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Cancer cell metabolism leads to a uniquely acidic microenvironment in solid tumors, but exploiting the labile extracellular pH differences between cancer and normal tissues for clinical use has been challenging. Here we describe the clinical translation of ONM-100, a nanoparticle-based fluorescent imaging agent. This is comprised of an ultra-pH sensitive amphiphilic polymer, conjugated with indocyanine green, which rapidly and irreversibly dissociates to fluoresce in the acidic extracellular tumor microenvironment due to the mechanism of nanoscale macromolecular cooperativity. Primary outcomes were safety, pharmacokinetics and imaging feasilibity of ONM-100. Secondary outcomes were to determine a range of safe doses of ONM-100 for intra-operative imaging using commonly used fluorescence camera systems. In this study (Netherlands National Trial Register #7085), we report that ONM-100 was well tolerated, and four solid tumor types could be visualized both in- and ex vivo in thirty subjects. ONM-100 enables detection of tumor-positive resection margins in 9/9 subjects and four additional otherwise missed occult lesions. Consequently, this pH-activatable optical imaging agent may be clinically beneficial in differentiating previously unexploitable narrow physiologic differences. It is well known that the pH of tumor tissue is lower than that of the corresponding normal adjacent tissue. Here, the authors report a clinical trial of a pH activatable nanoparticle for imaging tumours. [ABSTRACT FROM AUTHOR]

Background: Measurement of colonic transit time (CTT) is sometimes used in the evaluation of patients with chronic constipation. Aim: To investigate the relation between symptoms and CTT, and to assess the importance of symptoms and CTT in predicting outcome. Methods: Between 1995 and 2000, 169 consecutive patients (median age 8.4 years, 65% boys) fulfilling the criteria for constipation were enrolled. During the intervention and follow up period, all kept a diary to record symptoms. CTT was measured at entry to the study. Results: At entry, defecation frequency was lower in girls than in boys, while the frequency of encopresis episodes was higher in boys. CTT values were significantly higher in those with a low defecation frequency (&les;/week) and a high frequency of encopresis (&ges;2/day). However, 50% had CU values within the normal range. Successful outcome occurred more often in those with a rectal impaction. CTT results <100 hours were not predictive of outcome. However, those with CTT >100 hours were less likely to have had a successful outcome. Conclusion: The presence of a rectal impaction at presentation is associated with a better outcome at one year. A CTT >100 hours is associated with a poor outcome at one year. [ABSTRACT FROM AUTHOR]

Abstract Background Cutaneous leiomyosarcoma (CLM) is a very rare smooth muscle tumour that accounts for about 2–3% of all superficial soft tissue sarcomas. Although the development of various malignancies in scar tissue is well known, we report the first case of a CLM developing in a small pox scar. Case presentation A 66-year-old man presented with a painless, slow-growing lump in a small pox scar on his left shoulder. Histological biopsies showed the lesion to be a primary, well-differentiated cutaneous leiomyosarcoma. A CT scan of the thorax was conducted, which showed no signs of metastases. The complete lesion was then surgically excised, and histopathological examination revealed a radically excised cutaneous type leiomyosarcoma After 13 months’ review the patient was doing well with no evidence of tumour recurrence. Conclusions This is the first report of a CLM arising in a small pox scar. Although the extended time interval between scarring and malignant changes makes it difficult to advise strict follow-up for patients with small pox scars, one should be aware that atypical changes and/or symptoms occurring in a small pox scar could potentially mean malignant transformation.

The genus Gambierdiscus produces an array of bioactive hydrophilic and lipophilic secondary metabolites that range in mode of action and toxicity. In this study, the metabolite fingerprint was mapped for thirteen Gambierdiscus , five Coolia and two Fukuyoa species (34 isolates) by assessing the production of 56 characterised secondary metabolites. Gambierdiscus polynesiensis was the only species to produce Pacific-ciguatoxin-3B (P-CTX3B), P-CTX3C, iso-P-CTX3B/C, P-CTX4A, P-CTX4B and iso-P-CTX4A/B. G. australes produced maitotoxin-1 (MTX-1) and MTX-5, G. cheloniae produced MTX-6 and G. honu produced MTX-7. Ubiquitous production of 44-methylgambierone was observed amongst all the Gambierdiscus isolates, with nine species also producing gambierone. Additional gambierone analogues, including anhydrogambierone (tentatively described herein), were also detected in all Gambierdiscus species, two Coolia and two Fukuyoa species. Gambieroxide was detected in G. lewisii and G. pacificus and gambieric acid A was detected in ten Gambierdiscus species, with G. australes (CAWD381) being the only isolate to produce gambieric acids A-D. This study has demonstrated that the isolates tested to date produce the known CTXs or MTXs, but not both, and highlighted several species that produced 'unknown' compounds displaying characteristics of cyclic polyethers, which will be the focus of future compound discovery efforts.

