Defect unbinding on a toroidal nematic shell.

We study nematic liquid crystal textures exhibiting topological defects (TDs) on a two-dimensional (2D) toroidal shell. For the toroidal topology the total topological charge of TDs is equal to zero. We use a mesoscopic Landau-de Gennes approach which features a 2D nematic order tensor Q. We show that fat tori unbind TDs. If no extrinsic free energy couples Q with the Weingarten tensor of the torus, then defects and antidefects are assembled along the innermost and the outermost circles of the torus, respectively. In this case, we estimate the critical condition for the onset of TDs using an electrostatic analogy. If, on the other hand, an extrinsic free energy is present, then defects are repelled from these regions.

Amelioration of injury-induced tissue acidosis by a nonsteroidal analgesic attenuates antinociceptive effects of the pH-dependent opioid agonist NFEPP.

Opioid agonists are powerful drugs for managing pain. However, their central side effects are limiting their use and drugs with similar potency, but a lower risk profile are needed. (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (NFEPP) is a novel opioid agonist that preferentially activates opioid receptors at acidic extracellular pH. NFEPP was designed to activate peripheral opioid receptors in injured tissue, therefore precluding side effects elicited at normal pH in brain or intestinal wall. Considering the common combination of opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) in multimodal analgesia, we investigated the interaction between NFEPP and a widely prescribed prototypical NSAID, diclofenac (DCF), in a rat model of unilateral hindpaw inflammation induced by complete Freund's adjuvant. We evaluated the effects of systemically applied DCF on the paw tissue pH, on the expression of inflammatory mediators in immune cells from inflamed paws and on the expression of opioid receptors in dorsal root ganglia. Additionally, we investigated the antinociceptive efficacy of NFEPP injected into the inflamed paws after DCF treatment. We found that DCF reduced inflammation-induced nociceptive responses and tissue acidosis, but did not change the mRNA expression of IL-1ß, TNF-α, IL-6, IL-4, NGF, or of mu-, delta-, or kappa-opioid receptors. The treatment with DCF moderately reduced the antinociceptive efficacy of NFEPP, suggesting a correlation between an increase in local tissue pH and the decreased antinociceptive effect of this pH-sensitive opioid agonist.

Capecitabine as adjuvant treatment for stage III colon cancer.

BACKGROUND: Intravenous bolus fluorouracil plus leucovorin is the standard adjuvant treatment for colon cancer. The oral fluoropyrimidine capecitabine is an established alternative to bolus fluorouracil plus leucovorin as first-line treatment for metastatic colorectal cancer. We evaluated capecitabine in the adjuvant setting. METHODS: We randomly assigned a total of 1987 patients with resected stage III colon cancer to receive either oral capecitabine (1004 patients) or bolus fluorouracil plus leucovorin (Mayo Clinic regimen; 983 patients) over a period of 24 weeks. The primary efficacy end point was at least equivalence in disease-free survival; the primary safety end point was the incidence of grade 3 or 4 toxic effects due to fluoropyrimidines. RESULTS: Disease-free survival in the capecitabine group was at least equivalent to that in the fluorouracil-plus-leucovorin group (in the intention-to-treat analysis, P<0.001 for the comparison of the upper limit of the hazard ratio with the noninferiority margin of 1.20). Capecitabine improved relapse-free survival (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99; P=0.04) and was associated with significantly fewer adverse events than fluorouracil plus leucovorin (P<0.001). CONCLUSIONS: Oral capecitabine is an effective alternative to intravenous fluorouracil plus leucovorin in the adjuvant treatment of colon cancer.

Fingered core structure of nematic boojums.

Using the Landau-de Gennes phenomenological approach, we study the fine biaxial core structure of a boojum residing on the surface of a nematic liquid crystal phase. The core is formed by a negatively uniaxial finger, surrounded by a shell with maximal biaxiality. The characteristic finger's length and the shell's width are comparable to the biaxial correlation length. The finger tip is melted for topological reasons. Upon decreasing the surface anchoring strength below a critical value, the finger gradually leaves the bulk and it is expelled through the surface.

Polar steric interactions for V-shaped molecules.

