New and Common Haplotypes Shape Genetic Diversity in Asian Tiger Mosquito Populations from Costa Rica and Panamá.

The Asian tiger mosquito, Aedes albopictus (Skuse) (Diptera: Culicidae), is a vector of several human pathogens. Ae. albopictus is also an invasive species that, over recent years, has expanded its range out of its native Asia. Ae. albopictus was suspected to be present in Central America since the 1990s, and its presence was confirmed by most Central American nations by 2010. Recently, this species has been regularly found, yet in low numbers, in limited areas of Panamá and Costa Rica (CR). Here, we report that short sequences (∼558 bp) of the mitochondrial cytochrome oxidase subunit 1 (COI) and NADH dehydrogenase subunit 5 genes of Ae. albopictus, had no haplotype diversity. Instead, there was a common haplotype for each gene in both CR and Panamá. In contrast, a long COI sequence (∼1,390 bp) revealed that haplotype diversity (±SD) was relatively high in CR (0.72±0.04) when compared with Panamá (0.33±0.13), below the global estimate for reported samples (0.89±0.01). The long COI sequence allowed us to identify seven (five new) haplotypes in CR and two (one new) in Panamá. A haplotype network for the long COI gene sequence showed that samples from CR and Panamá belong to a single large group. The long COI gene sequences suggest that haplotypes in Panamá and CR, although similar to each other, had a significant geographic differentiation (Kst=1.33; P<0.001). Thus, most of our results suggest a recent range expansion in CR and Panamá.

Geographical Distribution of Aedes aegypti aegypti and Aedes aegypti formosus (Diptera: Culicidae) in Kenya and Environmental Factors Related to Their Relative Abundance.

The mosquito Aedes aegypti (L.) is the primary vector of various infectious viruses and is typified by a polymorphic color and abundance of white scales on the body. It has been conventionally separated into two subspecies, Ae. aeg. formosus (Walker) (Aaf) and Ae. aeg. aegypti (L.) (Aaa), with Aaf considered a 'sylvan' form and Aaa a 'domestic' form. Because the two subspecies show different susceptibilities to dengue viruses it is important to understand their distribution. In this study, we collected larvae from artificial and natural habitats in southern Kenya and reared them to adults to morphologically identify subspecies. We describe the geographical distribution and relative abundance of Aaa and Aaf in Kenya, and estimate the environmental factors associated with their distributions by GIS using climate and environment data. A total of 5,243 Ae. aegypti adults were collected from 249 sites, with Aaa accounting for 22% of the specimens. The relative abundance of Aaa was higher in coastal areas versus sites in western Kenya. Aaa abundance was also higher in urbanized than forested areas, which is consistent with known ecology. In contrast and inconsistent with previous studies, both Aaa and Aaf were sympatric in artificial and natural habitats. The high relative abundance of Aaa in coastal areas might derive from old populated cities, climate, and/or introduction from abroad.

Identification of Vortex Cores in Cerebral Aneurysms on 4D Flow MRI.

BACKGROUND AND PURPOSE: The complexity and instability of the vortex flow in aneurysms are factors related to the rupture risk of unruptured cerebral aneurysms. We identified aneurysm vortex cores on 4D flow MR imaging and examined the relationship of these factors with the characteristics of cerebral aneurysms. MATERIALS AND METHODS: We subjected 40 aneurysms (37 unruptured, 3 ruptured) to 4D flow MR imaging. We visualized streamlines with velocities below the threshold-that is, a percentage value of the aneurysm maximum inflow velocity-and progressively decreased the threshold to identify vortex cores as thin, streamline bundles with minimum velocities. Complexity and stability were compared in aneurysms with a smooth surface and those with blebs or daughter sacs. RESULTS: The threshold for visualizing vortex cores ranged from 3% to 13% of the maximum inflow velocity. Vortex cores could be visualized in 38 aneurysms; in 2, they were not visualized through the cardiac cycle. A simple flow pattern (single vortex core) was identified in 27 aneurysms; the other 13 exhibited a complex flow pattern. The cores were stable in 32 and unstable in 8 aneurysms. Significantly more aneurysms with-than-without blebs or daughter sacs had a complex flow pattern (P = .006). Of the 3 ruptured aneurysms, 1 aneurysm had an unstable vortex core; in the other 2, the vortex core was not visualized. CONCLUSIONS: The identification of vortex cores on 4D flow MR imaging may help to stratify the rupture risk of unruptured cerebral aneurysms.

Phase I/II study of irinotecan and UFT for advanced or metastatic colorectal cancer.

