Go beyond the limits of genetic algorithm in daily covariate selection practice.

Covariate identification is an important step in the development of a population pharmacokinetic/pharmacodynamic model. Among the different available approaches, the stepwise covariate model (SCM) is the most used. However, SCM is based on a local search strategy, in which the model-building process iteratively tests the addition or elimination of a single covariate at a time given all the others. This introduces a heuristic to limit the searching space and then the computational complexity, but, at the same time, can lead to a suboptimal solution. The application of genetic algorithms (GAs) for covariate selection has been proposed as a possible solution to overcome these limitations. However, their actual use during model building is limited by the extremely high computational costs and convergence issues, both related to the number of models being tested. In this paper, we proposed a new GA for covariate selection to address these challenges. The GA was first developed on a simulated case study where the heuristics introduced to overcome the limitations affecting currently available GA approaches resulted able to limit the selection of redundant covariates, increase replicability of results and reduce convergence times. Then, we tested the proposed GA on a real-world problem related to remifentanil. It obtained good results both in terms of selected covariates and fitness optimization, outperforming the SCM.

Cisplatin and etoposide as first-line chemotherapy for metastatic breast carcinoma: a prospective randomized trial of the Italian Oncology Group for Clinical Research.

In this prospective randomized study, first-line treatment with the combination of cisplatin (P) and etoposide (E) was compared with the standard cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in 140 patients. Complete remissions were obtained in 11% of 65 assessable patients on CMF and in 12% of 65 assessable patients on PE. Complete plus partial remission rates were 48% on CMF and 63% on PE (P = .08). Time to progression (median, 32 v 31 weeks), duration of response (48 v 39 weeks), and survival (75 v 76 weeks) were not different. Hematologic toxicity was significantly higher with PE, and gastrointestinal side effects were frequent with this treatment. This study demonstrated that the PE combination is effective as front-line chemotherapy. As far as response rate is concerned, a trend of superiority over CMF was observed, which was of borderline significance. Due to the lack of survival advantage and to toxicity, this combination is not recommended for routine clinical use. However, its high level of activity should be taken into account for further research.

Vinorelbine is well tolerated and active in the treatment of elderly patients with advanced non-small cell lung cancer. A two-stage phase II study.

More than 30% of lung cancers arise in patients aged 70 years or more; however, because elderly patients are not considered to tolerate chemotherapy, they are generally excluded from clinical trials and are not considered eligible for aggressive cisplatin-based chemotherapy in clinical practice. The aims of the present study were to test tolerability and activity of weekly vinorelbine in advanced non-small cell lung cancer (NSCLC) patients aged 70 years or more, and to define whether minimum conditions existed for a randomised comparison with best supportive care. The study was designed as a multicentre two-stage phase II trial according to Simon's optimal design: 8 or more responses out of 43 treated patients were expected at the end of the trial. Patients aged 70 years or more were eligible if they had a cytological or histological diagnosis of NSCLC at stage IIIb-IV and a performance status less than or equal to two according to the ECOG scale. Vinorelbine was given intravenously (i.v.) at a dose of 30 mg/m2 every week for 12 doses. As planned, 43 patients entered the study; median age was 73 years (range 70-80); 11 patients were older than 75 years. Median dose-intensity (mg/m2/week) of vinorelbine was 21.2 (range 7.5-30) and was not affected by age of patients. Toxicity was generally mild, mainly haematological and never life-threatening. ECOG performance status improved in 26% of patients; cough and pain improved in more than 40% of patients symptomatic at entry, while dyspnoea improved in 28%; approximately half the patients had a stabilisation of their symptoms. 10 patients (23-95% exact confidence interval (CI): 12-39%) obtained a partial response. Median time to progression was 11 weeks (95% CI 8-30) and median survival 36 weeks (95% CI 28-53). One-year estimated progression-free and overall survival rates are 16% and 36%, respectively. In conclusion, vinorelbine was well tolerated and active in the treatment of elderly NSCLC patients. A phase III trial (ELVIS-Elderly Lung Cancer Vinorelbine Italian Study) comparing best supportive care versus best supportive care plus vinorelbine is now ongoing.

Percutaneous embolization of an isolated hypogastric artery aneurysm. A case report.

We describe a case of an isolated aneurysm of the left hypogastric artery which came under our observation because of a syndrome of compression on the homolateral iliac vein. Having excluded the presence of aneurysms in other sites, it was decided to perform a percutaneous embolization of the hypogastric aneurysm. The follow-up revealed the disappearance of the compression on the ipsilateral iliac vein and a 30% reduction in the diameter of the thrombosed aneurysm. The method limited invasiveness, the reduction in volume of the aneurysmal mass, the disappearance of compression problems, and the shortened hospitalization time support the choice of embolization treatment.

Thrombocytopenia following treatment with low doses of aminoglutethimide.

The authors report a case of severe thrombocytopenia during treatment with low doses of aminoglutethimide in a woman with advanced breast cancer. Hematologic toxicity secondary to aminoglutethimide did not seem to be dose-related, and an immunologic mechanism may be postulated. Although the incidence of the side effect is probably low, monitoring of blood counts during the first months of therapy is necessary.

