Growing networks under geographical constraints.

Inspired by the structure of technological weblike systems, we discuss network evolution mechanisms which give rise to topological properties found in real spatial networks. Thus, we suggest that the peculiar structure of transport and distribution networks is fundamentally determined by two factors. These are the dependence of the spatial interaction range of vertices on the vertex attractiveness (or importance within the network) and on the inhomogeneous distribution of vertices in space. We propose and analyze numerically a simple model based on these generating mechanisms which seems, for instance, to be able to reproduce known structural features of the Internet.

Pharmacokinetics and pharmacodynamics of irinotecan during a phase II clinical trial in colorectal cancer. Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer.

PURPOSE: A pharmacokinetic study was performed during a phase II clinical trial of irinotecan (CPT-11) to confirm the pharmacokinetic profile of this drug and its metabolite and to investigate interpatient and intrapatient pharmacokinetic variations and pharmacokinetic-pharmacodynamic relationships. PATIENTS AND METHODS: Twenty-six men and 21 women (mean age, 61 years) with metastatic colorectal cancer, performance status less than 3 (World Health Organization [WHO] scale), and normal renal and hepatic function were administered CPT-11 (350 mg/m2) by 30-minute intravenous (IV) infusion every 21 days. CPT-11 and its metabolites SN-38 and SN-38 glucuronide (SN-38G) were determined by high-performance liquid chromatography (HPLC) using fluorimetric detection. RESULTS: The mean CPT-11 clearance and area under the concentration-time curve (AUC) were 15.2 L/h. m2 and 24,769ng. h/mL, respectively. The large difference in SN-38 and SN-38G AUCs (559 v 2,283 ng. h/mL) was suggestive of extensive glucuronidation of SN-38. Interindividual variation in the metabolic ratio ([AUCSN-38 + AUCSN-38Gl/AUCCPT-11) was marked (coefficient of variation [CV] = 51.6%] compared with intrapatient variation in this variable (CV = 32.6%). A significant relationship existed between percentage reduction in neutrophil count and the AUC of CPT-11 (r = .597, P < .001) and SN-38 (r = .559, P < .001). No relationship was identified between any pharmacokinetic parameter and delayed diarrhea or therapeutic outcome. CONCLUSION: Interindividual variations in the metabolic ratio suggest interpatient variation in carboxylesterase activity. Furthermore, glucuronidation of SN-38 may also be in part responsible for the large interpatient variability in the total SN-38 AUC. Conversely, low intrapatient variation of this parameter was observed in this study, which indicates a lack of autoinduction of the carboxylesterase system. The relationship between neutropenia and both CPT-11 and SN-38 pharmacokinetic parameters confirms the results of previous studies.

Phase II study of oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer patients.

PURPOSE: To evaluate the efficacy and safety of an oxaliplatin, fluorouracil (5-FU), and folinic acid (FA) combination in patients with metastatic or advanced gastric cancer (M/AGC). PATIENTS AND METHODS: Of the 54 eligible patients with measurable or assessable M/AGC, 53 received oxaliplatin 100 mg/m(2) and FA 400 mg/m(2) (2-hour intravenous infusion) followed by 5-FU bolus 400 mg/m(2) (10-minute infusion) and then 5-FU 3,000 mg/m(2) (46-hour continuous infusion) every 14 days. RESULTS: Patients (69% male, 31% female) had a median age of 61 years (range, 31 to 75 years), 89% had a performance status of 0 or 1, 70% had newly diagnosed disease, and 87% had metastatic disease. All had histologically confirmed adenocarcinoma. With a median of three involved organs, disease sites included the lymph nodes (67%), stomach (65%), and liver (61%). A median of 10 cycles per patient and 468 complete cycles were administered. Best responses in the 49 assessable patients were two complete responses and 20 partial responses, giving an overall best response rate of 44.9%. Eight patients underwent complementary treatment with curative intent (six with surgery and two with chemoradiotherapy). Median follow-up, time to progression, and overall survival were 18.6 months, 6.2 months, and 8.6 months, respectively. Grade 3/4 neutropenia, leukopenia, thrombocytopenia, and anemia occurred in 38%, 19%, 4%, and 11% of patients, respectively, and febrile neutropenia occurred in six patients (one episode each). Grade 3 peripheral neuropathy occurred in 21% of patients (oxaliplatin-specific scale). Seven patients withdrew because of treatment-related toxicity. CONCLUSION: This oxaliplatin/5-FU/FA regimen shows good efficacy and an acceptable safety profile in M/AGC patients, and may prove to be a suitable alternative regimen in this indication.