UNLABELLED: The aim of this study was to determine the recommended dose of irinotecan in combination with the fixed dose of oral UFT as first-line therapy in patients with advanced or recurrent colorectal cancer, and to evaluate the response rate and overall survival as a phase II study. PATIENTS AND METHODS: Thirteen patients were recruited into a phase I trial. Four doses of irinotecan ranging from 60 to 150 mg/m2/day were administered intravenously on day 1 and day 16 in combination with UFT given orally from day 2 to day 15. In a phase II study, 53 patients received at least one cycle of this therapy. RESULTS: The recommended dose of this combination was determined as irinotecan 120 mg/m2/day and UFT 400 mg/m2/day. Dose-limiting toxicities were neutropenia and prolonged leucopenia. On an intent-to-treat analysis, the response rate in the phase II study was 24.5% (95% confidence interval 13.8% to 38.2%). The median overall survival time was 20.3 months (95% confidence interval, 15.0-22.8 months). Out of 20 patients with stable disease, 17 who received more than 4 cycles of the regimen lived longer than the other 3 patients who received fewer than 3 cycles (p = 0.0353). Hematological adverse events were mainly grade 3/4 neutropenia observed in 6 out of 53 patients. Grade 3 non-hematological toxicities, such as diarrhea, anorexia, nausea/vomiting and alopecia were observed in 6 patients. CONCLUSION: Irinotecan combined with oral UFT was effective and well-tolerated. This regimen may be considered as a first-line therapy for advanced or metastatic colorectal cancer and may result in fairly long survival, even for patients with stable disease.

Anthelmintic activity of Rosmarinus officinalis against Dactylogyrus minutus (Monogenea) infections in Cyprinus carpio.

Monogenean parasites are important ectoparasites of fish, and are responsible for severe economic impacts in the aquaculture industry. They are usually treated with chemicals, but the chemicals can have harmful side effects in the fish and may pose threats to human health. Rosemary (Rosmarinus officinalis) is a common medicinal herb, with antimicrobial and antitumor properties. Here, we examined the anthelmintic activity of rosemary extract against the monogenean (Dactylogyrus minutus) in vitro and in vivo using bath treatment and oral administration. The in vitro experiments showed that parasite survival was affected by both rosemary extract concentration and the solvent (water and ethanol). Parasites were dead at 61.8±5.6 and 7.8±1.4min when exposed to 100 and 200g aqueous rosemary extract solution/L of water respectively. It took 166.7±48.2 and 5.4±1.01min to kill the parasites when exposed to 1 and 32g ethanol rosemary extract solution/L of water respectively. Moreover, pure component of rosemary extract obtained commercially used in in vitro experiments showed that 1,8-Cineole was the most toxic component of the main components tested. Parasite intensity and prevalence in fish exposed to 50 and 100g aqueous rosemary solution/L water for 30min were significantly lower than they were in controls (p<0.05). In oral treatment experiments, diets of Cyprinus carpio were supplemented with eight different concentrations of aqueous rosemary extract. The intensity of parasites was significantly less in fish fed for 30days with feed containing 60, 80 and 100ml aqueous extract/100g feed than in control (p<0.05). Together these results indicate that rosemary is a promising candidate for prevention and control of monogenean infection.

Inflow Jet Patterns of Unruptured Cerebral Aneurysms Based on the Flow Velocity in the Parent Artery: Evaluation Using 4D Flow MRI.

BACKGROUND AND PURPOSE: Inflow jet characteristics may be related to aneurysmal bleb formation and rupture. We investigated the visualization threshold on the basis of the flow velocity in the parent artery to classify the inflow jet patterns observed on 4D flow MR imaging. MATERIALS AND METHODS: Fifty-seven unruptured aneurysms (24 bifurcation and 33 sidewall aneurysms) were subjected to 4D flow MR imaging to visualize inflow streamline bundles whose velocity exceeded visualization thresholds corresponding to 60%, 75%, and 90% of the maximum flow velocity in the parent artery. The shape of the streamline bundle was determined visually, and the inflow jet patterns were classified as concentrated, diffuse, neck-limited, and unvisualized. RESULTS: At the 75% threshold, bifurcation aneurysms exhibited a concentrated inflow jet pattern at the highest rate. At this threshold, the inflow jets were concentrated in 13 aneurysms (group C, 22.8%), diffuse in 18 (group D, 31.6%), neck-limited in 11 (group N, 19.3%), and unvisualized in 15 (group U, 26.3%). In 16 (28.1%) of the 57 aneurysms, the inflow jet pattern was different at various thresholds. Most inflow parameters, including the maximum inflow velocity and rate, the inflow velocity ratio, and the inflow rate ratio, were significantly higher in groups C and D than in groups N and U. CONCLUSIONS: The inflow jet pattern may depend on the threshold applied to visualize the inflow streamlines on 4D flow MR imaging. For the classification of the inflow jet patterns on 4D flow MR imaging, the 75% threshold may be optimal among the 3 thresholds corresponding to 60%, 75%, and 90% of the maximum flow velocity in the parent artery.

