Unified three-dimensional finite elements for large strain analysis of compressible and nearly incompressible solids.

This work proposes a displacement-based finite element model for large strain analysis of isotropic compressible and nearly-incompressible hyperelastic materials. Constitutive law is written in terms of invariants of the right Cauchy-Green tensor; coupled and decoupled formulations of strain energy functions are presented, whereas a penalty function is used to impose an incompressibility constraint. Based on a total Lagrangian formulation, the nonlinear governing equations are thus obtained by employing the principle of virtual displacements. Analytic expression of both internal forces vector and tangent matrix of linear and high-order hexahedral finite elements are derived by adopting a three-dimensional formalism based on the Carrera Unified Formulation. Popular benchmark problems in hyperelasticity are analyzed to establish the capabilities of the present implementation of fully-nonlinear solid elements in the case of compressible and nearly-incompressible beams, cylindrical shells, and curved structures.

When less is better: the safety and efficacy of reduced intensity gemcitabine in a difficult patient population with advanced non-small-cell lung cancer.

Treatment of elderly or poor performance status (PS) patients with advanced non-small-cell lung cancer (NSCLC) is a debated topic. To evaluate the efficacy of a modified schedule of gemcitabine, 59 patients unfit for platinum were enrolled. Mean age was 75.8 years and 41 % of patients had an ECOG PS 2. Gemcitabine was given at 1000 mg/m(2) on days 1, 8 each 28. Most of patients received gemcitabine as first-line chemotherapy, which was continued as maintenance over 6 cycles in responding and stable patients. Median overall survival (OS) and progression-free survival (PFS) were 7.2 and 5 months. In those 45 evaluable patients, treatment resulted in 1 complete remission (CR), 9 partial remissions (PR), and 20 stable diseases (SDs) with a response rate (CR + PR) of 22 % and a clinical benefit (CR + PR + SD) of 68 %. Gemcitabine was continued over 6 cycles in 16 patients (27 %). These patients were treated until progression with a mean of further 8.6 cycles. Median OS and PFS in these selected patients were 19 and 16 months. The toxicity profile was excellent with only 8 % of overall G3-G4 adverse events. None of the 16 patients under the maintenance phase reported significant toxicity. Gemcitabine given at a lower dose intensity than standard should be considered as valuable therapeutic option in elderly or poor PS patients with advanced NSCLC unfit for platinum. Extending the treatment beyond 6 cycles in responding patients is feasible and may prolong survival.

Efficacy and safety of low-dose metronomic chemotherapy with capecitabine in heavily pretreated patients with metastatic breast cancer.

AIM: Registered dose capecitabine monotherapy is active against metastatic breast cancer (MBC), but retrospective analyses indicate that lower doses may be as effective and better tolerated. This study was conducted to assess the safety and efficacy of metronomic capecitabine in heavily pretreated patients with MBC. PATIENTS AND METHODS: In this phase II study 60 MBC patients received continuous metronomic capecitabine monotherapy (1500 mg once a day). Primary endpoint was clinical benefit rate, secondary end points were clinical benefit rates (CBRs), tumour response rates (RRs), overall survival (OS), time to progression (TTP), duration of response (DOR) and toxicity. RESULTS: Fifty eight assessable patients received two or more 28-day cycles of metronomic capecitabine. The CBR was 62%. Median DOR was 7 months. Median TTP and OS were 7 and 17 months, respectively. Two partial responses and 7 cases of stable disease were recorded in 13 patients who had previously received capecitabine intermittently (2000 mg/m(2)/day on days 1-14 every 21 days) as first- or subsequent-line treatment for MBC. Grade 3-4 adverse events were uncommon; haematologic toxicity was infrequent (5%) and consistently mild. CONCLUSION: This regimen of metronomic capecitabine displayed good activity and excellent tolerability in MBC patients, including those who had previously received the drug at standard doses.

Sequential use of sorafenib and sunitinib in advanced renal cell carcinoma: does the order of sequencing matter?

