functional theory (DFT)]. On the basis of this comparative study, we have obtained a reliable theoretical description of the spectroscopic data using the metageneralized gradient approximation functional within the unrestricted DFT (UDFT) formalism for all spin multiplets. We have also searched a stable electronic solution for each multiplet (particularly for the singlet state), in order to account for the nondynamic correlations.

Rovibrational and dynamical properties of the hydrogen bonded complex (CH2)2S-HF: a combined free jet, cell, and neon matrix-Fourier transform infrared study.

Fourier transform infrared spectra of the nu(s) (HF stretching) band of the (CH(2))(2)S-HF complex have been recorded at 0.1-0.5 cm(-1) resolution in a cooled cell, in a supersonic jet expansion seeded with argon and in a neon matrix at 4.5 K. The combination of controlled temperature effects over a range of 40-250 K and a sophisticated band contour simulation program allows the separation of homogeneous and inhomogeneous contributions and reveals significant anharmonic couplings between intramolecular and intermolecular vibrational modes similar to our previous work on (CH(2))(2)S-DF. The sign of the coupling constants is consistent with the expected strengthening of the hydrogen bond upon vibrational excitation of HF which also explains the observed small variations of the geometrical parameters in the excited state. The analysis of sum and difference combination bands involving nu(s) provides accurate values of intermolecular harmonic frequencies and anharmonicities and a good estimate of the dissociation energy of the complex. Frequencies and coupling parameters derived from gas phase spectra compare well with results from neon matrix experiments. The effective linewidth provides a lower bound for the predissociation lifetime of 10 ps. The comparison between effective linewidths and vibrational densities of states for (CH(2))(2)S-HF and -DF complexes highlights the important role of intramolecular vibrational redistribution in the vibrational dynamics of medium strength hydrogen bonds.

Cisplatin/carboplatin + etoposide + vinorelbine in advanced non-small-cell lung cancer: a multicentre randomised trial. Gruppo Oncologico Campano.

A multicentre randomised phase III trial in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) was undertaken to compare the therapeutic activity and toxicity of a cisplatin/carboplatin-etoposide-vinorelbine combination with that of a cisplatin-etoposide regimen. Patients with advanced (stage IIIB-IV) NSCLC were randomised, after stratification for stage (IIIB-IV) and performance status (0-1 and 2), to receive either (A) CDDP 40 mg m-2 + VP16 100 mg m-2 on days 1-3 as standard treatment or (B) CBDCA 250 mg m-2 on day 1 + CDDP 30 mg m-2 on days 2 and 3 + VP16 100 mg m-2 on days 1-3 + NVB 30 mg m-2 on day 1. Therapy was recycled on day 29 in both arms. We hypothesised a 15% minimum increment in the response rate with the experimental regimen over the 25% expected activity rate of the standard regimen. A two-stage design was chosen, which permitted the early termination of the trial (after the accrual of 52 patients in each arm) if the difference in response rates between the two regimens was less than 3% at the end of the first stage. A total of 112 patients (arm A = 57, arm B = 55) were enrolled in the study (53 with stage IIIB and 59 with stage IV), of which 105 eligible patients were evaluable for response on an "intention to treat' basis. Seven patients were excluded because they did not fulfil the inclusion criteria. Fifteen responses were observed in arm A (28%, 95% CI = 17-42) and 13 (one complete) in arm B (25%, 95% CI = 13-37). On multivariate logistic analysis, treatment did not affect the response rate, while stage IV and performance status 2 were significantly associated with a lower probability of response. Median survivals were similar in the two arms (31 vs 27 weeks). The experimental regimen was associated with an extremely poor median survival in patients with poor performance status (21 weeks). On Cox analysis, treatment failed to show a significant impact on survival: stage IV (relative risk = 1.6. CI = 1.0-2.6, P = 0.036) was the only prognostic variable significantly associated with a worse survival outcome and, although poor performance status adversely affected survival, this effect did not reach the level of statistical significance (relative risk = 1.6, CI = 0.98-2.5; P = 0.063). There were no significant differences in non-haematological toxicities between the two arms, although three patients in the control arm had to discontinue the treatment because of the persistence of severe nephrotoxicity (two patients) or neurotoxicity (one patient). In contrast, a significant increase in both neutropenia and thrombocytopenia was observed in the experimental arm. Four treatment-related deaths were registered in arm B (two due to neutropenic sepsis, one to myocardial failure and one to acute renal failure) compared with one toxic death (acute renal failure) in arm A. In view of these results, the trial was stopped and the null hypothesis (< 15% increase in response rate with the experimental regimen) has been accepted. Therefore, our combination does not deserve further evaluation as first-line treatment in advanced NSCLC patients. As our data suggest that an aggressive chemotherapy might have a negative impact on survival of patients with poor performance status, trials to evaluate the activity of new regimens should be conducted separately for each subset of patients with different performance status.