Parent artery curvature influences inflow zone location of unruptured sidewall internal carotid artery aneurysms.

BACKGROUND AND PURPOSE: Future aneurysmal behaviors or treatment outcomes of cerebral aneurysms may be related to the hemodynamics around the inflow zone. Here we investigated the influence of parent artery curvature on the inflow zone location of unruptured sidewall internal carotid artery aneurysms. MATERIALS AND METHODS: In 32 aneurysms, the inflow zone location was decided by 4D flow MR imaging, and the radius of the parent artery curvature was measured in 2D on an en face image of the section plane corresponding to the aneurysm orifice. RESULTS: The inflow zone was on the distal neck in 10 (group 1, 31.3%), on the lateral side in 19 (group 2, 59.4%), and on the proximal neck in 3 (group 3, 9.4%) aneurysms. The radius in group 1 was significantly larger than that in group 2 (8.3 mm [4.5 mm] versus 4.5 mm [1.9 mm]; median [interquartile range]; P < .0001). All 7 aneurysms with a radius of >8.0 mm were in group 1. All 18 aneurysms with a radius of <6.0 mm were in group 2 or 3. In two group 3 aneurysms, the inflow zone was located in a part of the neck extending beyond the central axis of the parent artery. CONCLUSIONS: The inflow zone locations of sidewall aneurysms can be influenced by the parent artery curvature evaluated in 2D on an en face image of the section plane corresponding to the aneurysm orifice.

Determination of heterogeneous transcription start points of two c-myc genes from the common carp (Cyprinus carpio).

We determined the heterogeneous transcription start points (tsp) of two c-myc genes from the common carp (Cyprinus carpio), tetraploid teleost, by the oligo-capping method and showed the existence of the first exon. This is the first report on the existence of the first exons of the fish c-myc gene. Transcription of the two carp c-myc genes started from at least four sites in CAM1, locating from -752 to -381bp upstream of the translation start site, and from 12 sites in CAM2, locating from -586 to -413bp upstream respectively. The first introns of CAM1 and CAM2 were deduced to be 335 and 356bp, respectively. They shared 86.9% nt identity, lower than those of the second exons (94.1%), and third exons (92.3%), which suggest that the first exons evolved faster. No nt identities were found between the c-myc first exons of carp and other vertebrates. The putative promoter regions in CAM1 and CAM2 contained no obvious TATA or CCAAT boxes in the expected positions.

Differential expression of max and two types of c-myc genes in a tetraploid fish, the common carp (Cyprinus carpio).

We cloned the full-length cDNA of max gene from the common carp (Cyprinus carpio). The cDNA clone of carp max consists of 1209 bp and contained an ATG-initiated ORF consisting of 156 aa. The carp MAX share 76.7-93.8% aa identity with those of human, mouse, rat, chicken, Xenopus and zebrafish, respectively. The 15 bp alternative splicing was observed in the loop region of helix-loop-helix and is not previously described in mammalian max sequences. Transcripts of max gene were observed in all of the tissues of carp investigated in this study. The highest expression was found in the ovary, and the transcripts in hepatopancreas and heart were low. Two carp c-myc genes (CAM1 and CAM2) showed differential expression pattern. The expression of max was concomitant with CAM2 expression, but not with CAM1. It has been reported that MYC/MAX heterodimer as a regulator of gene expression has been maintained throughout vertebrate evolution, and the expression of c-myc has been concomitant with max expression. In addition, according to phylogenetic analysis, CAM1 is evolving faster than CAM2 after gene duplication. Therefore, this result suggests that CAM1 may evolve to obtain a new function different from c-myc.

Molecular cloning of fresh water and deep-sea rod opsin genes from Japanese eel Anguilla japonica and expressional analyses during sexual maturation.