To investigate the sequential use of two tyrosine-kinase inhibitors (TKI), sorafenib (SOR) and sunitinib (SUN), in advanced renal carcinoma. We retrospectively analyzed the clinical outcome of 33 patients who had experienced progression or unacceptable toxicity after receiving either sorafenib or sunitinib and then switched to the other reciprocal agent. Progression-free survival (PFS) during the first TKI was similar regardless of drug with a median of 6 months in the SOR-SUN group (n = 15) and 7.5 months in the SUN-SOR group (n = 18). Interestingly, PFS during the second TKI was significantly longer in the SOR-SUN group as compared to the SUN-SOR group with median values of 11 and 3 months, respectively (P = 0.0377; HR 0.46; 95% CI: 0.16-0.95). As a consequence, total PFS (sum of PFS on first and second TKI) was significantly longer in the SOR-SUN group than in the SUN-SOR group with medians of 20 versus 10 months, respectively (P = 0.0393; HR 0.47; 95% CI: 0.18-0.96). Median wash-out period between the two TKI was 3 weeks in both groups. Differences in baseline characteristics, including histology and line of treatment, were not significant, and toxicity was not increased during the second part of the sequence. Here, we show that responses can be achieved when a second TKI is given soon after a TKI failure in renal cancer with apparent more durable disease control when SOR is followed by SUN.

Molecularly targeted endocrine therapies for breast cancer.

The identification of the estrogen receptor (ER) provided the first target for antiestrogenic therapeutic agents. Endocrine therapies, either by blocking or downregulating the receptor or by suppressing the estrogen production, inhibit the proliferative effect of estradiol on ER. While the activity on ER is considered a real target-mediated therapy, the effect on enzymatic activity involved in estrogen production (mainly inhibition of aromatase by aromatase inhibitors, AIs, and ovarian ablation) could be considered an "indirect" targeted strategy. In addiction to the direct ligand-ER signal, the complexity of endocrine and non endocrine pathways has led to combination therapies against different targets. Tamoxifen is the widely investigated, most used and representative of drugs blocking the ER and has been introduced in the advanced disease, in neoadjuvant and adjuvant setting and for chemo-prevention of high risk women. Its role has been challenged in the last years by the introduction of third generation aromatase inhibitors that have proven a higher activity than tamoxifen and different toxicity. Several other SERMs (selective estrogen receptor modulators) have been investigated, but none of them was clearly superior to tamoxifen. SERDs (selective estrogen receptor downregulators) act as pure estrogen antagonist. They are used in the treatment of advanced breast cancers and their role in other settings still needs further investigation. Here we discuss the well established data with SERMs, SERDs and AIs, mechanisms underlying resistance and rationale for recycling endocrine compounds and for simultaneously targeting different pathways.

Adjuvant endocrine treatment in premenopausal early breast cancer.

The impact of endocrine therapies in the adjuvant treatment of premenopausal patients with early breast cancer is well established. However, the right combination and duration of endocrine manipulations currently available (luteinizing hormone-releasing hormone analogs and tamoxifen) remain unclear. Moreover, the role of chemotherapy in addition to endocrine therapies is not clearly defined. The most recent Early Breast Cancer Trialists' Collaborative Group overview has confirmed the efficacy of five years of tamoxifen in reducing the annual recurrence rate and the annual breast cancer death rate by 41 and 34%, respectively, in an estrogen receptor-positive population. These results are largely irrespective of age, use of chemotherapy or other tumor features. Moreover, the expert panel of the St. Gallen Conference accepted both tamoxifen or tamoxifen plus ovarian suppression as standard endocrine therapy for premenopausal breast cancer patients with endocrine-responsive disease. The use of ovarian suppression or ablation also significantly reduced the risk of breast cancer-related death, mainly in the absence of other systemic therapies. Chemotherapy is widely used in this population; however, its role in endocrine-positive premenopausal women with hormone-positive disease treated with optimal endocrine therapy remains unclear.