The influence of blood phenylalanine levels on neurocognitive function in adult PKU patients.

It is well known that hyperphenylalaninemia caused by phenylketonuria (PKU) negatively influences cognitive performance. Several tests have been used to study these functions. Until now, no universal, optimal tool has been developed for detecting PKU-caused brain dysfunctions. Using computerized neuropsychological tests during daily routine would be helpful for screening subclinical brain deficits in adult PKU patients. In a monocentric, cross-sectional study, adult patients with PKU (n = 46; median age = 29.5 years; female/male ratio = 21/25) were tested with the computerized Cambridge Cognition (CANTAB) test measuring neurocognitive functions. Patients were divided into two groups: The "on diet" group included patients whose blood Phe-level was under 600 µmol/l (n = 20), and the "loose diet" group included patients whose blood Phe-level was above 600 µmol/l (n = 26) at the examination time. The results of the PKU-affected individuals were compared with a healthy control group (n = 31; median age = 25 years; female/male ratio = 11/20). Compared with the control group, PKU patients had significantly worse test results in memory, problem-solving skills, and strategy. However, there were no significant differences in response speed or initial thinking time. There was no correlation between the blood Phe-level, tyrosine (Tyr)-level or Phe/Tyr ratio and the different cognitive test results. There were no significant differences in test results between the two PKU subgroups. Several cognitive functions measured by CANTAB are negatively influenced by hyperphenylalaninemia in adult PKU patients. However, response speed and initial thinking time were not impaired as seriously as other functions. Patients with lower Phe-levels failed to achieve better test results than patients whose Phe-levels were notably elevated.

A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer.

BACKGROUND: Treatment options after first-line chemotherapy are limited in non-small cell lung cancer (NSCLC). Belagenpumatucel-L is a therapeutic vaccine comprised of 4 transforming growth factor (TGF)-ß2-antisense gene-modified, irradiated, allogeneic NSCLC cell lines that may be useful for maintenance after initial treatment. METHODS: Stage III/IV NSCLC patients who did not progress after platinum-based chemotherapy were randomised 1:1 to receive maintenance belagenpumatucel-L or placebo. Patients were eligible for randomisation between one and four months from the end of induction chemotherapy. The primary endpoint was overall survival. RESULTS: This phase III trial enrolled 270 patients in the belagenpumatucel-L arm and 262 in the control arm. Belagenpumatucel-L was well tolerated with no serious safety concerns. There was no difference in survival between the arms (median survival 20.3 versus 17.8months with belagenpumatucel-L versus placebo, respectively; hazard ratio (HR) 0.94, p=0.594). There were also no differences in progression-free survival (4.3months versus 4.0 for belagenpumatucel-L vs placebo, respectively; HR 0.99, p=0.947). A prespecified Cox regression analysis demonstrated that the time elapsed between randomisation and the end of induction chemotherapy had a significant impact on survival (p=0.002) and that prior radiation was a positive prognostic factor (median survival 28.4months with belagenpumatucel-L versus 16.0months with placebo; HR 0.61, p=0.032). CONCLUSIONS: Although the overall trial did not meet its survival endpoint, improved survival for belagenpumatucel-L is suggested in patients who were randomised within 12weeks of completion of chemotherapy and in those who had received prior radiation. Further studies of belagenpumatucel-L in NSCLC are warranted.

A randomized, double-blind, phase II study of erlotinib with or without sunitinib for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC).

