Predictive significance of preoperative serum VEGF-C and VEGF-D, independently and combined with Ca19-9, for the presence of malignancy and lymph node metastasis in patients with gastric cancer.

BACKGROUND: Cumulative evidence demonstrate that lymphangiogenic vascular endothelial growth factors (VEGF)-C and -D are over-expressed and associated to lymph node metastasis (LNM) in gastric cancer. The aim of this study is to investigate whether preoperative serum levels of VEGF-C and VEGF-D could be useful tumor markers in patients with operable gastric adenocarcinoma. METHODS: We prospectively examined serum samples from 40 patients and 40 non-cancer controls using enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was implemented. VEGF-C and VEGF-D were studied independently and in combination with Ca19-9. RESULTS: In gastric cancer patients, preoperative VEGF-C was significantly lower as compared to controls and to postoperative VEGF-C (P < 0.001); preoperative VEGF-D was significantly higher as compared to controls and to postoperative VEGF-D (P < 0.001). ROC curve analysis identified a VEGF-C/VEGF-D cut-off value of < 2.7 for the presence of gastric cancer, with 83% sensitivity and 75% specificity (P < 0.001). Backward stepwise selection modeling including sex, age, VEGF-D and Ca19-9, predicted the presence of LNM with 86% sensitivity and 82% specificity (P < 0.001). CONCLUSION: Circulating levels of VEGF-C and VEGF-D could play a role as biomarkers for serological detection and staging in gastric cancer.

Clinical features of hypersensitivity reactions to oxaliplatin: a 10-year experience.

BACKGROUND: Oxaliplatin has become one of the major cytotoxic agents for the treatment of gastrointestinal tumors. As a result, several cases of the so-called oxaliplatin-associated hypersensitivity reaction have been documented. PATIENTS AND METHODS: We have retrospectively evaluated and characterized these reactions in our patient group by reviewing the files of 1,224 patients exposed to an oxaliplatin-containing regimen in order to provide useful clinical information for diagnosis and management. RESULTS: Three hundred and eight (308) patients who have never been exposed to platinum compounds developed symptoms compatible with a reaction to oxaliplatin that was verified by manifestation of at least similar symptoms on rechallenging. The reactions occurred after the first 5 courses, with a median course number of 9 (range 1-24). These reactions could be distinguished as (1) mild reactions occurring in 195 (63%) patients manifesting with itching and small area erythema either during treatment or within the next hours, and (2) severe reactions occurring in 113 (37%) patients within minutes of drug infusion manifesting with diffuse erythroderma, facial swelling, chest tightness, bronchospasm and changes in blood pressure. Oxaliplatin withdrawal was not required in patients with a mild reaction. Forty-eight (42%) patients having a severe reaction with appropriate premedication and prolongation of the infusion duration could tolerate 2-4 subsequent courses. For the remaining 65 (58%) patients, oxaliplatin withdrawal was inevitable because of the very severe reactions occurring on rechallenging. In addition, 3 patients presented with thrombocytopenia and 3 others with hemolytic anemia, all reversible upon oxaliplatin discontinuation. CONCLUSIONS: Hypersensitivity reactions to oxaliplatin are underestimated. Although the reactions are not frequent during first courses, in extensively pretreated patients, they may become a serious problem. In the majority of patients, drug discontinuation might not be necessary. In patients manifesting a severe reaction, re-exposure to oxaliplatin should be considered only if the patient can tolerate the reaction and there has been clinical benefit from this therapy. Physicians and nursing staff should be aware of the risk and be well prepared.

Combination chemotherapy with carboplatin, paclitaxel and pegylated liposomal doxorubicin for advanced or recurrent carcinosarcoma of the uterus: clinical experience of a single institution.

OBJECTIVES: The purpose of this study was to evaluate the activity and toxicity of carboplatin, paclitaxel and pegylated liposomal doxorubicin combination in advanced or recurrent of the uterine carcinosarcoma. METHODS: Twenty-nine eligible patients with measurable disease were treated with carboplatin [area under the curve (AUC) 5], paclitaxel 175 mg/m(2) and pegylated liposomal doxorubicin 25 mg/m(2) every 3 weeks for 6-8 cycles. RESULTS: There were 10 complete responses (CRs) (34%) and 8 partial responses (PRs) (28%) for an overall response rate (RR) of 62% (95% confidence interval [CI], 43-81%). The median progression-free survival (PFS) was 8.2 months (95% CI, 4.1-12.2 months) and the median overall survival (OS) was 16.4 months (95% CI, 14.7-18.0 months). There was no statistically significant difference between histology and response to therapy. Patients with PS of 0 or 1 had a higher RR than those with worst PS. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 52% of patients and 10% experienced febrile neutropenia. Anemia grade 3 or 4 developed in 27% of patients and thrombocytopenia grade 3 or 4 in 31% of patients. Three patients (10%) developed grade 3 sensory neuropathy and only 2 patients (8%) grade 3 palmar-plantar erythrodysesthesias. No treatment-related deaths were recorded in our series. CONCLUSION: The combination of carboplatin, paclitaxel and pegylated liposomal doxorubicin appears to have activity in advanced, persistent or recurrent endometrial carcinosarcoma with an acceptable toxicity profile.