Cisplatin and low-dose cytosine arabinoside in advanced cancer.

Twenty-two patients with advanced malignancies were treated with low-dose cytosine arabinoside (ara-C) (45 mg/m2 sc every 12 h for 3 days) and cisplatin (DDP) (100 mg/m2 ev on day 2, 2 h after ara-C. Patients received 61 cycles of ara-C + DDP with a median number per patient of 2.7 cycles (range, 1-5). All patients were evaluable for toxicity and response. Overall, 6 of 22 patients (27%) obtained an objective response (2 CR + 4 PR) with a median response duration of 20 weeks. Hematologic and gastrointestinal toxicities were moderate. Our results show a low response rate with the ara-C and DDP combination compared to the interesting results obtained in vitro.

[Spontaneous nephro-cutaneous fistula]. / Fistola nefro-cutanea spontanea.

The authors report a rare case of spontaneous nephrocutaneous fistula. The patient was asymptomatic and with a negative history for renal lithiasis, inflammation, trauma or tuberculosis. Radiological and echographical examinations permitted a complete study of the fistulous tract and the renal function; the staghorn calculi and pyelonephritis guided the decision to operate on the patient performing a nephrectomy and ureterectomy with a quick complete recovery. Biological test for micobacterium tuberculosis resulted positive after 60 days.

[Cystic nephroma]. / Nefroma cistico.

The authors describe a rare case of cystic nephroma treated by partial surgical excision. Because there is concurrence in the association of multilocular cysts with Wilms tumors and others tumors of the kidney, it is underlined the importance of a differential diagnosis to avoid nephrectomy for treatment of this benign neoplasm.

[Nephro-jejunal fistula associated with nephro-cutaneous fistula]. / Fistola nefro-digiunale associata a fistola nefro-cutanea.

The development of a renal fistula is a rare event which results from an acute or chronic inflammatory process in the kidney. The authors report a very rare case of nephrojejunal and nephro-cutaneous fistulas due to acute and chronic pyelonephritis in a patient with staghorn stones of the left kidney.

[Ovarian pregnancy]. / La gravidanza ovarica.

A case of ovarian pregnancy in a patient with intrauterine device is reporter. The patient was hemodynamically instable and immediate laparotomy was indicated. The treatment was left oophorectomy. Ovarian pregnancy is a rare form of ectopic pregnancy in which the gestational sac is implanted in the ovary. The incidence appears to be of 1 to 3 per cent of all ectopic gestations with a frequency of one in 7000 to 40000 deliveries and it is now believed to occur four times more frequently than previously thought. It has been suggested that the increasing incidence is caused by the use of IUD. In contrast to patients with tubal pregnancy traditional risk factors such as pelvic inflammatory disease, prior surgical procedure upon the pelvis may not apply. The clinical signs are similar to those found in tubal pregnancies and in hemorrhagic corpus luteum cysts. The treatment is emergency laparatomy followed by oophorectomy in many instances. When the patient is hemodynamically stable laparoscopy and the ovarian wedge resection should be the treatment of choice.

[Central venous access systems in the oncologic patient]. / Gli accessi venosi centrali nel paziente oncologico.

BACKGROUND: A safe and dependable venous access is mandatory in order to perform cancer chemotherapy and monitor blood values in the neoplastic patient. Prolonged infusions of medications with sclerosing action may damage the vessel wall, inducing chemical thrombophlebitis. Furthermore, extravasation of necrotizing compounds may be a danger to the patient. The application of totally implantable venous access systems (VAS) started in 1982, in the United States of America, where at present 500,000 devices are implanted annually. In Italy such method has been introduced in a later period, with a constantly growing trend. VAS devices have evolved since their first presentation, and so have application techniques: the original surgical route has been supported by the percutaneous one, considered most appropriate by several Centers. In this study, personal experience concerning application of VAS in cancer patients is presented. METHODS: From July 1994 to February 1998, at the General Thoracic Surgery Dept. of the University of Perugia, 198 VAS have been implanted in 195 patients. During the first period all the systems have been applied by surgical cutdown of the cephalic vein (150 cases). In the last 12 month the percutaneous technique for vein puncture has been adopted in 48 patients. RESULTS: Immediate and late complications have occurred: among the former, pneumothorax, hematoma, malposition; among the latter, infection, subclavian vein thrombosis, catheter rupture. The results are analysed after an extensive review of the international literature; pros and cons of the different implantation techniques and the technical aspects useful for preventing complications are underlined.

Five-centimeter superior mesenteric artery aneurysm. A case report.

An unusual large mesenteric artery aneurysm presented as "angina abdominis" and abdominal mass is described. Endoaneurismectomy with reverse end-to-end saphenous vein graft was performed. The incidence, pathogenesis and diagnosis are reviewed and the treatment is discussed.

[Surgery of the carotid artery: locoregional anesthesia versus general anesthesia: Review of the literature]. / Chirurgia dell'arteria carotide: anestesia locoregionale versus anestesia generale. Revisione della letteratura.