We consider the effect of shape polarity in the excluded-volume interaction between V -shaped polar particles in orientationally ordered phases. We show that the polar component of the steric interaction between these polar particles, large enough in two space dimensions, can also become important in three space dimensions. Unexpectedly, polar steric interactions, up to now neglected, favor an "antiparallel" pair binding, which may be the building block of orientationally ordered phases for polar particles. An antiferromorphic smectic ordering, which is also antiferroelectric, could further be attained at high enough density by the same mechanism.

Objective response to chemotherapy as a potential surrogate end point of survival in metastatic breast cancer patients.

PURPOSE: To assess the validity of objective response to chemotherapy as a surrogate end point for survival in metastatic breast cancer. PATIENTS AND METHODS: We carried out a meta-analysis on individual data from 2,126 metastatic breast cancer patients who were enrolled onto 10 randomized trials comparing standard versus intensified epirubicin-containing chemotherapy. RESULTS: The intensified chemotherapy was associated with a significantly higher tumor response rate compared with standard chemotherapy (pooled odds ratio for nonresponse, 0.60; 95% CI, 0.51 to 0.72). The intensified regimens also led to better (although not significant) survival (pooled odds ratio, 0.94; 95% CI, 0.86 to 1.04; P = .22). Tumor response was a highly significant predictor of survival (P < .0001). When tumor response was introduced in the Cox model, the hazard ratio in favor of experimental treatment changed from 0.94 to 1.005 (95% CI, 0.91 to 1.11; P = .92), indicating that no residual effect of the experimental treatment on survival was present once tumor response was adjusted for. This suggests that the overall survival benefit of intensified epirubicin was a result of the increase in response rate. The median survival time of patients with complete response and partial response was 28.8 months (95% CI, 25.4 to 45.3 months) and 21.3 months (95% CI, 19.2 to 22.4 months), respectively; whereas, the median survival time of patients with no response was 14.6 months (95% CI, 13.9 to 15.4 months). CONCLUSION: These results support the hypothesis that the achievement of an objective response to chemotherapy in metastatic breast cancer is associated with a true survival benefit. The potential role of objective response as a surrogate end point for survival in chemotherapy trials of metastatic breast cancer warrants further investigation.

Platinum-etoposide chemotherapy in elderly patients with small-cell lung cancer: results of a randomized multicenter phase II study assessing attenuated-dose or full-dose with lenograstim prophylaxis--a Forza Operativa Nazionale Italiana Carcinoma Polmonare and Gruppo Studio Tumori Polmonari Veneto (FONICAP-GSTPV) study.

PURPOSE: Small-cell lung cancer (SCLC) is increasingly diagnosed in elderly patients, who are at higher risk of treatment-related morbidity and mortality. We conducted a randomized two-stage phase II study to assess the therapeutic index of two different platinum/etoposide regimens, attenuated-dose (AD) and full-dose (FD) plus prophylactic lenograstim. PATIENTS AND METHODS: SCLC patients older than 70 years were randomized to receive four courses of cisplatin 25 mg/m(2) on days 1 and 2, and etoposide 60 mg/m(2) on days 1, 2, and 3 every 3 weeks (AD); or cisplatin 40 mg/m(2) on days 1 and 2, and etoposide 100 mg/m(2) on days 1, 2, and 3 every 3 weeks, plus lenograstim 5 mg/kg days 5 through 12, every 3 weeks (FD). A combined primary end point named therapeutic success (TS), which took into account activity, toxicity, and compliance, was used. RESULTS: Ninety-five patients were enrolled. Seventy-five percent and 72% of the patients in the AD and FD arms, respectively, completed the treatment as per protocol. Response rate was 39% and 69% in the AD and FD arms, respectively, and 1-year survival probability was 18% and 39%, respectively. Treatment was well tolerated in both groups, with no grade 3 to 4 myelotoxicity in the AD arm, and 12% myelotoxicity in the FD arm. Overall, the observed TSs were 10 (36%) of 28 patients and 42 (63%) of 67 patients for AD and FD treatments, respectively. CONCLUSION: In elderly patients with SCLC a full-dose cisplatin/etoposide regimen combined with prophylactic lenograstim is active and feasible, while attenuated doses of the same regimen are associated with a poor therapeutic outcome.

