Pasqualina Giordano

Kinematic modeling and redundancy resolution for nonholonomic mobile manipulators

We consider robotic systems made of a nonholonomic mobile platform carrying a manipulator (nonholonomic mobile manipulator, NMM). By combining the manipulator differential kinematics with the admissible differential motion of the platform, a simple and general kinematic model for NMMs is derived. Assuming that the robotic system is kinematically redundant for a given task, we present the extension of redundancy resolution schemes originally developed for standard manipulators, in particular the projected gradient (PG) and the reduced gradient (RG) optimization-based methods. The case of a configuration-dependent task specification is also discussed. The proposed modeling approach is illustrated with reference to representative NMMs, and the performance of the PG and RG methods for redundancy resolution is compared on a series of numerical case studies

Early PET/CT scan is more effective than RECIST in predicting outcome of patients with liver metastases from colorectal cancer treated with preoperative chemotherapy plus bevacizumab.

Markers predictive of treatment effect might be useful to improve the treatment of patients with metastatic solid tumors. Particularly, early changes in tumor metabolism measured by PET/CT with 18F-FDG could predict the efficacy of treatment better than standard dimensional Response Evaluation Criteria In Solid Tumors (RECIST) response. Methods: We performed PET/CT evaluation before and after 1 cycle of treatment in patients with resectable liver metastases from colorectal cancer, within a phase 2 trial of preoperative FOLFIRI plus bevacizumab. For each lesion, the maximum standardized uptake value (SUV) and the total lesion glycolysis (TLG) were determined. On the basis of previous studies, a ≤ −50% change from baseline was used as a threshold for significant metabolic response for maximum SUV and, exploratively, for TLG. Standard RECIST response was assessed with CT after 3 mo of treatment. Pathologic response was assessed in patients undergoing resection. The association between metabolic and CT/RECIST and pathologic response was tested with the McNemar test; the ability to predict progression-free survival (PFS) and overall survival (OS) was tested with the Log-rank test and a multivariable Cox model. Results: Thirty-three patients were analyzed. After treatment, there was a notable decrease of all the parameters measured by PET/CT. Early metabolic PET/CT response (either SUV- or TLG-based) had a stronger, independent and statistically significant predictive value for PFS and OS than both CT/RECIST and pathologic response at multivariate analysis, although with different degrees of statistical significance. The predictive value of CT/RECIST response was not significant at multivariate analysis. Conclusion: PET/CT response was significantly predictive of long-term outcomes during preoperative treatment of patients with liver metastases from colorectal cancer, and its predictive ability was higher than that of CT/RECIST response after 3 mo of treatment. Such findings need to be confirmed by larger prospective trials.

Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: The CAPPA-2 study

Platinum-based chemotherapy is the standard treatment for patients with advanced non-small cell lung cancer (NSCLC), but the evidence of its efficacy among ECOG performance status (PS)2 patients is weak because these patients are usually excluded from clinical trials; concern exists about tolerability and feasibility of standard chemotherapy in these patients. No prospective randomized trial has tested the addition of cisplatin to single-agent chemotherapy in patients with advanced NSCLC and PS2. CAPPA-2 was a multicenter, randomized phase 3 study for first-line treatment of PS2 patients with advanced NSCLC. Patients, aged 18-70, were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes (TNM VI edition) and adequate organ function. Patients in standard arm received gemcitabine 1200 mg/m(2) days 1 and 8. Patients in experimental arm received cisplatin 60 mg/m(2) day 1 plus gemcitabine 1000 mg/m(2) days 1 and 8. All treatments were repeated every 3 weeks, up to 4 cycles, unless disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). To have 80% power of detecting hazard ratio (HR) 0.71, corresponding to an increase in median OS from 4.8 to 6.8 months, 285 deaths were required. The study was stopped in June 2012 after the enrolment of 57 patients, due to the slow accrual and the report of positive results from a similar study. Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin plus gemcitabine (HR 0.52, 95% CI 0.28-0.98, p = 0.039). Combination chemotherapy produced longer PFS (median 1.7 vs. 3.3 months, HR 0.49, 95% CI 0.27-0.89, p = 0.017) and higher response rate (4% vs. 18%, p = 0.19), without substantial increase in toxicity. The addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC.