The aim of the study was to compare locoregional and general anesthesia in carotid artery surgery in order to establish whether differences exist in terms of perioperative results, use of intraoperative shunts and costs. Seventeen studies, comprising 14,776 carotid endarterectomies performed with either locoregional or general anesthetic and published over the period from 1990 to March 2000, were reviewed. There were no statistically significant differences in the cardiovascular risk factors of the patients. Neurological morbidity and mortality were similar in the two groups, even if the use of shunts in the locoregional anesthesia group was lower than in the general anesthesia group and in four studies was associated with a significant difference (P < 0.01). No statistical differences in cardiac morbidity or mortality were found between the groups, except in two studies. Additional randomised prospective trials are needed in large numbers of patients. Locoregional anesthesia appears to allow a limited use of intraoperative shunts, but with neurological mortality and stroke rates very similar to those in the general anesthesia group. Routine use of locoregional anesthesia makes it possible to lower the cost of carotid surgery without sacrificing quality.

[Cranial and neck nerve injuries following carotid endarterectomy intervention. Review of the literature]. / Le lesioni dei nervi cranici e cervicali in seguito ad intervento di endoarteriectomia carotidea. Revisione della letteratura.

The aim of the study was to establish the operative techniques and findings that can influence the reported incidence of cranial and cervical nerve injuries. Eight main studies comprising 1,616 carotid endarterectomies and published over the period from 1990 to October 2000 were reviewed. There were no statistically significant differences between neck incision (vertical or transverse) and number of injuries. In one study, multiple deficits were observed most frequently in patients treated by the eversion technique (P = 0.2). Additional prospective trials are needed in large numbers of patients to assess the incidence of cranial and cervical nerve injuries. Most injuries are transient and involve the vagus and hypoglossal nerves. A number of factors related to the operation, such as general anaesthesia, eversion technique and the surgeon's experience, may influence the incidence of such injuries. Repeat endarterectomy is associated with a high incidence of cranial and/or cervical nerve injuries. This is extremely important for establishing the real advantage of endovascular angioplasty or stenting of the carotid artery.

[Arteriomegaly in the aorto-iliac-femoral area with or without associated aneurysm]. / Arteriomegalia del distretto aorto-iliaco-femorale con o senza aneurismi associati.

The authors present a group of 199 patients with arteriomegaly, an affection characterized by elongated and distended blood vessels of the arterial system, with or without accompanying aneurysms. Our study on this group of patients, drawn from a large arteriographic series of peripheral abdominal and lower limb arterial disorders, focuses on a comparison between atherosclerotic arteriopathy and arteriomegaly. Small tissue blocks were taken from the arterial wall of patients operated on for megadolichoarteries. Electron microscopic examination of such specimens revealed a specific alteration of the elastic component of the vessel wall. The authors believe that surgical treatment of this condition is indicated in order to prevent thromboembolic complications or aneurysmal rupture.

[Hemothorax in the posterior mediastinum in extramedullary hemopoiesis]. / Hemotorax zadního mediastina pri extramedulární hemopoéze.

The authors describe a rare case of spontaneous haemothorax in a 19-year-old woman suffering from beta-thalassaemia major which developed as a result of extramedullary haematopoiesis. In intrathoracic disorders of obscure origin they recommend therefore to make first a cytological examination of the punctate to prevent unnecessary surgery.

[Bouveret's syndrome]. / La sindrome di Bouveret.

Bouveret's syndrome is represented by an intestinal occlusion due to a gallstone passed through a cholecysto-duodenal fistula and impacted in the duodenum. The authors report a case of this rare syndrome and discuss the optimal surgical approach.

[Coarctation of he abdominal aorta]. / Coarctation of the abdominal aorta.

The Authors report a 49-year-old woman complaining of slight nocturnal lower limb pain in whom an uncommon type IV coarctation of the infrarenal aorta associated with multiple renal arteries, slight hypoplasia of iliac and femoral arteries bilaterally, and a retroaortic left vein were found. She underwent an aorto-aortic prosthetic repair. The correction of this vascular condition was followed by partial improvement of her symptoms. The suspicion of an associated ischaemic spinal origin of these painful symptoms may be suggested by the typical and often complex presence of multiple vascular malformations described in patients with coarctation of the abdominal aorta.

[Fibrous tumors localized in the pleura]. / Tumori fibrosi localizzati della pleura (TFLP).

Localized fibrous tumour of the pleura is an uncommon condition which in few cases may exhibit malignant behaviour. Herein the Authors report a large review on this intrathoracic neoplasm focusing, in particular, on differential diagnosis between benign and malignant variants.

Adjuvant arteriovenous fistula in infrapopliteal bypasses.

The poor results obtained with the use of prosthesis in infrapopliteal arterial bypass grafting for critical limb ischaemia led to the introduction of several types of adjuvant arteriovenous fistula to improve the patency and limb salvage rates in patients who have no suitable autologous vein. The main aim of adjunctive arteriovenous fistula in infrageniculate prosthetic bypass is to accelerate the blood flow velocity through the prosthetic graft above the thrombotic threshold level. Since they are subject of great debate among vascular surgeons, the Authors have briefly reviewed the haemodynamic aspects and results reported with the use of such procedures.