Michele Di Natale

Randomized Trial Comparing Cisplatin, Gemcitabine, and Vinorelbine With Either Cisplatin and Gemcitabine or Cisplatin and Vinorelbine in Advanced Non–Small-Cell Lung Cancer: Interim Analysis of a Phase III Trial of the Southern Italy Cooperative Oncology Group

PURPOSE In our previous phase II study, the cisplatin, gemcitabine, and vinorelbine (PGV) regimen produced a median survival time (MST) of approximately 1 year in advanced non-small-cell lung cancer (NSCLC) patients. The present study was aimed at comparing the MST of patients treated with this triplet regimen with the MSTs of patients receiving cisplatin and vinorelbine (PV) or cisplatin and gemcitabine (PG). PATIENTS AND METHODS From April 1997, patients with locally advanced or metastatic NSCLC, an age of < or = 70 years, and an Eastern Cooperative Oncology Group performance status < or = 1 were randomized to receive one of the following regimens: cisplatin 50 mg/m(2), gemcitabine 1,000 mg/m(2), and vinorelbine 25 mg/m(2) on days 1 and 8 every 3 weeks (arm A); cisplatin 100 mg/m(2) on day 1 and gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks (arm B); or cisplatin 120 mg/m(2) on days 1 and 29 and vinorelbine 30 mg/m(2)/wk (arm C). According to the two-stage design for phase III trials, an interim analysis was planned when the first 60 patients per arm were assessable for survival. RESULTS The survival data of 180 NSCLC patients (stage IIIB, 76 patients; stage IV, 104 patients) were analyzed in April 1999. Overall, 128 patients had died (PGV, n = 33; PG, n = 42; and PV, n = 53). The MST of patients in the PGV, PG, and PV arms was 51, 42, and 35 weeks, respectively, and the corresponding 1-year projected survival rates were 45%, 40%, and 34%, respectively. When only patients with stage IV disease were considered, an even stronger difference was seen between PGV (MST = 47 weeks) and both PG (34 weeks) and PV (27 weeks). At multivariate Cox analysis, the estimate hazard of death for patients receiving PGV compared with those receiving PV was 0.35 (95% confidence interval, 0.16 to 0.77; P <.01). The response rates were 47% in the PGV arm, 30% in the PG arm, 25% in the PV arm. Both hematologic and nonhematologic toxicities were not substantially worse in patients who received the PGV regimen. CONCLUSION The PGV regimen is associated with a substantial survival gain (MST > 3 months longer) when compared with the PV combination. Because this difference in survival met one of the early stopping rules, the accrual in the PV arm has been stopped (null hypothesis rejected). Enrollment still continues in the PGV and PG arm to ascertain whether the PGV regimen can also produce a significantly longer survival than that obtained with the PG regimen.

Cisplatin, Gemcitabine, and Vinorelbine Combination Therapy in Advanced Non–Small-Cell Lung Cancer: A Phase II Randomized Study of the Southern Italy Cooperative Oncology Group

PURPOSE In a previous phase I study cisplatin (CDDP), gemcitabine (GEM), and vinorelbine (VNR) combination therapy was safe and very active in patients with non-small-cell lung cancer (NSCLC). This study was aimed at better defining the activity and toxicity of this regimen. PATIENTS AND METHODS One hundred eleven chemotherapy-naive patients, age < or = 70 years, with stage IIIB or IV NSCLC and a performance status of 0 or 1 (Eastern Cooperative Oncology Group scale) were randomized to two treatment arms. Patients on arm A received CDDP 50 mg/m2, GEM 1,000 mg/m2, and VNR 25 mg/m2 on days 1 and 8 of an every-3-weeks cycle (57 patients). Patients on arm B received CDDP 80 mg/m2, epirubicin 80 mg/m2, and vindesine 3 mg/m2, all delivered on day 1 every 4 weeks, plus lonidamine orally 150 mg three times daily (54 patients). In December 1996, randomization was stopped early, and an additional 30 patients were treated with the experimental regimen to obtain a more accurate estimation of its activity rate. RESULTS Among 87 patients who received the CDDP-GEM-VNR combination, four complete responses (CRs) and 46 partial responses (PRs) were observed, for an overall response rate of 57% (95% confidence interval [CI], 46% to 68%). Two CRs and 18 PRs were recorded among 54 patients on arm B, giving a 37% activity rate (95% CI , 24% to 51%). After a median follow-up duration of 19 months, the median progression-free and overall survival durations were 32 and 50 weeks in arm A, and 18 and 33 weeks in arm B, respectively. World Health Organization grade 3 to 4 neutropenia and thrombocytopenia occurred in 46% and 14% of patients in arm A and in 22% and 11% of those in arm B, respectively. Severe nonhematologic toxicity was uncommon in both arms. CONCLUSION The CDDP-GEM-VNR combination is a highly effective treatment for patients with advanced NSCLC and has a manageable toxicity. A phase III trial comparing this new combination with both CDDP-VNR and CDDP-GEM regimens is underway.

