Ixodes ticks belonging to the Ixodes ricinus complex encode a family of anticomplement proteins.

The alternative pathway of complement is an important innate defence against pathogens including ticks. This component of the immune system has selected for pathogens that have evolved countermeasures. Recently, a salivary protein able to inhibit the alternative pathway was cloned from the American tick Ixodes scapularis (Valenzuela et al., 2000; J. Biol. Chem. 275, 18717-18723). Here, we isolated two different sequences, similar to Isac, from the transcriptome of I. ricinus salivary glands. Expression of these sequences revealed that they both encode secreted proteins able to inhibit the complement alternative pathway. These proteins, called I. ricinus anticomplement (IRAC) protein I and II, are coexpressed constitutively in I. ricinus salivary glands and are upregulated during blood feeding. Also, we demonstrated that they are the products of different genes and not of alleles of the same locus. Finally, phylogenetic analyses demonstrate that ticks belonging to the Ixodes ricinus complex encode a family of relatively small anticomplement molecules undergoing diversification by positive Darwinian selection.

Phase II study of cisplatin, gemcitabine and 5-fluorouracil in advanced pancreatic cancer.

BACKGROUND: The aim of this study was to determine the activity of the combination of cisplatin, gemcitabine and 5-fluorouracil (5-FU) as therapy for metastatic or locally advanced inoperable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with histologically proven advanced or metastatic pancreatic adenocarcinoma received first-line chemotherapy comprising cisplatin (20 mg/m2 on days 1, 8, 15, 22, 29 and 36), gemcitabine (1000 mg/m2 on days 1, 8, 29 and 36) and 5-FU (200 mg/m2 as continuous infusion on days 1-42) every 56 days. RESULTS: A total of 34 patients were studied. Eighty courses were administered (median two courses per patient). Among 32 patients evaluable for response, two patients had a complete response and four a partial response for an overall response rate of 19% (95% confidence interval 7% to 36%). Thirteen patients had stable disease (40%) and 13 progressed. Median progression-free survival was 4.7 months, median survival 9.0 months and 26% of patients achieved 1-year survival. Ten of 25 patients (40%) with pain at presentation had a sustained reduction of analgesic consumption. The principal grade 3/4 toxicities were neutropenia, thrombocytopenia, anaemia and mucositis, occurring in 24%, 21%, 9% and 3% of patients. CONCLUSION: This schedule seems well tolerated and active in pancreatic cancer and worthwhile of further evaluation.

Chemohyperthermia for advanced abdominal malignancies: a new procedure with closed abdomen and previously performed anastomosis.

ChemoHyperthermic Peritoneal Perfusion (CHPP) after cytoreductive surgery is a relatively new procedure in the treatment of abdominal carcinomatosis or sarcomatosis. An assessment of the CHPP technique performed on 20 patients suffering from abdominal malignancies was carried out. After surgical debulking and gastrointestinal anastomosis, two Tenckhoff catheters were positioned for the immediate performance of CHPP, which was carried out at 42-43 degrees C for 1 h, after closing the abdomen. In 19 assessable patients, 47.3% and 36.8% complete responses (CR) were recorded at 1 and 6 months, respectively, with responses of 37.5% in patients affected with gastrointestinal cancer and 50% in patients affected with ovarian cancer. CR were obtained only in patients who had undergone accurate peritoneal debulking. Survival rate for gastrointestinal and ovarian cancer was 68% at 12 months. Patients who underwent radical cytoreductive surgery are all alive at a follow-up median time of 17 months. Two anastomotic leakages with spontaneous recovery were observed, along with one hydrothorax, which was immediately drained during the procedure, three cases of chemotherapic gastrointestinal toxicity, one sepsis, one renal failure that required a transient dialysis, and one cholecystitis that required cholecystectomy. One patient died 30 days after CHPP of a cardiac ischaemia not strictly related to the surgical procedure. In the authors' experience, CHPP with closed abdomen after reconstructive gastrointestinal surgery is a safe and feasible treatment with acceptable side effects.

Combined regional and systemic chemotherapy by a mini-invasive approach for the treatment of colorectal liver metastases.