Hypothyroidism and the aorta. evidence of increased oxidative DNA damage to the aorta of hypothyroid rats.

BACKGROUND: Although it has been suggested that the hypometabolic state is associated with a decrease in oxidative stress, literature data are controversial, revealing an individuality of oxidant status in relation to tissue properties and responsiveness. Hypothyroidism has profound direct and indirect actions on the vascular system, inducing characteristic hemodynamic changes while the aorta represents an important determinant of vascular performance. This study aims to examine the oxidant status on the aorta in chronic experimental hypothyroidism. MATERIALS AND METHODS: Chronic hypothyroidism was successfully induced in 20 male Wistar rats by administration of 0.05% 6-n-propyl 2-thiouracil in their drinking water for 8 weeks. Age-matched euthyroid rats were used as controls. Lipid peroxidation in the serum was determined by the end-product malondialdehyde (MDA). Oxidative damage to genomic DNA of aortic tissue and serum was investigated by measuring 8-oxo-dG, one of the base modifications produced in DNA by the reaction of reactive oxygen species. Serum lipids measurement was performed. RESULTS: A hypothyroid state was confirmed by levels of serum thyroid hormones, lipidemic profile, clinical examination, pathological findings and cardiovascular hemodynamics parameters. Hypothyroidism was associated with a significant increase in lipid peroxidation. (MDA 1.44 +/-0.93 vs 0.64 +/- 0.53 nmol/l, p < 0 .01). Levels of 8-oxo-dG on the aortic ring, expressing the oxidant damage on genomic DNA and in the serum, were observed to be significantly raised in the hypothyroid group compared to controls (8-oxodG(serum) 29.22 +/- 17.78 vs. 17.56 +/- 4.44 ng/ml, p < 0.01; 8-oxo-dG(aorta)11.58 +/- 2.70 vs. 4.09 +/- 1.27 ng/ml, p < 0. 001). A statistical correlation between measurements of 8-oxo-dG in the aorta and serum was found (correlation coefficient = 0.36, p < 0.05). A hyperlipidemic profile in hypothyroid animals was revealed. CONCLUSION: Vascular oxidative stress seems to play a pivotal role in the evolution of vascular pathology. Hypothyroidism was associated with increased DNA oxidative damage to the aorta. Hypercholesterolemia and an increase in mean arterial pressure associated with hypothyroidism may have a contributive role in the accumulation of damage in nuclear DNA of the vascular wall. 8-Oxo-dG is one of the mutagenic base modifications produced in DNA. Although clinical studies in other tissues have indicated a direct correlation between in vivo 8-oxo-dG formation and pathological processes, its role on the vascular wall needs further investigation.

Subsets of patients with advanced gastric cancer responding to second-line chemotherapy with docetaxel-cisplatin.

The role of docetaxel in combination with cisplatin in the management of gastric cancer resistant to first-line chemotherapy has not yet been defined. This multicenter prospective phase II study evaluated the activity and toxicity of the docetaxel-cisplatin combination in gastric cancer patients, whose tumors were primarily resistant to first-line chemotherapy or had tumor recurrence after chemotherapy. Treatment consisted of docetaxel 70 mg/m2 i.v. followed by cisplatin 70 mg/m2 both administered on day one, every three weeks. Thirty-two patients were enrolled in the study. The median age was 60 years and the median performance status (ECOG) was 1. Six (19%) patients had tumor progression during adjuvant chemotherapy, 19 (59%) had tumor recurrence after primary chemotherapy and 7 (22%) had tumor progressing while on first-line chemotherapy. Twenty (62%) patients had received non-platinum agents as first-line chemotherapy, while the rest had received the so-called "new generation" regimen that contained cisplatin. Among 32 patients evaluable for response, there were 5 (16%) (CI 95%-8%-35%) partial responses, all in patients that had received non-platinum agents as first-line chemotherapy. Stable disease was recorded in 8 (25%) and progressive disease in 19 (59%) patients. The median response duration was 4 (range 3-6) months, the median time to progression was 5 (range 3-6) months, the median survival after second-line chemotherapy was 6 (range 2-24) months and the median survival after first-line chemotherapy was 12 (range 4-36) months. Myelotoxicity was the main toxicity with grade 3-4 neutropenia occurring in 19 (59%) of the patients and febrile neutropenia in 4 (12%) patients. G-CSF support was given to 25 (78%) patients. Grade 3-4 thrombocytopenia was recorded in 4 (12%) patients. In conclusion, the combination of docetaxel plus cisplatin appears to be a moderately effective regimen with acceptable toxicity when G-CSF support is provided. According to our results, it seems that patients, whose tumors were not exposed to cisplatin during first-line chemotherapy, were more likely to respond to this regimen.