BACKGROUND: Combined inhibition of vascular, platelet-derived, and epidermal growth factor receptor (EGFR) pathways may overcome refractoriness to single agents in platinum-pretreated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This randomized, double-blind, multicenter, phase II trial evaluated sunitinib 37.5 mg/day plus erlotinib 150 mg/day versus placebo plus erlotinib continuously in 4-week cycles. Eligible patients had histologically confirmed stage IIIB or IV NSCLC previously treated with one or two chemotherapy regimens, including one platinum-based regimen. The primary end point was progression-free survival (PFS) by an independent central review. RESULTS: One hundred and thirty-two patients were randomly assigned, and the median duration of follow-up was 17.7 months. The median PFS was 2.8 versus 2.0 months for the combination versus erlotinib alone (HR 0.898, P = 0.321). The median overall survival (OS) was 8.2 versus 7.6 months (HR 1.066, P = 0.617). Objective response rates (ORRs) were 4.6% and 3.0%, respectively. Sunitinib plus erlotinib was fairly well tolerated although most treatment-related adverse events (AEs) were more frequent than with erlotinib alone: diarrhea (55% versus 33%), rash (41% versus 30%), fatigue (31% versus 25%), decreased appetite (30% versus 13%), nausea (28% versus 14%), and thrombocytopenia (13% versus 0%). CONCLUSIONS: The addition of sunitinib to erlotinib did not significantly improve PFS in patients with advanced, platinum-pretreated NSCLC.

Significance and imaging of lumbar veins and early-branching arteries in planning living-donor laparoscopic nephrectomy: two case reports from 21 months' experience.

A key aspect in planning laparoscopic living-donor nephrectomy is mapping of vascular variations. Lumbar veins and early-branching renal arteries are of utmost importance. To date, 43 candidates including 18 men and 25 women aged 25 to 67 years have been examined at our clinic using 16-section multidetector-row computed tomography angiography. Each examination was double-checked by an experienced radiologist. Of the 43 patients, 31 underwent surgery. In 29 of 31 patients (93.5%), the anatomy observed during surgery was identical to that demonstrated on the preoperative computed tomography scan. In 1 of 2 patients, 2 separate arteries were found at surgery, rather than the prognosticated early-branching arteries. In this patient, conversion to open surgery was necessary. In the other patient, a lumbar vein running into a retroaortic renal vein was discovered. In this patient, a 6-mm length of the joint stem contained the wall of the aorta and the periaortic tissue; thus, technically they were of separate origins. Careful mapping of the anatomy helps to prevent unexpected operative complications that are difficult to manage. Correct interpretation of the data must always be based on agreement between the radiologist and the surgeon.

Alterations of carbohydrate and lipoprotein metabolism in childhood obesity--impact of insulin resistance and acanthosis nigricans.

AIM: To study the prevalence of alterations of glucose and lipoprotein metabolism and the impact of acanthosis nigricans (AN) in childhood obesity. PATIENTS AND METHODS: 113 obese children, 57 with simple obesity (SO) and 58 with obesity and AN (OAN). Oral glucose tolerance test was performed, serum glucose, insulin and lipoprotein parameters were determined, and insulin resistance/sensitivity indices were calculated. RESULTS: Insulin resistance, basal and reactive hyperinsulinemia, impaired glucose tolerance (IGT) and dyslipidemia were found to be frequent conditions in children with OS as well as OAN. Reactive insulinemia was more pronounced in OAN than in SO, and insulin resistance was more frequent when AN was more prominent. Triglycerides were higher and HDL-C was lower, and atherogenic dyslipidemia was more frequent in OAN compared to SO. CONCLUSION: Children with obesity form a risk population. AN is a factor which can be used in metabolic risk factor clustering estimation in childhood obesity.

Alterations of glucoregulation in childhood obesity--association with insulin resistance and hyperinsulinemia.

AIM: To study the prevalence of alterations of glucoregulation in childhood obesity. PARTICIPANTS: 250 obese children. Oral glucose tolerance test was performed, serum glucose and insulin were determined, and HOMA-IR was calculated. RESULTS: Impaired fasting glucose (IFG) was found in 1.2% according to World Health Organisation criteria and 4.4% according to the criteria of the International Diabetes Federation. Impaired glucose tolerance (IGT) was found in 13.6%, type 2 diabetes mellitus (DM2) in 2.4%. Frequency of fasting glucose (FG) above 7.0 mmol/l was 1.2%. Basal hyperinsulinemia was increased in 70%, reactive hyperinsulinemia in 88%, frequency of elevated HOMA-IR was 78%. 120' insulin was increased in all cases with abnormal FG, IGT and DM2, HOMA-IR was elevated in 79% of patients with IGT and all patients with abnormal FG and DM2. Significant positive correlations were demonstrated between body mass index and insulin levels. CONCLUSION: Our data show that hyperinsulinemia can successfully compensate for insulin resistance in the majority of the obese children. Since IFG is less frequent than IGT there is a need for performing OGTT to demonstrate abnormality of glucoregulation in obese children.