A heuristic design support methodology based on graph theory for district metering of water supply networks

The management of existing water supply networks can be substantially improved by permanent water district metering (WDM) which is one of the most efficient techniques for water loss detection and pressure management. However, WDM may compromise water system performance, since some pipes are usually closed to delimit districts in order not to have too many metering stations, to decrease costs and simplify water balance. This may reduce the reliability of the whole system and not guarantee the delivery of water at the different network nodes. In practical applications, the design of district meter areas (DMAs) is generally based on empirical approaches or on limited field experiences. In this work a design support methodology (DSM) is proposed, which helps to identify the position of flow meters and of boundary valves needed to define permanent DMAs. The DSM is based on graph theory and is applied to a test case.The management of existing water supply networks can be substantially improved by permanent water district metering (WDM) which is one of the most efficient techniques for water loss detection and pressure management. However, WDM may compromise water system performance, since some pipes are usually closed to delimit districts in order not to have too many metering stations, to decrease costs and simplify water balance. This may reduce the reliability of the whole system and not guarantee the delivery of water at the different network nodes. In practical applications, the design of district meter areas (DMAs) is generally based on empirical approaches or on limited field experiences. In this work a design support methodology (DSM) is proposed, which helps to identify the position of flow meters and of boundary valves needed to define permanent DMAs. The DSM is based on graph theory and is applied to a test case.

Water Network Sectorization Based on Graph Theory and Energy Performance Indices

AbstractThis paper proposes a new methodology for the optimal design of water network sectorization, which is an essential technique for improving the management and security of multiple-source water supply systems. In particular, the network sectorization problem under consideration concerns the definition of isolated district meter areas, each of which is supplied by its own source (or sources) and is completely disconnected from the rest of the water system through boundary valves or permanent pipe sectioning. The proposed methodology uses graph theory principles and a heuristic procedure based on minimizing the amount of dissipated power in the water network. The procedure has been tested on two existing water distribution networks (WDNs) (in Parete, Italy and San Luis Rio Colorado, Mexico) using different performance indices. The simulation results, which confirmed the effectiveness of the proposed methodology, surpass empirical trial-and-error approaches and offer water utilities a tool for the desi...

Cisplatin, Gemcitabine, and Paclitaxel in Locally Advanced or Metastatic Non–Small-Cell Lung Cancer: A Phase I-II Study

PURPOSE Because both cisplatin-paclitaxel and cisplatin-gemcitabine combinations are generally considered to be among the most active regimens in non-small-cell lung cancer (NSCLC) patients, this study aimed to determine the maximum-tolerated dose (MTD) of paclitaxel when combined with fixed doses of cisplatin and gemcitabine in advanced NSCLC patients and aimed to define the therapeutic activity of this new regimen. PATIENTS AND METHODS From October 1996 to September 1998, 75 patients with stage IIIB-IV NSCLC, who were either chemotherapy-naive (65 patients) or who had been pretreated (10 patients), received fixed doses of cisplatin (50 mg/m(2)) and gemcitabine (1,000 mg/m(2)) and escalating doses of paclitaxel in a 1-hour infusion, all on days 1 and 8, every 3 weeks. RESULTS Five different paclitaxel doses were tested, for a total of 275 cycles delivered. The escalation was stopped at the paclitaxel dose of 75 mg/m(2) in pretreated patients, whereas it continued to 150 mg/m(2) in chemotherapy-naive patients. A total of 65 chemotherapy-naive patients were treated. A paclitaxel dose of 125 mg/m(2) was recommended for phase II, and a total of 39 patients were treated at this level, for a total of 158 cycles delivered. No treatment-related deaths occurred. Five patients were hospitalized because of sepsis, and packed RBC transfusion was required in 13 patients. Grade 4 neutropenia and thrombocytopenia occurred in 23 (31%) and eight (11%) patients, respectively. Overall, 74 of the 75 patients were assessable for response. Four complete (CR) and 38 partial (PR) responses were recorded, for an overall response rate (ORR) of 57%. Three of the ten pretreated patients achieved a PR, compared with four CRs and 35 PRs in the 64 chemotherapy-naive patients (ORR, 61%). Thirty-eight of 39 patients included in phase II were assessable for response and quality of life (QOL) (one patients disease was not measurable). Two CRs and 24 PRs were recorded in this group, for an ORR of 68% (95% confidence interval, 51% to 82%). The QOL score improved in 27 of 38 (71%) patients. The median survival time was 15 months in the 65 chemotherapy-naive patients, but it had not yet been reached in the 39 patients included in phase II, for whom the 1-year projected survival was 70%. CONCLUSION The cisplatin-gemcitabine-paclitaxel combination is a feasible and well-tolerated approach in advanced NSCLC patients. Both a major response and a QOL improvement can be obtained in a high proportion of patients, with a median survival time exceeding 1 year. A phase III trial comparing this combination with other effective regimens is under way.