From February 1996 to December 1998, 95 patients affected with colorectal liver metastases underwent the positioning of an intraarterial hepatic catheter by a transcutaneous subclavian access, under local anesthesia. All patients were evaluated for catheter implantation complications. Moreover, 61 patients of 95 treated at our center were retrospectively evaluated for results of chemotherapy performed with two different schedules of hepatic artery infusion (HAI) combined with systemic chemotherapy (SC). Eleven patients (group A) were treated with combined SC (5-fluorouracil continuous infusion) and HAI (floxuridine). A subsequent 50 patients underwent HAI (floxuridine, 4 cycles) followed, if a response or stable disease were observed, by combined SC and HAI (group B). Three cases of aneurysm of subclavian artery occurred, which were treated by the positioning of a radiologic arterial stent and the reimplantation of the catheter by a femoral access. Thrombosis of the hepatic artery was registered in four cases. We observed 10.5% occurrence of dislocation of the catheter, which was always moved again in the hepatic artery. In group A, with 45% clinical objective response rate and 10% stable disease rate, median survival time and median time to extrahepatic progression were 9 and 6 months, respectively. In group B, we observed 44% clinical objective responses and 26% stable disease after HAI. Patients without disease progression and therefore submitted to sequential SC and HAI had a median survival time of 21 months and a median time to extrahepatic progression of 16 months. The development of the mini-invasive technique of implantation of an arterial port can avoid laparotomy for HAI. Percutaneous implantation of an arterial port has a low rate of technical complications. HAI followed by combined systemic and regional chemotherapy has good results in terms of survival and time to extrahepatic progression.

Intra-arterial continuous infusion for treatment of pancreatic and biliary tract cancer.

BACKGROUND: Systemic chemotherapy does not satisfactorily improve the poor prognosis of pancreas and biliary tract cancer unresectable or metastatic to the liver. Intra-arterial infusion of antineoplastic agents can give higher concentrations to the tumor and slighter concentrations to the whole body, with a potential of efficacy and lower toxicity, due to the hepatic clearance. METHODS: Based on a safe and ambulatorial technique of transcutaneous arterial port implantation, this study was designed to evaluate feasibility and toxicity of 5-fluorouracil (5-FU) intra-arterial continuous infusion combined with systemic gemcitabine with dose escalation. Seventeen patients affected by pancreatic (14) or biliary tract (3) cancer received up to six cycles of treatment. Treatment consisted of intravenous gemcitabine on d 1 and 8 and intra-arterial 5-FU continuous infusion on d 1-14 every 21 d. Dose-escalation levels were 900 and 1000 mg/m2 for gemcitabine and 8, 10, 12, 15, and 17 mg/kg/d for 5-FU. Consecutive cohorts of three patients were planned at each dose level. RESULTS: Gastrointestinal toxicity (vomiting and diarrhea [3rd-4th degree] and gastritis), constituted the dose-limiting toxicity, with a maximum-tolerated dose of 1000 mg/m2 for gemcitabine and 15 mg/kg/d for 5-FU. Hematological toxicity was present in a minority of patients. No patient had acute or later complications such as arterial thrombosis related to the implanted arterial port, sclerosis cholangitis, or chemical cholecistitis. CONCLUSION: 5-Fluorouracil intra-arterial continuous infusion, combined with systemic gemcitabine, seems to be a feasible and safe regimen that could give interesting results in pancreatic cancer.

Technetium-99m labelled macroaggregated albumin arterial catheter perfusion scintigraphy: prediction of gastrointestinal toxicity in hepatic arterial chemotherapy.

Gastrointestinal toxicity from hepatic arterial infusion (HAI) of floxuridine in patients with liver metastases is probably due to extrahepatic perfusion or to partial escape of the drug from first-pass liver extraction. The aim of this study was to verify the role of technetium-99m-labelled macroaggregated albumin (99mTc-MAA) arterial catheter perfusion scintigraphy at the beginning of each chemotherapy cycle in decreasing or preventing gastrointestinal toxicity. We studied 167 consecutive patients. On the basis of the scintigraphic follow-up and the presence or absence of an intrahepatic arteriovenous shunt (IHAVS), we classified our patients into the following groups: (1) FU+ hepatic distribution pattern (DP), comprising 29 patients with regular scintigraphic follow-up who showed the expected distribution pattern at each control or a distribution pattern with transient alterations (extrahepatic escape) promptly reversed by the replacement of the catheter. Among these 29 patients there was one case of gastrointestinal toxicity. (2) FU- hepatic DP, comprising 128 patients who were evaluated with 99mTc-MAA only at the beginning of the first chemotherapy cycle, showed the expected distribution pattern and underwent HAI with no further scintigraphic evaluation. Among these 128 patients there were 28 cases of gastrointestinal toxicity. (3) FU+ pulmonary DP, comprising three patients with abnormally elevated pulmonary uptake (higher than 5%) and with regular scintigraphic follow-up. There were two cases of gastrointestinal toxicity among these three patients. (4) FU- pulmonary DP, comprising seven patients with abnormally elevated pulmonary uptake and without regular scintigraphic follow-up. There were four cases of gastrointestinal toxicity among these seven patients. The incidence of toxicity was significantly higher in group FU- hepatic DP than in group FU+ hepatic DP (21.9% vs 3.4%, P<0.05). In both the FU+ pulmonary DP and FU- pulmonary DP groups, the incidence of gastrointestinal toxicity was higher than 50%, with no significant difference between them. We conclude that, when performing 99mTc-MAA perfusion scintigraphy, the presence of an abnormally elevated pulmonary uptake (IHAVS higher than 5%) is the most relevant positive prognostic index for the development of gastrointestinal toxicity. Furthermore, in the absence of abnormal pulmonary uptake (IHAVS lower than 5%), strict scintigraphic follow-up is useful since it is able to promptly diagnose the presence of extrahepatic abdominal perfusion and thus to prevent the occurrence of gastrointestinal toxicity.