Phase I/II study of a 3 weekly oral taxane (DJ-927) in patients with recurrent, advanced non-small cell lung cancer.

INTRODUCTION: A phase I/II study was performed to assess the efficacy and toxicity of a new oral taxane in patients with recurrent, advanced Non-small Cell Lung Cancer. PATIENTS AND METHODS: Patients who were treated with one prior, taxane free chemotherapy regimen, were eligible for this study. A single oral dose of DJ-927 (27 mg/m) was given every 3 weeks. In case of good tolerance, one dose escalation to 35 mg/m was allowed. Response and toxicity were measured and plasma pharmacokinetic analysis was performed during the first course. RESULTS: From October 2004 to September 2005, 36 patients gave informed consent and 34 received medication. The mean age was 58 years (range, 33-75 years). The majority of patients were pretreated with a combination of cisplatin and gemcitabine. Median interval between end of first treatment and the registration of this study was 7 months (range, 0.8-22 months). Twelve patients died on study of which eight due to disease progression. In four patients with preexisting cardiac disease, toxicity led to cardiac worsening and subsequent death. Grade 3 and 4 toxicities according to the National Cancer Institute Common Toxicity Criteria were neutropenia in 18 patients (53%), anemia in six patients (18%), nausea and fatigue in two patients (6%), febrile neutropenia and neurotoxicity in one patient (3%). The overall response rate for all patients was 5.6% (Confidence Interval [CI] 0.7-18.7%). The percentage of patients with stabilization for >6 weeks was 47%. The median time to progression was 97 days (CI: 47-167 days) and the median survival time was 120 days (CI: 68-222 days) for the ITT group. Since only a minority of patients (3) tolerated the higher drug dose we omitted this dose level because of hematological toxicity. Pharmacokinetic analysis showed that the median area under the curve (t = 0-168 hours) was 1752 +/- 1355 ngr/ml/h and the half-life was 167 +/- 77 hours. CONCLUSION: When administered once every 3 weeks, this oral taxane formulation of DJ-927 was well-absorbed with a long terminal half-life of 167 +/- 77 hour. DJ-927 has antitumor activity against Non-small Cell Lung Cancer when given as second-line monotherapy (overall response rate in 5.6%; CI 0.7-18.7%). Ten patients experienced SD for more than 8 weeks. Different types of dose administration (metronomic dosing) or combination with other cytotoxic agents should be considered in future studies.

Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative, for the treatment of patients with non-small cell lung cancer.

PURPOSE: The purpose of this phase I study was to evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), the recommended dose for phase II study, pharmacokinetics, and antitumor activity of TZT-1,027 (soblidotin) in patients with non-small cell lung cancer (NSCLC) when administered every 3-4 weeks. METHODS: Eligible patients had the following characteristics: stage III/b or IV NSCLC that was refractory to conventional therapy or for which no standard therapy was available; Eastern Cooperative Oncology Group (ECOG) performance status (PS) or=20 and <75 years. The patients were administered TZT-1,027 in escalating doses from 0.5 to 5.6 mg/m(2). Pharmacokinetic samples were collected during each treatment course. RESULTS: Forty-nine patients were enrolled. Three patients had DLTs, including neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The common toxicities included constipation, anorexia, alopecia, nausea, leukopenia, and neutropenia. One complete response and three partial responses were observed. The pharmacokinetic parameters (AUC and C (max)) of TZT-1,027 tended to increase linearly with dose. CONCLUSIONS: DLTs included neutropenia, neutropenia complicated by fever, myalgia, and neuropathic pain. The MTD was 4.8 mg/m(2). The recommended phase II study dose of TZT-1027 is 4.8 mg/m(2) administered every 3-4 weeks.