Quadrupolar projection of excluded-volume interactions in biaxial nematic liquid crystals.

We compute the quadrupolar approximation to the excluded-volume interaction between hard spherocuboids, which applies to both platelets and spheroplatelets as special cases. We show that this approximation can be written as the superposition of two London interactions: one attractive and the other repulsive. This conclusion also proves why the phase diagram for the excluded-volume interaction of spherocuboids is expected to feature a direct isotropic-to-biaxial transition at a single Landau point.

Elastic actions exchanged by eccentric cylinders in liquid crystals.

Equilibria of a nematic liquid crystal confined between two eccentric cylinders are studied within a purely director approach. A planar equilibrium configuration competes against a three-dimensional one. A stability diagram is obtained in terms of both the ratio between the radii of the bounding cylinders and the distance between their axes. It turns out that the nonplanar minimizer has a structure more complex than that envisaged in the tensorial approach employed by McKay and Virga [Phys. Rev. E 71, 041702 (2005)] and that the planar configuration cannot be the absolute minimizer when the outer cylinder becomes a plane wall. The mechanical actions transmitted by the nematic liquid crystal on both bounding cylinders are computed and compared with other results available in the literature.

Residual stability of sessile droplets with negative line tension.

We study the local stability of a sessile droplet with nonvanishing line tension along the contact line, where three phases are in equilibrium. We confirm Widom's results [J. Phys. Chem. 99, 2803 (1995)] on the local stability of a droplet with positive line tension in a larger class of perturbations. When the line tension is negative, we prove that the restricted class of perturbations employed by Widom fails to capture the instability of equilibria. A notion of residual stability is introduced, which makes quantitative the condition under which equilibrium of droplets with negative line tension are likely to be observed.

Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer.

BACKGROUND: Irinotecan and raltitrexed are active agents in advanced colorectal cancer (ACC) and preclinical data suggest a remarkable synergistic activity. Phase I studies demonstrated that single-agent full dose of both drugs can be administered with moderate toxicity. The aim of this phase II trial was to assess the activity and tolerability of the combination in untreated ACC. PATIENTS AND METHODS: Forty-eight patients entered the trial and received irinotecan 350 mg/m2 d.1 and raltitrexed 3 mg/m2 d.2, every three weeks. After recruitment of the first 16 patients, grade III-IV toxicity was observed in 6 patients (38%). Therefore, an amendment reduced by 15% the dose of both drugs (irinotecan 300 mg/m2, raltitrexed 2.6 mg/m2). RESULTS: A total of 290 cycles were administered (range 1-18, median number 6). According to intention-to-treat analysis, the overall response rate was 27% (95% confidence interval 16%-42%), including 3 complete responses and 10 partial responses. The median duration of response was 10 months, while median progression-free survival and overall survival were 5 and 14 months, respectively. In the first 16 patients, the main toxicities were grade III-IV diarrhea in 25% and grade III-IV neutropenia in 13%. In the subsequent 32 patients, they were grade III-IV diarrhea in 34% and grade III neutropenia in 6%. Two toxic deaths occurred. CONCLUSION: The combination irinotecan-raltitrexed is an active regimen, but the significant incidence of side-effects requires accurate patient selection and, eventually, new schedules.

Phase II study of Taxol combined With ifosfamide and carboplatin in the treatment of stage IIIb-IV non-small-cell lung cancer.

The objective of the present study was to evaluate the activity and the toxicity of an original combination of paclitaxel (Taxol), ifosfamide, and carboplatin in patients with stage IIIB-IV non-small-cell lung cancer (NSCLC). Sixty-one patients with previously untreated stage IIIB-IV NSCLC were enrolled by five institutions. Paclitaxel was given at the dose of 200 mg/m iv in 3 hours, ifosfamide (with mesna) at the dose of 3 g/m and carboplatin at an area under the curve 5, on day 1, every 21 days for a total of six cycles in responding or stabilized patients. Among the 59 patients evaluable for response, 2 complete remissions and 25 partial remissions were achieved for an overall response rate of 45.7% (95% CI = 32.7-59.2). According to an intention-to-treat analysis, the response rate was 44.2%. Thirteen patients had a stable disease, whereas 19 progressed. The median time to progression was 7.7 months (range: 1-18), whereas the median overall survival was 10 months (range: 1-30+). The 1-year survival rate was 43%. Hematologic toxicity was exceptionally mild, and peripheral neurologic toxicity of grade III was experienced by only three patients. There was one toxic death. This original triplet regimen based on paclitaxel, ifosfamide, and carboplatin has proved active, safe, and easy to deliver on an outpatient basis for patients with advanced NSCLC. Randomized studies both versus carboplatin-paclitaxel and other triplets are clearly warranted.