Our experience of conservative treatment of anal canal carcinoma combining external irradiation and interstitial implant: 32 cases treated between 1973 and 1982.

Between 1973 and 1982, a selected group of 32 patients with anal canal carcinoma received conservative treatment combining external irradiation and 192Iridium implant in a split course. Survival rates at 3 and 5 years are 78 and 61%, respectively. The overall control rate at the primary site is 75%. Tumor response to external irradiation appears to be the major predicting factor of the primary growth control after subsequent interstitial therapy. Two patients (6%) showed severe radionecrosis. The probability to preserve good anal function is 69%. Interstitial irradiation preceded by an external radiotherapy offers a good alternative in the conservative treatment of anal canal carcinoma.

A toxicokinetic model to assess the risk of azinphosmethyl exposure in humans through measures of urinary elimination of alkylphosphates.

Azinphosmethyl (APM) is one of the most common insecticides used in fruit farming. The object of this paper is to develop a quick and practical test for assessing the risk for humans coming into contact with APM. It has been shown that the principal component of occupational and/or accidental exposure is through the skin (C. A. Franklin et al., 1981, J. Toxicol. Environ. Health 7, 715-731), but our approach is applicable to exposures via any route or a combination of routes. The method proposed in the present paper can accommodate a single-event exposure or repeated exposures over long periods. Urinary alkylphosphate (AP) metabolites are reliable bioindicators of the presence of APM in the body; they are easily accessible and can be used to estimate APM body burden. We developed a simple toxicokinetic model to link the time varying APM body burden to absorbed doses and to rates of elimination in the form of AP urinary metabolites. Using this model and data available in the literature, we are able to propose a "no observed adverse effect level" (NOAEL) for APM body levels and for corresponding absorbed doses. We have established that after a single exposure, the safe limit corresponding to the NOAEL is reached at a cumulative 0.215 mumoles AP/kg bw eliminated in urine in the first 24 hours following the beginning of exposure. For repeated daily exposures at steady state, the corresponding urinary AP metabolite level is equal to a cumulative 0.266 mumoles AP/kg bw eliminated per 24 hours.

A biologically based dynamic model for predicting the disposition of methanol and its metabolites in animals and humans.

A multicompartment biologically based dynamic model was developed to describe the time evolution of methanol and its metabolites in the whole body and in accessible biological matrices of rats, monkeys, and humans following different exposure scenarios. The dynamic of intercompartment exchanges was described mathematically by a mass balance differential equation system. The model's conceptual and functional representation was the same for rats, monkeys, and humans, but relevant published data specific to the species of interest served to determine the critical parameters of the kinetics. Simulations provided a close approximation to kinetic data available in the published literature. The average pulmonary absorption fraction of methanol was estimated to be 0.60 in rats, 0.69 in monkeys, and 0.58-0.82 in human volunteers. The corresponding average elimination half-life of absorbed methanol through metabolism to formaldehyde was estimated to be 1.3, 0.7-3.2, and 1.7 h. Saturation of methanol metabolism appeared to occur at a lower exposure in rats than in monkeys and humans. Also, the main species difference in the kinetics was attributed to a metabolism rate constant of whole body formaldehyde to formate estimated to be twice as high in rats as in monkeys. Inversely, in monkeys and in humans, a larger fraction of body burden of formaldehyde is rapidly transferred to a long-term component. The latter represents the formaldehyde that (directly or after oxidation to formate) binds to various endogenous molecules or is taken up by the tetrahydrofolic-acid-dependent one-carbon pathway to become the building block of synthetic pathways. This model can be used to quantitatively relate methanol or its metabolites in biological matrices to the absorbed dose and tissue burden at any point in time in rats, monkeys, and humans for different exposures, thus reducing uncertainties in the dose-response relationship, and animal-to-human and exposure scenario comparisons. The model, adapted to kinetic data in human volunteers exposed acutely to methanol vapors, predicts that 8-h inhalation exposures ranging from 500 to 2000 ppm, without physical activities, are needed to increase concentrations of blood formate and urinary formic acid above mean background values reported by various authors (4.9-10.3 and 6.3-13 mg/liter, respectively). This leaves blood and urinary methanol concentrations as the most sensitive biomarkers of absorbed methanol.