Percutaneous implantation of arterial Port-a-cath via trans-subclavin access.

BACKGROUND: Hepatic artery infusion is the best choice of treatment for colorectal liver metastases, but it could be suggested for other hepatic tumors or locally advanced pancreatic cancer. The need of a laparotomy for the positioning of the arterial catheter has been the limiting factor for the diffusion of regional treatments. MATERIALS AND METHODS: 170 patients suffering from primary or secondary liver tumours and pancreatic or bile ducts cancer, underwent the positioning of intra-arterial hepatic part-a-cath by a transcutaneous subclavian access in local anaesthesia. In 163 patients, a catheter was placed into the hepatic artery, 4 into the splenic and 3 into the gastroduodenal artery. RESULTS: The procedure was performed successfully in all patients. We observed 5 aneurysms of the subclavian artery and 9 thrombosis of the hepatic artery. Only in 7 patients was arterial infusion suspended for technical complications. We observed 10.6% of dislocation, but dislodged catheters were always moved again into the hepatic artery. CONCLUSIONS: The development of percutaneous techniques of arterial port-a-cath implantation could enlarge the indication of regional chemotherapy.

Prognostic implications of detection of troponin I in patients with unstable angina pectoris.

In our study, troponin I was not a predictor of cardiac events and a negative troponin I test did not exclude the presence of severe coronary artery disease. A positive troponin I test in patients with unstable angina identified a subgroup with probable, more active coronary disease (with higher levels of C-reactive protein).

Transaxillary access to perform hepatic artery infusion (HAI) for secondary or primitive hepatic tumors.

There is a renewed interest in locoregional chemotherapy for hepatic tumors; trials in progress are experimenting with new therapeutic protocols with an approach combining different systems of infusion (HAI and systematic) or with the use of HAI as adjuvant or neoadjuvant of the surgical treatment or cryosurgical treatment of the hepatic metastases from colo-rectal cancer. However, HAI is practicable principally with the implantation of a catheter in the hepatic artery (port of Infusaid) by laparotomic access. This intervention limits wide-scale use of the infusion method, traditionally less toxic and more efficient in terms of results than systemic treatment. Limited experience of percutaneous access for HAI required more catheterisation with repeated puncturing of the artery and later necessity of surgery in cases of HAI with continuous spraying. Motivated by the first experience of certain authors from Chiba University, we have devised a system of catheterisation of the hepatic artery with transcutaneous access, with subcutaneous port that allows the use of HAI without recourse to the usual intervention. Access is made through the left axillary artery; the positioning of the catheter is in the hepatic artery with possible embolization of the collateral or abnormal hepatic artery that could hamper complete diffusion of the drug to the liver, or increase to toxicity of the method. The implantation is done in day-surgery. In the cases performed up to now there have been no complications regarding the method and the catheters function all perfectly thanks to the collaboration of ematologists to avoid possible thrombosis of the catheters.

[Extranodal non-Hodgkin's lymphomas. Review and our experience]. / I linfomi non-Hodgkin extranodali. Review e nostra esperienza.

The authors report their experience concerning 12 cases of extranodal lymphoma (6 gastric, 1 duodenal, 2 ileal, 1 rectal, 1 splenic, 1 mammary). Extranodal lymphomas are increasing because of the high number of patients with AIDS and new extra-European immigration. Surgery is important not only for diagnosis, but above all for therapy. The great majority of extranodal lymphomas is diffuse rather nodular. Diffuse histiocytic type is the most commun pathologic feature. Prognosis of gastroenteric lymphomas is better than adenocarcinomas of gastrointestinal tract. The surgical techniques are the same as those used for the others tumors, and combined-modality therapy appears superior to local therapy alone for patients with extranodal disease characterized by unfavorable histology, site or stage. The classification is that of Ann Arbor, but for many authors the TNM system was an useful predictor of survival in patients treated with surgery.