Correlation between oxidative stress and immunosuppressive therapy in renal transplant recipients with an uneventful postoperative course and stable renal function.

BACKGROUND: Reactive oxygen species (ROS) are important mediators of cellular damage and lipid peroxidation is the most important expression of ROS-induced oxidative stress. Recent studies have suggested that increased plasma malondialdehyde (MDA) levels are a consequence of specific immunosuppressive therapies. This study aims at investigating the relation between oxidative stress and immunosuppressive therapies in renal transplant patients with stable renal function and uneventful postoperative course. METHODS: The study group included 26 renal patients. Two groups of renal transplant recipients, treated with a different combination of immunosuppressive agents were studied (Group A: CyA, MMF, Steroids and Basiliximab, Group B: Tacrolimus, MMF, Steroids and Daclizumab). All patients had an uneventful postoperative course. Plasma MDA levels were measured before transplantation, 1 and 6 months after. Plasma concentration of endogenous creatinine (Cr) was used as a measure of stable renal function. RESULTS: Levels of MDA were increased before the transplantation in all renal patients (MDA: 7.81 +/- 4.81, normal levels: 2.23-4.08 nmol/ml, P < 0.05). Combined therapy with CyA was associated with high values of MDA at 6 months measurement after transplantation. However this tendency of increased MDA levels did not achieve a statistical significance (Group A: 6.97 vs. 9.06 nmol/ml, P>0.05). On the contrary, statistically significant diminution of MDA levels was observed in Group B patients (Tacrolimus-MMF-steroids) at 6 months measurement after transplantation. (Group B: 8.61 vs. 4.11 nmol/ml, P<0.02<0.05). CONCLUSIONS: Immunosuppressive combined therapy with CyA was associated with the high values of MDA that were measured posttransplantly. Our study provides strong evidence that Tacrolimus is significantly associated with improved free radical metabolism.

Weekly Gemcitabine plus Fluorouracil-Folinic Acid Given Weekly for Two Days in Patients with Advanced Pancreatic Cancer : A Phase II Study.

OBJECTIVE: To investigate the efficacy and toxicity of gemcitabine administration followed by the combination of fluorouracil (5-FU) modulated by folinic acid in patients with advanced, symptomatic pancreatic cancer. The main objective was to estimate tumour response and any improvement in patients' quality of life. PATIENTS: The study included 48 evaluable patients with metastatic disease with no prior chemotherapy. The study duration was 3 years. INTERVENTIONS: Gemcitabine 1000 mg/m(2) intravenously was given on days 1 and 8 followed by fluorouracil 350 mg/m(2) intravenously as a bolus biologically modulated by folinic acid 350 mg/m(2) intravenously given on days 1, 2, 8 and 9 in order to develop the conditions for any potential drug synergism. The regimen was administered every 3 weeks for 1 year or until disease progression. RESULTS: Objective partial responses were documented in ten (21%) patients (95% CI 10.5, 35). Twenty-two (46%) patients had stable disease while 16 (33%) patients had progressive disease. The median response duration was 8 months (range 4-20). The median time to progression was 6 months (range 2-24), while the median survival of the group was 7 months (range 3-36) and the probability of surviving beyond 12 months was 20%. Of the 44 patients with tumour-related symptoms who were considered evaluable for clinical-benefit response, 28 (70%) patients had pain improvement, 25 (52%) patients had improvement of their performance status, and nine (28%) patients experienced weight gain during treatment. Serum concentrations of cancer antigen (Ca-19-9) were decreased by more than 50% in 14 (37%) of the 38 assessable patients. Chemotherapy was well tolerated, with mild myelotoxicity. Gastrointestinal toxicity was moderate with mild mucositis. CONCLUSION: The regimen of gemcitabine and fluorouracil administered in this study was well tolerated and showed a moderate antitumour activity and a significant palliative effect on tumour-related symptoms. Because fluorouracil is a low toxicity combination agent for gemcitabine, other forms of the two-drug combination warrant further investigation.

Effects of oral administration of (L)-arginine, (L)-NAME and allopurinol on intestinal ischemia/reperfusion injury in rats.