Toxicity of a pendimethalin containing herbicide formulation and three heavy metals in chicken embryos.

The toxic effects of a widely used herbicide (Stomp 330 containing 33% pendimethalin as active ingredient) applied alone or in combination with three heavy elements (copper sulphate, cadmium sulphate and lead acetate) modelling the heavy metal load of the environment were studied on chicken embryos with injection treatment. The treatment was done on day 0 of incubation. Solutions and emulsions of different concentrations were made from the test materials and injected in 0.1 ml volume into the air space of eggs. The macroscopical evaluations were done on day 19 of the incubation. Summarizing the findings, it can be established that the individual administration of the 33% pendimethalin containing herbicide formulation was less toxic compared to the control group than the simultaneous administration of the pesticide and heavy elements. As compared with each other the results from the combined administrations of the 33% pendimethalin containing herbicide formulation and heavy elements the simultaneous administration of cadmium and the herbicide caused the highest embryomortality while the incidence of developmental anomalies were the highest in the interaction study of the copper and the pesticide.

Teratogenicity testing of a 2,4-D containing herbicide formulation and three heavy metals in chicken embryos.

The toxic effects of a widely used herbicide (Dikamin D containing 72% 2,4-D-amine Na as active ingredient) applied alone or in combination with three heavy elements (copper sulphate, cadmium sulphate and lead acetate) modelling the heavy metal load of the environment were studied on chicken embryos with injection treatment. The treatment was done on day 0 of incubation. Solutions and emulsions of different concentrations were made from the test materials and injected in 0.1 ml volume into the air space of eggs. The macroscopical evaluations were done on day 19 of the incubation. Summarizing the findings, it can be established that the individual administration of the 72% 2,4-D containing herbicide formulation was less toxic compared to the control group than the simultaneous administration of the pesticide and heavy elements. As compared with each other the results from the combined administrations of the 72% 2,4-D containing herbicide formulation and heavy elements the simultaneous administration of cadmium and the herbicide caused the highest embryomortality while the incidence of developmental anomalies were the highest in the interaction study of the copper and the pesticide.

Early embryogenesis study on a dimethoate containing formulation and Cd-sulphate in chicken embryos.

The toxic effects of a widely used organophosphate insecticide (BI 58 EC containing 38% dimethoate as active ingredient) applied alone or in combination with cadmium sulphate modelling the heavy metal load of the environment were studied on chicken embryos in the early phase of development. Solutions and emulsions of different concentrations were made from the test materials and injected in 0.1 ml volume into the air space of eggs on the first day (day 0) of incubation. Subsequently, on days 2 and 3 of incubation permanent preparations were made from the embryos in order to study the early developmental stage. Embryos fixed on slides and stained with osmium tetroxide solution were studied under light microscope. Summarising the findings, it can be established that the embryotoxicity increased after the simultaneous administration of Cd-sulphate and 38% dimethoate containing insecticide formulation compared to the control or the individually treated groups.

Teratogenicity study of some pesticides in chicken embryos.

The use of pesticides involves the risk of poisoning on wild animals. Teratological tests carried out on avian embryos provide useful data for environmental protection and facilitate the development of environment-friendly chemical plant protection techniques. A 30% dimethoate containing insecticide formulation (BI 58 EC) and a 20% benfluralin containing herbicide formulation (Flubalex) and a 960 g/l S-metolachlor containing herbicide formulation (Dual Gold 960 EC) were studied in chicken embryos after single administration by immersion and injection technique. Treatment was done on day 0 of incubation. Applied concentration of pesticides were 0.1% (dimethoate) and 2.05% (S-metolachlor) and 0.375% (benfluralin) corresponding to that used in plant protection practice. Test materials were injected into the air chamber in a volume of 0.1 ml/egg, or eggs were treated by the immersion technique for 30 min. at 37 degrees C. Evaluation was done on day 19 of incubation. Injection treatment: the administration of S-metolachlor and benfluralin did not result a significant decrease in the average body weight of embryos. At the same time the body weight of embryos significantly decreased because of single administration of dimethoate. The embryomortality increased markedly after the administration of test materials (S-metolachlor, benfluralin, dimethoate). Immersion treatment: the administration of S-metolachlor and benfluralin and dimethoate did not result a significant decrease in the average body weight of embryos. The rate of embryomortality was low after the administration of S-metolachlor, benfluralin and dimethoate. After the immersion and the injection treatment the incidences of developmental anomalies were sporadic. In summary it can be established that the injection treatment was more toxic than immersion technique of the test materials in our study.