We have determined the complete cDNA sequences of fresh water rod opsin gene (fwo) and deep-sea rod opsin gene (dso) from Japanese eel Anguilla japonica. The cDNA clones of fwo and dso consisted of 1437 and 1497 nucleotides, respectively. The predicted opsins of both genes consisted of 352 amino acid residues. Southern blot and PCR analyses of genomic DNA indicated that the Japanese eel genome contains only one fwo and one dso and they are intronless. Quantitative RT-PCR analyses revealed that the expression of fwo decreases with sexual maturation while that of dso increases.

Assessment of blood flow in the small intestine by laser Doppler flowmetry: comparison of healthy small intestine and small intestine in Crohn's disease.

Blood flow and blood distribution were investigated in 40 patients with normal small intestine and the relation between blood flow and the morphological features of Crohn's disease was examined in 11 patients with Crohn's disease by laser Doppler flowmetry from the serosal side during surgery. In normal small intestine, blood flow was measured at six points: upper, middle, and lower small intestine, each of the mesenteric borders, and the antimesenteric surface. In Crohn's disease, macroscopically normal tissue and affected lesions were observed in detail by intraoperative endoscopy after blood flow measurement. The blood flow values in the normal small intestine gradually decreased from the upper to the lower small intestine. As the level of inflammation progressed in Crohn's disease the blood flow values gradually decreased; the exudative stage of Crohn's disease (aphthoid ulcer) showed blood flow values that were slightly below those in macroscopically normal tissue. These results are the first to demonstrate decreased blood flow in affected lesions in Crohn's disease and changes in blood flow according to the degree of inflammation in vivo.

Orbitozygomatic temporopolar approach for a high basilar tip aneurysm associated with a short intracranial internal carotid artery: a new surgical approach.

For two cases of a high basilar tip aneurysm accompanied by a short intracranial internal carotid artery, the orbitozygomatic temporopolar approach consisting of an en bloc fronto-orbitozygomatic temporal craniotomy and temporopolar approach was carried out. On angiograms, the height of the bifurcation of an elongated basilar artery and the length of the intracranial internal carotid artery from the interclinoid line between the anterior and posterior clinoid process were 20 mm and 6 mm in Case 1, and 18 mm and 5 mm in Case 2, respectively. The skin flap was separated subfascially to preserve the frontotemporal branch of the facial nerve. The fronto-orbitozygomatic temporal bone flap was made, and a part of the basal bony structures of the orbital roof, the sphenoid ridge, and the temporal bone were removed. The basilar tip aneurysm could be seen and clipped easily by upward and oblique viewing from below through the wide operative space consisting of the less retracted internal carotid and middle cerebral arteries, the oculomotor nerve, the tentorial hiatus, and the emptied anterior temporal fossa obtained by partial division of the temporal bridging veins. The operative procedure is presented in detail and compared with other surgical approaches that have been described previously.

Coagulative and fibrinolytic activation in cerebrospinal fluid and plasma after subarachnoid hemorrhage.

OBJECTIVE: Intrathecal fibrinolytic therapy has been used as one of the anticerebral vasospasm (VS) preventative therapies in patients with subarachnoid hemorrhage (SAH). However, the changes in coagulation and fibrinolysis in the blood and cerebrospinal fluid (CSF) after SAH remain unknown. METHODS: Fifty patients with SAH caused by ruptured cerebral aneurysms were studied postoperatively to detect the serial changes of the thrombin-antithrombin III complex, active plasminogen activator inhibitor (PAI)-1, and tissue plasminogen activator (tPA)-PAI complex (tPA-PAI) activities in the plasma and CSF collected from cisternal drainage catheters. RESULTS: The CSF levels of all parameters and plasma PAI-1 levels were significantly higher in patients with severe SAH than in those with mild SAH. There was no relationship between the CSF and plasma levels of these parameters (except the CSF levels of tPA-PAI) and the initial neurological statuses. The CSF PAI-1 levels increased to greater than 20 ng/ml near the time of the occurrence of cerebral VS, whereas they remained below 20 ng/ml in patients without VS. The CSF tPA-PAI levels showed the highest peak near the time of VS remission. The CSF PAI-1 and tPA-PAI levels were significantly lower in patients with good outcomes than in those with poor outcomes. CONCLUSION: Both the coagulative and fibrinolytic systems were activated in the CSF and plasma after SAH in correlating to the amount of SAH clot. The intrathecal administration of fibrinolytic agents should be started early after surgery, before CSF PAI-1 levels increase, for patients with severe SAH. Patients with CSF PAI-1 levels greater than 20 ng/ml experienced high incidence of VS and poor outcomes.