Gefitinib in Non Small Cell Lung Cancer

Gefitinib is an oral, reversible, tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) that plays a key role in the biology of non small cell lung cancer (NSCLC). Phase I studies indicated that the recommended dose of gefitinib was 250 mg/day. Rash, diarrhea, and nausea were the most common adverse events. The positive results obtained in early phase 2 clinical trials with gefitinib were not confirmed in large phase 3 trials in unselected patients with advanced NSCLC. The subsequent discovery that the presence of somatic mutations in the kinase domain of EGFR strongly correlates with increased responsiveness to EGFR tyrosine kinase inhibitors prompted phase 2 and 3 trials with gefitinib in the first line-treatment of EGFR-mutated NSCLC. The results of these trials have demonstrated the efficacy of gefitinib that can be now considered as the standard first-line treatment of patients with advanced NSCLC harbouring activating EGFR mutations.

Neoadjuvant FOLFIRI+bevacizumab in patients with resectable liver metastases from colorectal cancer: a phase 2 trial

Background:Preoperative treatment of resectable liver metastases from colorectal cancer (CRC) is a matter of debate. The aim of this study was to assess the feasibility and activity of bevacizumab plus FOLFIRI in this setting.Methods:Patients aged 18–75 years, PS 0–1, with resectable liver-confined metastases from CRC were eligible. They received bevacizumab 5 mg kg−1 followed by irinotecan 180 mg m−2, leucovorin 200 mg m−2, 5-fluorouracil 400 mg m−2 bolus and 5-fluorouracil 2400 mg m−2 46-h infusion, biweekly, for 7 cycles. Bevacizumab was stopped at cycle 6. A single-stage, single-arm phase 2 study design was applied with 1-year progression-free rate as the primary end point, and 39 patients required.Results:From October 2007 to December 2009, 39 patients were enrolled in a single institution. Objective response rate was 66.7% (95% exact CI: 49.8–80.9). Of these, 37 patients (94.9%) underwent surgery, with a R0 rate of 84.6%. Five patients had a pathological complete remission (14%). Out of 37 patients, 16 (43.2%) had at least one surgical complication (most frequently biloma). At 1 year of follow-up, 24 patients were alive and free from disease progression (61.6%, 95% CI: 44.6–76.6). Median PFS and OS were 14 (95% CI: 11–24) and 38 (95% CI: 28–NA) months, respectively.Conclusion:Preoperative treatment of patients with resectable liver metastases from CRC with bevacizumab plus FOLFIRI is feasible, but further studies are needed to define its clinical relevance.

Cetuximab in non-small-cell lung cancer.

Cetuximab is a chimeric human–mouse anti-EGF receptor monoclonal antibody. In Phase I studies, no dose-limiting toxicities were observed with cetuximab as a single agent or combined with chemotherapy; pharmacokinetic and pharmacodynamic analyses supported 250 mg/m2 weekly administration. Skin toxicity, diarrhea and fatigue were the most common toxicities. The positive results obtained in Phase II trials in patients with advanced non-small-cell lung cancer prompted two randomized Phase III trials evaluating cetuximab in addition to first-line chemotherapy. Both trials showed a small benefit in overall survival for the experimental treatment, which was considered insufficient by the EMA for marketing approval. However, a subgroup analysis of the FLEX Phase III trial recently demonstrated a larger survival benefit from the experimental treatment in patients with high immunohistochemical EGF receptor expression. This finding, if confirmed prospectively, could represent a new opportunity for positioning cetuximab into the standard treatment of advanced non-small-cell lung carcinoma.

Time spent for activation of non-profit studies in oncology in Italy.