AIMS: Intestinal ischemia/reperfusion (I/R) injury is implicated in many clinical conditions, and it performs a fundamental role in their pathophysiologies. Oral administration of antioxidants and nitric oxide (NO) donors ameliorate intestinal injury. Here, the effects of l-arginine, allopurinol and N(G)-nitro-l-arginine methyl ester (l-NAME) were investigated. MAIN METHODS: One hundred twenty-eight male Wistar rats were separated into 4 groups and subjected to occlusion of the superior mesenteric artery for 60 min. The Control group did not receive any substance before the surgical operation. However, the 3 other groups received the following: l-arginine (800 mg/kg body weight; l-Arg group), l-NAME (50mg/kg; l-NAME group) or allopurinol (100mg/kg; Allo group). Each substance was given by mouth in 3 equal doses 24, 12 and 1h before the surgical operation. Each group was then divided into 4 subgroups, which underwent different durations of reperfusion (0, 1, 8 or 24h). At the end of each time point, blood and tissue samples were collected, and histological examinations were performed. Serum nitrite and catalase, intestinal tissue myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and nitrotyrosine (NT) levels were determined. KEY FINDINGS: At each reperfusion time point, the Allo group exhibited the mildest histological lesions in contrast to the l-NAME group, which showed the most severe lesions. MPO was decreased significantly in the Allo and l-Arg groups during reperfusion, and allopurinol administration caused earlier and stronger effect. iNOS and NT levels were higher in the l-Arg group and lower in the Allo group. Serum nitrite and catalase were increased in the l-NAME group after 24h. SIGNIFICANCE: Oral administration of allopurinol exerted a strong and protective effect on the intestinal tissue that was subjected to I/R earlier than l-arginine. This finding was also supported with the MPO, iNOS and NT data.

Predictive value of telomerase reverse transcriptase expression in patients with high risk superficial bladder cancer treated with adjuvant BCG immunotherapy.

PURPOSE: We conducted a prospective study to determine whether expression of telomerase reverse transcriptase (hTERT) is associated with recurrence-free-survival (RFS) or development of invasive disease in patients with high risk superficial bladder cancer (SBC) that received adjuvant BCG immunotherapy. METHODS: Thirty patients with high-grade T1 tumors were evaluated. Pre-BCG TURBT and post-BCG specimens were analyzed for hTERT nucleolar expression by immunohistochemistry. RESULTS: Post-BCG hTERT expression was statistically significantly lower than pre-BCG hTERT expression. Pre-BCG hTERT nucleolar staining in more than 75% of cells was associated with worse RFS (9 months vs. not yet reached, P = 0.05), while post-BCG hTERT nucleolar staining in more than 50% of the cells was associated with worse RFS (6 months vs. not yet reached, P = 0.001) and development of invasive disease. In multivariate analysis, post-BCG hTERT expression was independently associated with RFS and development of invasive disease. CONCLUSIONS: Immunohistochemical evaluation of hTERT may help define a subset of high risk SBC patients that will eventually fail BCG and may therefore benefit from early salvage cystectomy.

Association between plasma levels and immunolocalization of cytokines in heart valve lesions: a possible target for treatment?

OBJECTIVE: To compare the distribution of pro-inflammatory cytokines in heart valve lesions with their plasma levels. METHODS: Plasma levels of TNF-alpha and IL-10 were determined in 70 patients with heart valve lesions. TNF-alpha and IL-6 levels were also quantified in tissue specimens obtained from these patients after valve replacement. RESULTS: Plasma concentrations of TNF-alpha and the extent of calcium deposits were significantly higher in patients with aortic valve stenosis compared with individuals with mitral valve stenosis. A direct relationship was demonstrated between TNF-alpha blood and tissue levels. There was an increase in TNF-alpha and IL-6 tissue immunoreactivity with the progression of heart valve disease from mild to advanced inflammation. The increased accumulation of calcium deposits in damaged heart valves correlated with plasma TNF-alpha and IL-10 levels. CONCLUSIONS: The association between plasma and tissue sample cytokine concentrations suggests that plasma cytokine levels reflect the extent and severity of valvular lesions. Statins may attenuate progressive calcific valve stenosis. Statins also affect TNF-alpha and IL-10 plasma levels. These associations may help not only predict the progression but also attenuate the deterioration of valvular lesions. Verification of these results in larger scale studies is required before definite conclusions can be drawn.

Transverse bronchoplasty of the membranous wall after resection of an endobronchial hamartoma.

Lung hamartomas are rare benign tumors of the bronchi. Their management consists of bronchoscopic excision or removal through a thoracotomy and bronchotomy whenever there is a large tumor totally obstructing the bronchial lumen. As a lung-sparing procedure is usually the aim, various bronchoplastic techniques have been described, providing a functional lumen of the repaired bronchus. We describe a simple technique that can be safely undertaken to preserve a satisfactory diameter of the bronchus or trachea and prevent a stenosis at the site of repair.