Cancer chemotherapy in the elderly: a series of 51 patients aged greater than 70 years.

A total of 2,238 new cancer patients were treated in our institution in 1988; among the 423 (18.9%) who were greater than 70 years old, 51 underwent chemotherapy. The median age was 75.8 years, and the Karnofsky performance status (KPS) was greater than or equal to 70% for 40 patients. Malignancies were hematopoietic in 24 cases (47%) and digestive in 15 patients (29%), and 12 subjects (24%) had other types of cancers. The first chemotherapy course was given at the full dose to 23/51 (45.1%) patients. The drug dose was reduced for 28/51 (54.9%) patients, due in 25 cases to the subjects being greater than 70 years old. Neither age, KPS, pretreatment assessment, nor cancer extent was correlated with the modifications made to the first cycle. An overall toxicity of grade 3 + 4 (WHO grading scale) was noted in 10 subjects (19.6%). Although these elderly patients were probably selected, analysis of their charts did not evidence an increase in chemotherapy toxicity, regardless of the dose they received.

Analysis of a series of sixty soft tissue sarcomas in adults treated with a cyclophosphamide-vincristine-adriamycin-dacarbazine (CYVADIC) combination.

From 1976 to 1983, a group of 60 adult patients presenting with metastatic and/or locally advanced soft tissue sarcomas was treated with combination chemotherapy consisting in cyclophosphamide, vincristine, adriamycin, and DTIC (CYVADIC). A tumor response was obtained for 29 patients (48.3%), with 4 (6.7%) cases of complete regression. The median duration of the response was 10 months. Responses were noted in 14/22 patients receiving induction chemotherapy for advanced, and previously nonirradiated, primary tumors; among the patients with metastatic disease tumor regression was recorded in 17/32 patients with pulmonary metastases, but in none of the patients with metastases at other sites. Moreover, the attainment of a response was found to correlated with the patient's general condition, while response duration depended on the histoprognostic grade of the tumors.

A comparative study of controlled-release morphine (CRM) suspension and CRM tablets in chronic cancer pain.

This study compared the efficacy and the adverse effects of controlled-release morphine (CRM) suspension (SAR 213) and CRM tablets (Moscontin) in the treatment of cancer pain. This multicenter, randomized, double-blind, double-dummy, crossover study was carried out on 52 patients. Each patient received both study treatments given at an equivalent dosage of morphine during each of two 7-day periods. The primary outcome variable was the severity of pain assessed three times daily by means of a visual analogue scale. Secondary criteria of efficacy were the severity of pain assessed by verbal rating scale, the need for "rescue" doses of immediate-release morphine, treatment preference, and indices of quality of life (activity, mood, sleep). There were no statistically significant differences in the parameters assessed when comparing the two groups. This study shows that, when prescribed at the same doses, CRM suspension and CRM tablets have similar efficacy and adverse effects, as well as the same duration of action. The results of this first clinical study carried out on CRM suspension are especially relevant for patients with cancer pain who have difficulty swallowing.

Surgical treatment of liver metastases by radiofrequency ablation, resection, or in combination.

AIMS: Radiofrequency ablation (RFA) has a role in the treatment of unresectable liver metastases either percutaneously or in open surgery. The aim of this study was to determine the feasibility and value using RFA, resection or in combination to cure liver metastases of colorectal or other origin. METHODS: Fifty-two consecutive patients were operated on with the intention to treat their liver metastases using both techniques of RFA and resection in the same curative intent. A CT scan was performed 2 months postoperatively and then every 4 months. RESULTS: Fifty patients with 137 metastases could be treated: 55 lesions were resected and 82 were ablated. Curative treatment of 13 patients could only be achieved by using RFA combined with resection. Morbidity was 16% and local treatment proved insufficient in three cases. Estimated 1-year survival probabilities were, respectively, 0.85 in the colorectal group and 0.80 in the non-colorectal group. CONCLUSIONS: RFA increased resectability of liver metastases and reduced the morbidity. Respective indications of both techniques were complementary and depend on the size and the topography of the lesion to be treated.