Sign of line tension in liquid bridge stability.

We apply the stability criterion we recently proposed for a general wetting functional [Phys. Rev. E 68, 012601 (2003)] to find out whether straight liquid bridges can be stable when subject to line tension of either sign. Our main conclusion is that, even when the line tension is negative, a straight liquid bridge can be stable, and so observable, provided that the line tension is not too large in absolute value.

General stability criterion for wetting.

We propose a general stability criterion for the wetting of solid substrates, both arbitrarily curved and inhomogeneous. In addition to the classical surface tension, the adhering drops can also exhibit a tension along the contact line where three phases meet, namely, the solid, the liquid, and the environment fluid. Moreover, we show how some stability issues currently debated in the specialized literature of disparate fields could profit from the application of this general criterion.

Local elastic stability for nematic liquid crystals.

We derive a stability criterion for nematic liquid crystals from a general study of the second variation of Frank's elastic free-energy functional. When applied to elementary director alignments compatible with the boundary conditions, such as the uniform alignment in a hybrid cell, this criterion is able to determine whether the most likely destabilizing mode is periodic or not, and to estimate the modulation length of such a mode, when it is periodic.

Order reconstruction in frustrated nematic twist cells.

Within the Landau-de Gennes theory of liquid crystals, we study the equilibrium configurations of a nematic cell with twist boundary conditions. Under the assumption that the order tensor Q be uniaxial on both bounding plates, we find three separate classes of solutions, one of which contains the absolute energy minimizer, a twistlike solution that exists for all values of the distance d between the plates. The solutions in the remaining two classes exist only if d exceeds a critical value d(c). One class consists of metastable, twistlike solutions, while the other consists of unstable, exchangelike solutions, where the eigenvalues of Q are exchanged across the cell. When d=d(c), the metastable solution relaxes back to the absolute energy minimizer, undergoing an order reconstruction somewhere within the cell. The critical distance d(c) equals, in general, a few biaxial coherence lengths. This scenario applies to all the values of the boundary twist but pi/2, which thus appears as a very special case, though it is the one more studied in the literature. In fact, when the directors prescribed on the two plates are at right angles, two symmetric twistlike solutions merge continuously into an exchangelike solution at the critical value of d where the latter becomes unstable. Our analysis shows how the classical bifurcation associated with this phenomenon is unfolded by perturbing the boundary conditions.

Late local treatment morbidity after accelerated radiotherapy or alternating chemoradiotherapy for advanced head and neck carcinoma.

BACKGROUND: To report local long-term morbidity after concomitant boost radiotherapy (AFRT) or alternating chemoradiotherapy (CTRT), we analyzed the toxicity data recorded in 168 patients with advanced head and neck squamous cell carcinoma treated at our institution within phase II-III studies. PATIENTS AND METHODS: All patients enrolled in three consecutive phase II-III studies and followed for a minimum of three months after the end of treatment were included in the present analysis. Local late reactions were scored prospectively. The actuarial incidence of grade 2 or more (2-4) late local toxicity according to RTOG/EORTC was taken as endpoint. The median follow-up is 32.0 months (range, 3.3-138.1 months). For living patients the minimum and median follow-up are 12.1 and 69.3 months, respectively. RESULTS: The five-year actuarial incidence of grade 2+ and grade 3+ toxicity are 56.7 +/- 5% and 21 +/- 4%, respectively. At multivariate analysis, acute mucositis grade, complementary surgery, primary site and performance status proved to be independent predictive factors of grade 2+ late toxicity with P values of <0.001, 0.009, 0.022 and 0.033, respectively. No effect was found for treatment itself on the incidence of late toxicity, although patients treated with accelerated radiotherapy had a higher probability of confluent mucositis than patients treated with alternating chemoradiotherapy (68% vs 32%, P <0.01). CONCLUSIONS: A substantial proportion of surviving patients develops late complications, although severe irreversible reactions occur in a minority of patients. Acute local toxicity can be used to predict local late toxicity that arises within five years of the end of treatment.