Oxidative damage in human liver transplantation.

The aim of this study was to evaluate oxygen-dependent hepatic reperfusion injury in humans following orthotopic liver transplantation. To this end, a number of blood indices of impaired tissue redox balance were monitored in 19 adult patients for 3 weeks after liver transplantation. Both red cell malonaldehyde and plasma lipid peroxides increased significantly soon after organ reperfusion. This finding was consistently accompanied by decreased plasma vitamin E and red cell total glutathione. A peak of oxidative stress, as measured by the parameters monitored, was evident within 24 h after reperfusion, together with a maximum expression of cytolysis, as measured by plasma alanine aminotransferase. The occurrence of redox imbalance after hepatic reperfusion was shown to be linearly related to irreversible cell damage. As regards the low plasma levels of the two antioxidants after reperfusion, only that of vitamin E appeared statistically related to oxidative stress. With the background of an increasing body of proof, mainly from animal models, the involvement of toxic oxygen metabolites in hepatic cytolysis following orthotopic liver transplantation appears likely. The statistical correlation among the markers of redox imbalance monitored indicates their combined use in further investigation.

Oxidative stress in the development of human ischemic hepatitis during circulatory shock.

An increasing number of studies support the involvement of free radical-mediated oxidative reactions in the pathogenesis of tissue injury following ischemia reperfusion. In particular, a condition of oxidative stress is evident in patients with circulatory shock, a disease process often complicated by progressive organ failure sustained by inflammatory reactions. In all shock patients without signs of organ failure, a consistent increase of intermediate and final products of lipid peroxidation (lipid peroxides and aldehydes respectively) was observed. Impairment of the redox equilibrium in the tissues of these patients was confirmed by a significant reduction of glutathione and vitamin E hematic concentrations. Moreover, a selective increase of plasma aldehyde-protein adducts, actual proof of oxidative damage of macromolecules, is only present in the shock patients who, in addition, show hepatic cytolysis (ischemic hepatitis) as estimated by plasma levels of LDH5 isoenzyme. Aldehyde adducts well mark the progression of the disease towards multiple organ failure. Finally, the good statistical correlation between aldehyde-modified proteins and LDH5, as well as their distinct behaviour in control and ischemic hepatitis, support the involvement of oxidative damage in the expression and worsening of circulatory shock.

[Breast carcinoma in the elderly patient: which treatment?]. / Carcinoma mammario nell'anziano: quale trattamento?

We here describe our experience of the treatment of "breast cancer" in the elderly. The results in this group of patients (37 over 75 years) are like the younger group if: the local control is done; hormonotherapy is prescribed; chemotherapy is done even in the 70-80-year-old group. If a radical mastectomy isn't impossible in the patients over 80, even a simple mastectomy is safe. In this patients a conservative local treatment of the breast is not mandatory. Our over-75-year-old patients have no psychological problem related to mastectomy. They often don't accept obligatory radiotherapy after the conservative treatment of breast cancer, and moreover the breast cancer in the elderly is usual smaller, fibrotic and bigger than 3 cm. Lymph nodal status isn't important for overall survival, but only for the eventual chemotherapeutic treatment, so in patients over 80 year-old simple mastectomy is sufficient because we don't use chemotherapy for the general conditions of the same. The local control of axillary lymph nodes is obtained with radiotherapy if necessary. Screening for breast cancer must also include 70-75-year-old patients. Why is the breast cancer in elderly like the others patients? Some authors have seen that the immuno-reaction around the cancer in elderly is less than the same reaction observed in younger patients. So in the elderly there is a smaller production of "growth factors" important for the growth of the tumor and of "angiogenesis factor", fundamental for the initial growth of the cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Impairment of erythropoiesis in rats exposed to environmental pollutants.

The extent to which halogen compounds interfere with erythropoiesis is still unclear. This paper reports an evaluation of the effect of repeated exposure to carbon tetrachloride (CCl4) in air on red blood cell (RBC) creatine concentration. Creatine is neither synthetised nor metabolised in circulating RBC and decreases over the lifespan of red cells. It can thus be taken as a reliable indicator of mean RBC age, and hence of cell viability and bone marrow efficiency. Following inducement of hemolysis with phenylhydrazine (PHH) to stimulate erythropoiesis, creatine levels rose in the controls. This increase was significantly less in the CCl4-treated animals. It is not yet certain whether this inhibition reflects impaired marrow efficiency, enhanced RBC destruction in the marrow, or block of the release of mature RBC. The fact that such inhibition takes place, however, is of importance as a predictive factor in environmental toxicology, since it appears before changes in other blood parameters or signs of liver toxicity are observed.