The toxicokinetics of pyrene and its metabolites in rats.

Five experiments were conducted in male Sprague-Dawley rats regarding the kinetic of urinary excretion of 1-hydroxypyrene (1-OHP) following i.v., oral and dermal exposure to 0.5-50 micromol/kg pyrene either as a single substance or as mixture of various polycyclic aromatic hydrocarbons (PAH). Frequent urine collections over 48 h after exposure and a tissue versus time distribution experiment using [14C]pyrene allowed to define the kinetic profile of both pyrene and 1-OHP. For all exposure routes, there is a linear relationship over two orders of magnitude between the dose of pyrene and the urinary excretion of 1-OHP. Differences in biliary/urinary 1-OHP excretion ratio in canulated rats (3) versus faecal/urinary 1-OHP excretion ratio in non-canulated rats (0.6) indicate major enterohepatic recirculation of the metabolite. Half-lives of both pyrene and 1-OHP in all measured tissues were all comprised between 3.1 and 5.4 h, and 5.2-6.7 h, respectively, so that no long term accumulation would be predicted from these values for any tissue. Binary and ternary mixtures involving naphthalene and benzo(a)pyrene in addition to pyrene has no influence on the urinary excretion profile of 1-OHP. All these observations led to the proposal of a dynamic compartment model of pyrene and metabolite flows indicating that following rapid initial distribution to fatty tissues, pyrene is rapidly biotransformed into various metabolites and undergoes major enterohepatic recycling. Part of the initially formed and part of the recirculated 1-OHP eventually undergoes urinary excretion such that close to 60% of pyrene is eliminated as metabolites in urine by 24 h after injection while 20% is excreted in the faeces over the same period.

Dacarbazine, fluorouracil, and leucovorin in patients with advanced neuroendocrine tumors: a phase II trial.

Chemotherapy of neuroendocrine tumors must be improved. The most widely used regimen, which combines streptozotocin with fluorouracil, commonly obtains poor results. The best response rate that has been reported for carcinoid tumors is 33%. From July 1991 through September 1994, 18 patients who had advanced neuroendocrine tumors-including nine carcinoid tumors, seven neuroendocrine tumors of unknown primary site, one insulinoma, and one paraganglioma-were treated with a regimen of dacarbazine, 400 mg/m2/day, plus fluorouracil, 1 g/m2/day, with leucovorin, 200 mg/m2/day, for 2 days every 21 days (DTIC-LVFU2 protocol). The results were assessed according to the World Health Organization criteria of toxicity and response. Toxicity was moderate. The most severe side effects were grade 3 vomiting in two patients, grade 3 leukopenia in three patients, and grade 3 mucositis in one patient. The overall response rate was 27%, with only one partial response for carcinoid tumors but one complete and three partial responses for the other tumor types. Efficacy was insufficient in patients who had carcinoid tumors but the combination of dacarbazine with fluorouracil and leucovorin could be an effective regimen for the treatment of neuroendocrine tumors of unknown primary site.

Evolving networks with disadvantaged long-range connections.

We consider a growing network, whose growth algorithm is based on the preferential attachment typical for scale-free constructions, but where the long-range bonds are disadvantaged. Thus, the probability of getting connected to a site at distance d is proportional to d(-alpha), where alpha is a tunable parameter of the model. We show that the properties of the networks grown with alpha<1 are close to those of the genuine scale-free construction, while for alpha>1 the structure of the network is quite different. Thus, in this regime, the node degree distribution is no longer a power law, and it is well represented by a stretched exponential. On the other hand, the small-world property of the growing networks is preserved at all values of alpha.

Reshuffling scale-free networks: from random to assortative.

To analyze the role of assortativity in networks we introduce an algorithm which produces assortative mixing to a desired degree. This degree is governed by one parameter p . Changing this parameter one can construct networks ranging from fully random (p=0) to totally assortative (p=1) . We apply the algorithm to a Barabási-Albert scale-free network and show that the degree of assortativity is an important parameter governing the geometrical and transport properties of networks. Thus, the average path length of the network increases dramatically with the degree of assortativity. Moreover, the concentration dependences of the size of the giant component in the node percolation problem for uncorrelated and assortative networks are strongly different. The behavior of the clustering coefficient is also discussed.