Intracranial lipoma associated with cerebral saccular aneurysm. Case report.

The authors present a case of lipoma in the sylvian fissure associated with a saccular aneurysm of the middle cerebral artery. The aneurysm was successfully clipped following the partial resection of the tumor. This is the first reported case of this combined pathology. The value of cerebral angiography in this disease entity and the possible etiology of the association of an aneurysm with a lipoma are discussed.

Roles of membrane type 1 matrix metalloproteinase and tissue inhibitor of metalloproteinases 2 in invasion and dissemination of human malignant glioma.

OBJECT: Acquisition of invasive and metastatic potentials through proteinase expression is an essential event in tumor progression. Among proteinases, matrix metalloproteinases (MMPs) are thought to play a key role in tumor progression through the degradation of the extracellular matrix. In the present study, the authors examined the role of MMP-2 (gelatinase A) and membrane type 1 MMP (MT1-MMP), an activator of the zymogen of MMP-2, proMMP-2, together with tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in the invasion of astrocytic tumors in humans. METHODS: Analyses performed using sandwich enzyme immunoassays demonstrated that the production levels of pro-MMP-2 and TIMP-1, but not TIMP-2, are significantly higher in glioblastomas multiforme than in other grades of astrocytic tumors. Quantitative reverse transcription-polymerase chain reaction indicated that MT1-MMP is expressed predominantly in glioblastoma tissues, and its expression levels are significantly enhanced as tumor grade increases. In addition, the expression levels and proMMP-2 activation ratio were remarkably higher in glioblastomas associated with cerebrospinal fluid (CSF) dissemination than in those not associated with CSF dissemination. In contrast, an examination of TIMP-2 levels showed a reverse correlation. Like MT1-MMP, TIMP-1 and TIMP-2 were immunolocalized to neoplastic cells in glioblastoma samples. To study the roles of these molecules in the invasion of astrocytic tumors more fully, stable transfectants expressing the MT1-MMP gene were developed in a U251 human glioblastoma cell line. The MT1-MMP transfectants displayed prominent activation of proMMP-2 and invasive growth in three-dimensional collagen gel; however, mock transfectants and parental cells displayed noninvasive growth without the activation. The invasion and gelatinolytic activity of the transfectants were completely inhibited by addition of recombinant TIMP-2, but not recombinant TIMP-1. CONCLUSIONS: These results indicate that MT1-MMP may contribute to tumor invasion and CSF dissemination of glioblastoma cells on the basis of an imbalance of TIMP-2.

Effects of head elevation on intracranial hemodynamics in patients with ventriculoperitoneal shunts.

The present study was performed to investigate the effects of head elevation on intracranial hemodynamics in patients with ventriculoperitoneal (VP) shunts. The series included 35 hydrocephalic patients and five individuals without hydrocephalus who were used as controls. The hydrocephalic patients were divided into three groups: 15 patients who received VP shunts with a differential-pressure valve (DP group); 11 who received VP shunts with a variable-resistance valve (VR group), and 13 hydrocephalic patients (Hyd group) who had not received shunts (four underwent VP shunts later). The cerebral blood flow (CBF) of patients in the supine and upright positions was measured by technetium-99m hexamethylpropylenamine oxide (HMPAO) single-photon emission computerized tomography in each patient, using the subtraction technique. Cerebral perfusion pressure (CPP) was taken as the difference between the mean arterial blood pressure and ventricular fluid pressure, both referenced to the level of the foramen of Mono. The patients' heads were elevated stepwise from supine to upright. Percent changes of the mean CBF in the upright position (% delta mCBFupr) were 24.9% +/- 4.3% (mean +/- standard error of the mean) in the DP group, 6.2% +/- 2.7% in the VR group, 3.5% +/- 2.6% in the Hyd group, and 4.5% +/- 2.2% in the control group. Patients in the DP group showed a pathological increase in CPP with head elevation, whereas those in the Hyd and VR groups showed a physiological decrease in CPP. Three patients with differential-pressure valves, whose % delta mCBFupr was markedly high, developed low-intracranial pressure syndrome. In conclusion, shunted patients with a DP valve showed pathological intracranial hemodynamics in the upright position. This pathological hemodynamic stress in patients with long-standing differential-pressure valve implantation may induce pathological changes in the brain such as subependymal gliosis.

Immunohistochemical expression of thymidylate synthase as a prognostic factor and as a chemotherapeutic efficacy index in patients with colorectal carcinoma.