Partial substitution of cisplatin with carboplatin in combination with etoposide in advanced non-small cell lung cancer (NSCLC): a multicentric randomised phase II trial.

Seventy previously untreated patients with advanced NSCLC were randomised, after stratification for stage (IIIB vs. IV) and Performance Status (0-1 vs. 2), to receive either treatment A: CDDP 40 mg/m2 + VP16 100 mg/m2 day 1-3 (37 patients); or treatment B: CBDCA 250 mg/m2 day 1 + CDDP 30 mg/m2 day 2, 3 + VP16 100 mg/m2 day 1-3 (33 patients). Therapy was recycled on day 29 in both arms. The two arms were well balanced for the main pretreatment characteristics. Sixty-six patients (32 with Stage IIIB and 34 with Stage IV disease) were evaluable for toxicity and response (arm A = 34, arm B = 32), while four ineligible patients were excluded from analysis. Acute toxicity was assessed at recycling. Non-hematologic toxicity was higher in arm A. However, the reduction of nephrotoxicity (9% vs. 23%) in arm B was lower than expected. Leukopenia (15 vs. 5 patients) or thrombocytopenia (7 vs. 0 patients) of any grade affected more patients of arm B. Moreover, Grade 3-4 leukopenia (six patients) or thrombocytopenia (four patients) was observed only in arm B. Seventeen patients responded: 11/34 (32%; 95% C.I. = 17-50%) in arm A, and 6/32 (19%; 95% C.I. = 7-36%) in arm B. Median survival times of 40 and 34 weeks, respectively, were reported in arm A and B. Stage IIIB and squamous cell histology were associated with a higher probability of response. In conclusion, the partial replacement of CDDP with CBDCA in combination with VP16 slightly improves the tolerance of the treatment in terms of nephro- and neurotoxicity; however, it induces a significant increase in hematologic toxicity. In view of this unfavourable toxicologic profile and of the discouraging response rate observed, this regimen cannot be recommended as standard treatment in advanced NSCLC.

Weekly low dose epirubicin in elderly cancer patients.

AIMS AND BACKGROUND: The treatment of elderly patients with metastatic solid tumours is still a debated problem. Patients over 75 years are generally excluded from combination chemotherapy trials because of higher toxicity. Several clinical studies have shown that weekly low dose epirubicin is a well tolerated and effective treatment for elderly cancer patients (breast, prostate, lung). METHODS: We report a study of patients aged between 75 and 85 years affected by metastatic anthracyclines-sensible carcinomas, to assess the tolerance of epirubicin given weekly at a dose of 25 mg/m2. RESULTS: 25 patients (13 males, 12 females; ECOG P.S. 0-2) entered the study and were evaluable for side effects. One-hundred and ninety-six cycles of therapy have been administered. Side effects were never severe. Mucositis (9 patients), leucopenia (7 patients), anemia (5 patients) were usually of grade 1 or 2. Grade 1 cardiotoxicity (tachycardia) was observed in only one case. Grade 3 toxicity consisted in anemia (1 patient) and mucositis (1 patient), while grade 4 toxicity never occurred. Nineteen patients were evaluable for response: 0 CR, 4 PR (1 lung, 3 breast), 8 SD (3 lung, 3 breast, 2 prostate) have been observed. Compliance was encouraging and the majority of patients showed a decrease in symptoms and an improvement in performance status. CONCLUSIONS: Weekly low-dose epirubicin is a very well tolerated treatment in elderly cancer patients. In view of the negligible toxicity encountered, it could be of utility to test this regimen in patients aged 75 years or older, affected by anthracyclines-sensible metastatic tumors, also to assess activity.