Correlations in scale-free networks: tomography and percolation.

We discuss three related models of scale-free networks with the same degree distribution but different correlation properties. Starting from the Barabási-Albert construction based on growth and preferential attachment we discuss two other networks emerging when randomizing it with respect to links or nodes. We point out that the Barabási-Albert model displays dissortative behavior with respect to the nodes' degrees, while the node-randomized network shows assortative mixing. These kinds of correlations are visualized by discussing the shell structure of the networks around an arbitrary node. In spite of different correlation behaviors, all three constructions exhibit similar percolation properties. This result for percolation is also detected for a network with finite second moment and its corresponding randomized models.

On the distribution of vaccine protection under heterogeneous response.

We assume that individuals in a vaccinated cohort respond heterogeneously and acquire a continuous spectrum of effective protection against an environmental exposure to infection that can be varying in time. The notion of dynamical invariants is applied to a proportional hazard model with an unvaccinated or placebo cohort as baseline. The hazard is expressed as a susceptibility factor times a measure of environmental exposure to infection. Using the time-evolving information for the aggregated vaccinated cohort and the unvaccinated cohort, it is possible to reconstruct the distribution of effective protection imparted by the vaccination at the beginning of observation. Efficacy is defined in terms of the hazard ratio at the beginning of observation.

Phase II study of a 5-fluorouracil, teniposide and mitomycin-C combination chemotherapy in advanced colorectal carcinomas.

Fifteen patients (median age 62, with a mean Karnofsky performance status of 70%) presenting with advanced colorectal carcinoma were included in the study. The treatment combination consisted of 5-fluorouracil (800 mg/m2 in a 30 min infusion, days 1 and 8), teniposide (80 mg/m2 in i.v. push, day 1), and mitomycin-C (10 mg/m2 in i.v. push, day 1); therapy was resumed every 29 days. A partial objective response (for 4 months) was noted in one patient who had received no prior chemotherapy; the overall median survival of the 15 patients was 5 months. Toxicity was acceptable, with leukopenia (1 case), mucositis (1 case) and diarrhea (1 case), leading to drug dose reduction. Chemotherapy was stopped once owing to severe hematologic toxicity. With the doses and schedule used, the drug combination appears to have minimal activity in advanced colorectal cancer.

Colonic metastasis of a renal carcinoma. A case report.

A 64 year-old man with a metastatic clear-cell renal carcinoma experienced low intestinal bleeding. The endoscopy revealed a polypoid mass in the left colon which proved to be a metastasis of the renal carcinoma. This is an uncommon cause of intestinal hemorrhage, and a rare localization of metastatic deposits.

Malignant lymphoplasmacytoid lymphomas. Clinical and evolutive data.

A series of 31 cases of malignant lymphoplasmacytoid lymphomas (excluding Waldenström disease) is analyzed. Two-thirds of the patients initially had localizations elsewhere than in the lymph nodes and presented clinical stage I or II. The median survival is around 4 years and is particularly favorable for stage I and II patients who have received an association of radiotherapy and systematic chemotherapy; the estimated "cure rate" for these patients is around 80%.

[Palliative chemotherapy of adult soft tissue sarcomas with an association of cyclophosphamide-vincristine-adriamycine-dacarbazine (CYVADIC) (author's transl)]. / Chimiothérapie palliative des sarcomes des tissus mous de l'adulte par une association cyclophosphamide-vincristine-adriamycine-dacarbazine (CYVADIC).

From January 1976 to December 1979, 23 adults with advanced soft tissue sarcomas were treated with palliative chemotherapy associating cyclophosphamide, vincristine, adriamycin and dacarbazine (CYVADIC) according to two different schema administered successively. A higher than 50 per cent rate of tumoral response was observed in 52 per cent of cases with 13 per cent complete remissions. Median survival was 14 months in patients who responded to treatment, and 4 months in non-responders (p less than 0,01). Side effects were severe however, and it was necessary to discontinue treatment in 5 patients, and modify dosage in 9 other patients. The CYVADIC protocol is effective but requires some modifications to improve tolerance.