BACKGROUND: We assessed the importance of Thymidylate Synthase (TS) expression as a prognostic factor and as an index of therapeutic efficacy in patients with colorectal carcinoma. PATIENTS AND METHODS: TS expression in 66 patients with colorectal carcinoma was immunohistochemically assessed using the anti-TS antibody. TS expression, TS activity, clinicopathological characteristics and survival were evaluated and the correlation among them was studied. RESULTS: The cases studied included 53 patients with low grade positive/negative and 13 patients with high grade positive TS expression. TS levels were 8.69 +/- 10.01 pmol/g and 14.82 +/- 11.38 pmol/g, respectively. There was not correlation between clinicopathological characteristics and TS expression. Considering TS expression, the 5-year survival rate was significantly better for the 75.5% of the patients with low grade positive/negative TS than for the 38.5% of the patients with high grade positive TS (p < 0.01). CONCLUSION: The immunohistochemical expression of TS should be further investigated as a prognostic factor of survival and as an index of chemotherapeutic efficacy in colorectal carcinoma.

Do the expression of CD44, apoptosis and thymidylate synthase inhibition rate correlate with the efficacy of chemotherapy in colorectal cancer?

BACKGROUND: Tegafur-uracil(UFT;TAIHO Pharmaceutical Co.Ltd, Tokyo, Japan) is commonly used to treat digestive cancers. However, the inhibitors of metastasis in this agent have not been fully examined. To investigate a cell adhesion molecule, CD44, which may very well contribute to the pathogenesis of metastasis, we examined the association of CD44 and the thymidylate synthase inhibition rate(TSIR) with prognosis, and examined the expression of apoptosis in patients who were administrated tegafur-uracil before surgery for colorectal cancer. MATERIALS AND METHODS: This study included 66 patients who underwent curative resection of colorectal cancer. In these patients, tegafur-uracil(600 mg) was orally administered every day for 3 to 7 days before surgery, and Tegafur-uracil (400 mg) was orally administered every day for 2 years after surgery. CD44 and apoptosis were detected immunohistochemically and by the TUNNEL method, respectively. The TSIR was calculated from the total TS level, and free TS levels by modified Spears' method using fresh tumor tissue specimens. RESULTS: The TSIR of non-recurrent patients was significantly higher than that of recurrent patients(p < 0.05). The 5-year survival rate in CD44-low grade positive/negative patients (81.6%) was significantly higher than that in CD44-high grade positive patients (46.4%) (p < 0.005). The 5-year survival rate in apoptosis-high grade positive patients (89.7%) was significantly higher than that in apoptosis-low grade positive/negative patients(46.4%) (p < 0.001). With respect to the relationship between CD44 and apoptosis, the proportion of apoptosis-high grade positive patients among CD44-low grade positive/negative patients (55.3%) was significantly higher than that among CD44-high grade positive patients(28.6%) (p < 0.05). In the multivariate analysis, the CD44 expression was suggestive of an independent prognostic factor. CONCLUSION: Based on our results for TSIR, Tegafur-uracil may induce apoptosis of tumor cells in patients by the inhibition of thymidylate synthase. It was suggested that CD44 expression could be used as a possible independent predictor of survival. In addition, it was suggested that UFT, via the inhibition of CD44 expression caused the inhibition of distant metastasis.

Endogenous TNF induction therapy using rTNF-SAM2 in patients with pulmonary metastases from colorectal cancer.

BACKGROUND: Distant metastases from colorectal cancer are generally refractory to conventional therapies, with the exception of surgical resection. The aim of this study was to evaluate the clinical application of endogenous TNF induction therapy by using a mutant TNF (rTNF-SAM2) as a primer in endogenous/exogenous TNF therapy (EET therapy) in patients with pulmonary metastases from colorectal cancer. METHODS: The subjects were 17 patients, 5 of whom underwent EET therapy alone and 12 of whom underwent EET therapy and the administration of anticancer agents. RESULTS: Partial response was observed in 6 patients (50%) who underwent EET therapy with anticancer agents. In seven (53.8%) of 13 patients who showed a high serum CEA value, their CEA levels were considered to be improved. Severe toxic effects occurred in 3 of the patients studied (17.6%). The mean survival was 26.0 months among those with a partial response and 16.6 months among those with no change. No significant difference was observed between these two groups. Histological assessments indicated that tumor necrosis, fibrosis and cellular infiltration tended to intensify in cases treated with EET therapy compared with the cases who received surgery alone. CONCLUSION: EET therapy with anticancer agents is well-tolerated and effective for pulmonary metastases from colorectal cancer.