An Automated Tool for Smart Water Network Partitioning

Water Network Partitioning (WNP) represents the application of the “divide and conquer” paradigm to a Smart WAter Network (SWAN) that allows the improved application of techniques for water balance and pressure control. Indeed, these techniques can be applied with greater effectiveness by defining smaller permanent network parts, called District Meter Areas (DMAs), created by the insertion of gate valves and flow meters. The traditional criteria for the design of network DMAs are based on empirical suggestions (number of properties, length of pipes, etc.) and on approaches such as ‘trial and error’, even if used together with hydraulic simulation software. Nevertheless, these indications and procedures are very difficult to apply to large water supply systems because the insertion of gate valves modifies the original network layout and may considerably worsen the hydraulic performance of the water network. The proposed tool, based on some graph partitioning techniques, commonly applied in distributed computing, and on an original optimisation technique, allows the automatic design of a WNP comparing different possible layouts that are compliant with hydraulic performance. In this paper, the methodology was tested on a real case study using some performance indices to compare different WNPs. The proposed tool was developed in Phyton and integrates graph partitioning, hydraulic simulation techniques and a heuristic optimisation criterion. It allows the definition of DMAs with resulting performance indices that are very similar to the original network layout.

Water Network Protection from Intentional Contamination by Sectorization

Each single phase of a water supply network, from water adduction to distribution to end-users, is exposed to many diverse potential sources of intentional contamination (or malicious attacks). One of the most dangerous threats is a backflow attack that occurs when a pump system, easily available on the market, is utilized to overcome the pressure gradient of network pipes. In this work, a simple backflow attack with cyanide being introduced into a real-water system is modeled and the most dangerous introduction points for a contaminant incident are defined. Moreover, the network vulnerability has been analyzed by computing the lethal dose of cyanide ingested by users and the total length of the contaminated water system. Eventually the effects of network partitioning and district isolation to protect water supply systems have been investigated. The results show how district closing - by network sectorization techniques used to improve leakage search and reduction - can significantly decrease contaminant diffusion and protect part of the users from cyanide uptake. Network sectorization can also reduce the risk of simple malicious attacks because several introduction points are necessary to have a massive negative impact on the network. Simulation results also show that in some cases water network partitioning may worsen water network protection and further studies are necessary to design water districts for network security and safety.

A DESIGN SUPPORT METHODOLOGY FOR DISTRICT METERING OF WATER SUPPLY NETWORKS

Water District Metering (WDM) is one of the most efficient techniques for water loss detection and pressure management and consists in partitioning a water network into subsystems called District Meter Areas (DMA).The division of the network in hydraulically independent districts can be obtained by installing flow meters and boundary valves. Pipe closure can compromise original water system performance because it reduces the network reliability. When water systems are already in operation it is more difficult to set the number and dimension of districts and, in practical applications, the WDM design is generally based on empirical approaches or on limited field experiences. In this work an original approach to define the Water District Metering, based on graph theory principles, is put forward. The methodology proposed, arranged in a Design Support Methodology (DSM), allows to choose the position of flow meters and of boundary valves needed to define permanent DMAs using graph visualization of water network, minimum dissipated power paths and different performance indices based also on resilience concept. The DSM is tested on two case studies allowing to get rapidly good DMA layouts compatible with the level of service of water systems.

Permeable reactive barrier for groundwater PCE remediation: the case study of a solid waste landfill pollution

The remediation of a tetrachloroethylene (PCE) contaminated aquifer near a solid waste landfill, by an activated carbon Permeable Reactive Barrier (PRB) is presented as a case study. A 2D numerical model has been used to describe the pollutant transport within a groundwater and the pollutant adsorption on the barrier. The results show that the barrier has a good efficiency since the PCE concentration flowing out of the PRB is always lower than the limits provided for in the currently enforced Italian legislation.

Water Supply Network Partitioning Based On Weighted Spectral Clustering

Water Network Partitioning (WNP) in District Meter Area (DMA), obtained inserting remote control valves and flow meters in water supply systems, allows simplifying the water balance and pressure control in order to reduce water leakage and to improve water quality protection. Traditionally, the WNP is based on empirical suggestions and on trial and error approaches used with hydraulic simulation software, difficult to apply to large networks. Recently, some heuristic procedures, based on graph and network theory, have shown that it is possible to find optimal solutions in terms of number, shape and dimension of DMAs. In this paper, spectral clustering theory was used to define the water districts, taking into account the spatial and hydraulic constraints, through weight matrices. A comparison between different spectral clustering methods was achieved on a real water network measuring some energy performance indices, in order to identify the optimal water network partitioning.