Toxicity of a dichlorvos containing insecticide formulation and an atrazine containing herbicide formulation in chicken embryos after individual administration.

A 50% dichlorvos containing insecticide formulation (Unifosz 50 EC) and a 50% atrazine containing herbicide formulation (Hungazin PK 50 WP) were studied in chicken embryos after administration as single compounds. Applied concentrations of dichlorvos were 0.1% (corresponding to the plant protection practice), 0.05%, 0.02%, 0.01%. Applied concentrations of atrazine were 0.66% (corresponding to the plant protection practice), 0.33%, 0.132%, 0.066%. The test materials were injected directly into the air-chamber of eggs on day 0 of the hatching period and evaulation was carried out on day 19 of incubation. The chicken embryos were examined for the following: rate of embryo mortality, body mass, type of developmental anomalies. After the single administrations of dichlorvos containing insecticide formulation and atrazine containing herbicide formulation on day 0 of incubation, the average body weight of chicken embryos significantly did not decrease as compared to the control. After the individual administrations of pesticides the incidence of developmental anomalies was sporadic. The embryonic mortality markedly increased at the highest concentrations of pesticides. The rate of embrio mortality were 61% (dichlorvos insecticide containing formulation) and 52% (atrazine containing herbicide formulation). In summary, the 50% dichlorvos containing insecide formulation (Unifosz 50 EC) and the 50% atrazine containing herbicide formulation (Hungazin PK 50 WP) were toxic to the developing chicken embryos at the highest concentration in our study. The toxic effect was expressed in the high rate of embrio mortality.

Subclinical pulmonary involvement assessed by bronchoalveolar lavage in patients with early undifferentiated connective tissue disease.

OBJECTIVE: To assess the presence of neutrophil and lymphocyte fibrosing alveolitis by bronchoalveolar lavage in patients with early undifferentiated connective tissue disease (EUCTD) and systemic sclerosis (SSc). METHOD: Bronchoalveolar lavage (BAL) was performed in 13 patients with EUCTD who exhibited signs of lung involvement by non-invasive methods including lung function tests and high resolution computed tomography. The mean age of cases was 48.1 +/- 6.6, and the mean disease duration was 1.8 +/- 0.8 years. Differential cell counts of BAL were evaluated. Eleven patients with systemic sclerosis and 5 healthy control subjects were also investigated. RESULTS: Eleven of the 13 EUCTD and 10 of the 11 SSc patients showed an elevated total cell number (above the median cell/ml of control + 2 SD) in the BAL fluid. In patients with EUCTD, the lymphocyte count was elevated in 6, and the polymorphonuclear neutrophil count in 2 patients. One of the patients with EUCTD had simultaneously elevated lymphocyte and neutrophil granulocyte counts. In the SSc group, 6 patients had an elevated lymphocyte and 6 an increased neutrophil count. Three of these cases had both increased neutrophil and elevated lymphocyte counts, simultaneously. CONCLUSION: Subclinical, predominantly lymphocyte alveolitis can be present in patients with EUCTD. Patients with SSc tend to exhibit neutrophil alveolitis.

Predictive value of MRI in lung cancer.