Aim The aim of this paper is to describe the time spent to activate oncological non-profit clinical trials promoted in Italy by the National Cancer Institute of Naples, following the implementation of recent European laws. Methodology Data about the process of activation of 5 non-profit multicentre clinical trials were prospectively collected through a web-based system. The impact of European guidelines was assessed by comparing the efficiency of the process between applications started before and after the decree introducing in Italy the Clinical Trial Application form (MD-CTA). Outcomes of the descriptive analyses were the time to EC opinion, the time to administrative agreement signature after a positive EC opinion, and the cumulative percentage of submissions that came to closure (either positive or negative) within four subsequent time cohorts. Principal Findings From March 2007 to October 2009, 202 applications were submitted to 107 centres. Forty-four (59%) applications of those submitted before were successful, compared to 71 (55%) of those submitted after MD-CTA. Most of the failures were due to missing EC response (27% and 22%) or administrative reasons (10% and 16%, before and after, respectively); very few (4% and 7%) were due to EC refusal. The impact of the MD-CTA on time to EC opinion looked positive (median 4.1 vs 2.4 months, before and after, respectively) but a subgroup analysis revealed that the impact was limited to a comparison biased by the selection of EC. After a positive EC opinion, there was no difference before and after MD-CTA in the time to administrative agreement signature (median 3.6 and 3.8 months, respectively). A trend to shortening time to closure of the whole submission process over the time was evident, with 58% of the applications coming to closure within 6 months from submission in the most recent cohort. Conclusions In our experience there is reassuring evidence of a trend toward shortening the time spent to activate non-profit clinical trials in Italy, but the whole process still remains inefficient. Efforts should be made to improve the process, also focusing on administrative procedures.

The motion control problem for the CyberCarpet

Exploration of virtual worlds with unconstrained locomotion possibilities for the user is the main objective of the European research project CyberWalk. This should be achieved through the use of an actuated platform (the CyberCarpet) that compensates for the walkers locomotion in such a way to keep her/him close to the platform center. This paper presents the control problem for the platform motion, including objectives and constraints, overall control architecture, and kinematic modeling. Since the platform has only two actuating devices (linear and angular), the control problem is similar to that of output regulation for nonholonomic wheeled mobile robots in the presence of an unpredictable disturbance due to walkers locomotion. Based on the kinematic model, a velocity control design achieving input-output decoupling and linearization is proposed and its performance is verified by simulations

Acceleration-level control of the CyberCarpet

The CyberCarpet is an actuated platform that allows unconstrained locomotion of a walking user for VR exploration. The platform has two actuating devices (linear and angular) and the motion control problem is dual to that of nonholonomic wheeled mobile robots. The main control objective is to keep the walker close to the platform center. We first recall global kinematic control schemes developed at the velocity level, i.e., with the linear and angular velocities of the platform as input commands. Then, we use backstepping techniques and the theory of cascaded systems to move the design to control laws at the acceleration level. Acceleration control is more suitable to take into account the limitations imposed to the platform motion by the actuation system and/or the physiological bounds on the human walker. In particular, the availability of platform accelerations allows the analytical computation of the apparent accelerations felt by the user.

New drugs in advanced non-small-cell lung cancer: searching for the correct clinical development

Importance of the field: Non-small-cell lung cancer (NSCLC) is one of the most active fields of research in oncology, with many drugs under clinical development. Most of these drugs offer novel mechanisms of action compared with drugs currently used in clinical practice. Areas covered in this review: In this article, results recently obtained with most promising new drugs for advanced NSCLC are briefly described. What the reader will gain: Most of the new drugs are currently being tested without a biomarker-driven selection, due to inadequate knowledge of predictive factors. A few drugs are tested in biologically selected samples of NSCLC patients. The results obtained with crizotinib in patients with ALK gene rearrangement are a good example of the speed with which biological discoveries can be translated to clinical testing. Take home message: Emerging clinical and molecular data demonstrate that NSCLC is a family of related but distinct diseases. Some drugs tested in unselected population will probably obtain an incremental benefit compared to the current standard, but this will not substantially change the unfavorable prognosis of NSCLC patients. By contrast, unprecedented and much more cost-effective results can be obtained when targeted agents are administered following appropriate biomarker-driven patient selection.