Finite-size effects on order reconstruction around nematic defects.

By use of the Landau-de Gennes phenomenological theory, we study the texture of a nematic liquid crystal confined within a hybrid cell. Precisely, we consider cylindrically symmetric solutions containing topological defects dictated by appropriate boundary conditions. We focus our attention on cells whose dimensions are comparable with the biaxial correlation length xi(b) . For such severe confinements the order reconstruction (OR) configuration could be stable. Its structural details reflect the balance among boundary-enforced frustration, elastic penalties, and finite-size effects. In particular, we analyze the interplay between finite-size effects and topological defects. We show that defects are always pinned to the negatively (planar) uniaxial sheet of the OR structure. The presence of a ring defect can dramatically increase the critical threshold below which the OR structure is stable.

Paclitaxel, cisplatin and 5-fluorouracil in recurrent squamous cell carcinoma of the head and neck: a phase II trial from an Italian cooperative group.

The aim of this multicenter trial was to test the feasibility and the activity of a three-drug combination where paclitaxel is added to cisplatin and 5-fluorouracil. Patients with metastatic or relapsed SCC-HN unsuitable for further loco-regional radical treatment, not previously treated with chemotherapy, were eligible to receive paclitaxel 160 mg/m2 (3-hr infusion) day 1, CDDP 25 mg/m2/day and 5-FU 250 mg/m2/day bolus on days 1, 2, 3 every three weeks up to a maximum of five courses. Fourty-seven patients were enrolled by five Institutions in Italy. Main grade III-IV toxicities were: neutropenia (48%), thrombocytopenia (6%), anemia (4%), diarrhea (2%), mucositis (2%). Six patients had a complete response (13.3%) and eight a partial response (17.8%). Median progression free survival and overall survival are 4.1 and 7.9 months. One-year progression free survival and overall survival are 16% and 29%. This three-drug regimen has an excellent safety profile. The activity in the palliation of recurrent SCC-HN, however, does not appear to be improved in comparison with cisplatin and 5-fluorouracil or cisplatin and paclitaxel regimens. Recent studies indicate a more promising role of taxanes including triplets in the induction therapy of previously untreated patients.

Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies.

BACKGROUND: The expectation of improvement in patient survival with administration of new chemotherapy agents for metastatic breast carcinoma (MBC) is not consistently supported by data from clinical trials, which are often underpowered and have not detected moderate survival advantage. The aim of this study was to evaluate the impact of new agents on prognosis of MBC patients enrolled in clinical trials of first-line chemotherapy. METHODS: Between 1983 and 2001, 640 MBC patients were entered into 6 consecutive trials; the present analysis was limited to patients. The date of diagnosis of metastatic breast disease was used to define 5 arbitrarily chosen 3-year time cohorts, 1983-1986, 1987-1989, 1992-1994, 1995-1997, and 1998-2001. Multivariate proportion of hazard (PH) models were used to evaluate changes in overall survival (OS) and progression-free survival (PFS) over time and to detect changes associated with the use of taxanes, while adjusting for differences in baseline factors among 5 cohorts. RESULTS: Patient characteristics were evenly distributed across the 5 cohorts. Median OS was 18 months, 17.2 months, 19.2 months, 26.1 months, and 23.6 months, respectively, in cohorts 1983-1986, 1987-1989, 1992-1994, 1995-1997, 1998-2001 (P < 0.0001). Age, performance status, relapse-free survival, type of adjuvant treatment, metastatic site, and taxane first-line chemotherapy were all associated with survival. These data failed to provide an indication of temporal trend and suggested a reduction in hazard of death in two cohorts (1995-1997 and 1998-2001) where taxane was added to first-line chemotherapy. CONCLUSIONS: The analysis provided evidence of improvement in prognosis of MBC patients that was associated with use of modern chemotherapeutic agents independent of time.