Pathologic results of 543 lymph nodes removed during 164 radical surgery for lung cancer is compared with the expected findings based on preoperative MRI imaging. Specificity of T2 weighted MRI images were 95.5% for individual lymph nodes and 88.1% for TNM staging, respectively. Sensitivity was found to be 89.4% for lymph nodes and 94.6% for TNM staging of the patient. The accuracy of the MRI imaging was 84.7%. Properly chose MRI imaging and interpretation sounds to be no inferior to more invasive methods as collar mediastinoscopy, Chamberlain procedure or VATS exploration.

[Helicobacter pylori infection in diabetic patients]. / Diabetes mellitusos betegek Helicobacter pylori fertözöttsége.

The purpose of our research was to prove the occurrence of Helicobacter pylori infection in diabetic patients. Out of the 100 patients who were treated at the diabetological clinic, the antibody of Helicobacter pylori could be shown in 57 patients. Through histological tests carried out in the course of upper panendoscopia of the patients having positive results of serological test, Helicobacter pylori infection could be actually proved in 39 cases. On the basis of the evaluated material of diabetic patients, the occurrence of Helicobacter pylori infection was not higher than that in of the average population. No connection has been found between the frequency of the infection, and type of diabetes or its duration. The eradicational treatment was successful with 85% of the patients.

Calcifying liver metastases in a case of primary lung cancer.

A 50-year-old man presented with primary lung cancer with bone lesions and calcifying liver nodi. Two months after stopping chemotherapy, he died. Autopsy revealed multiple organ metastases. Histologically, the calcified nodi in the liver proved to be affected by tumor metastasis.

[The role of computerized tomography in the staging of lung cancer]. / A komputertomográfia helye a tüdódaganatok stádiumba sorolásánál.

Staging of lung cancer place significant role in the prognosis and treatment of the disease. Beside bronchoscopy, CT one of the important method for the tumor staging. 135 CT examinations with diagnosis of suspected lung cancer were evaluated and radiologic diagnosis was compared with the cyto-histological and surgical results. In 112 cases both CT and histological diagnosis were performed: both method revealed malignant tumors in 108 cases. Five lesions were regarded as tumour by CT but histological result proved aspergilloma, or specific processes. Abnormal lymph nodes were recognised at 98 tumours patients. There was a good correlation-regarding the number, size measurement-between CT and surgery. Histological diagnosis proved that all of the lymph nodes larger, then 2 cm of diameter contained metastic cells. In the 1-2 cm size almost all of the lymph nodes were metastatic. In addition tumour cells were found in some lymph nodes smaller, than 1 cm, too. This gives warning sign: smaller lymph nodes need more attention than we assumed. CT prove to be confident method for the evaluation, measurement and localisation of the tumours and lymph nodes in the chest.

[Thoracic actinomycosis]. / Thoracalis actinomycosis.

The authors describe in their case study the history of a 51 year old man, at whom they verified without thoracotomy thoracal actinomycosis. They achieved recovery giving permanently high doses of Penicillin. In connection with this rare case the authors review pathogenesis, the symptomatology, the diagnosis and the therapy of actinomycosis. The authors have found only one case in the Hungarian literature, which was recognized without thoracotomy and was cured by antibiotic therapy within a short period of time.

High lipoprotein(a) levels with predominance of high molecular weight apo(a) isoforms in patients with pulmonary embolism.

Lipoprotein(a) (Lp(a)) may interact with the cellular components and protein co-factors of fibrinolysis. To evaluate the effect of Lp(a) in thromboembolic diseases of the venous system, we measured serum levels and the isoform distribution of apo(a) in 25 patients with pulmonary embolism (18 men, 7 women, aged 21-77 years). The control group was adjusted for sex and age (P = 0.189). Serum Lp(a) concentration was significantly higher in the study group (median: 9.3 vs. 4.3 mg dL-1). As the distribution of high and low molecular weight subtypes of apo(a) did not show any differences (P = 0.127) between the two groups, the elevated Lp(a) levels in patients with pulmonary embolism could not be attributed to the investigated kringle-4 polymorphism of the apo(a) gene and therefore other genetic or non-genetic implications are indicated.