Identifying compounds responsible for the observed toxicity of the Gambierdiscus species is a critical step to ascertaining whether they contribute to ciguatera poisoning. Macroalgae samples were collected during research expeditions to Rarotonga (Cook Islands) and North Meyer Island (Kermadec Islands), from which two new Gambierdiscus species were characterized, G. cheloniae CAWD232 and G. honu CAWD242. Previous chemical and toxicological investigations of these species demonstrated that they did not produce the routinely monitored Pacific ciguatoxins nor maitotoxin-1 (MTX-1), yet were highly toxic to mice via intraperitoneal (i.p.) injection. Bioassay-guided fractionation of methanolic extracts, incorporating wet chemistry and chromatographic techniques, was used to isolate two new MTX analogs; MTX-6 from G. cheloniae CAWD232 and MTX-7 from G. honu CAWD242. Structural characterization of the new MTX analogs used a combination of analytical chemistry techniques, including LC-MS, LC-MS/MS, HR-MS, oxidative cleavage and reduction, and NMR spectroscopy. A substantial portion of the MTX-7 structure was elucidated, and (to a lesser extent) that of MTX-6. Key differences from MTX-1 included monosulfation, additional hydroxyl groups, an extra double bond, and in the case of MTX-7, an additional methyl group. To date, this is the most extensive structural characterization performed on an MTX analog since the complete structure of MTX-1 was published in 1993. MTX-7 was extremely toxic to mice via i.p. injection (LD 50 of 0.235 µg/kg), although no toxicity was observed at the highest dose rate via oral administration (155.8 µg/kg). Future research is required to investigate the bioaccumulation and likely biotransformation of the MTX analogs in the marine food web.

Understanding the toxicity and production rates of the various secondary metabolites produced by Gambierdiscus and cohabitating benthic dinoflagellates is essential to unravelling the complexities associated with ciguatera poisoning. In the present study, a sulphated cyclic polyether, gambierone, was purified from Gambierdiscus cheloniae CAWD232 and its acute toxicity was determined using intraperitoneal injection into mice. It was shown to be of low toxicity with an LD 50 of 2.4 mg/kg, 9600 times less toxic than the commonly implicated Pacific ciguatoxin-1B, indicating it is unlikely to play a role in ciguatera poisoning. In addition, the production of gambierone and 44-methylgambierone was assessed from 20 isolates of ten Gambierdiscus , two Coolia and two Fukuyoa species using quantitative liquid chromatography-tandem mass spectrometry. Gambierone was produced by seven Gambierdiscus species, ranging from 1 to 87 pg/cell, and one species from each of the genera Coolia and Fukuyoa , ranging from 2 to 17 pg/cell. The production of 44-methylgambierone ranged from 5 to 270 pg/cell and was ubiquitous to all Gambierdiscus species tested, as well as both species of Coolia and Fukuyoa . The relative production ratio of these two secondary metabolites revealed that only two species produced more gambierone, G. carpenteri CAWD237 and G. cheloniae CAWD232. This represents the first report of gambierone acute toxicity and production by these cohabitating benthic dinoflagellate species. While these results demonstrate that gambierones are unlikely to pose a risk to human health, further research is required to understand if they bioaccumulate in the marine food web.

Most marine biotoxins are produced by microalgae. The neurotoxin tetrodotoxin (TTX) has been reported in many seafood species worldwide but its source is unknown, making accumulation and depuration studies in shellfish difficult. Tetrodotoxin is a water-soluble toxin and cannot be directly ingested by shellfish. In the present study, a method was developed which involved binding TTX to solid particles of humic acid and encapsulating them in agar-gelatin capsules. A controlled quantity of TTX-containing microcapsules (size range 20-280 μm) was fed to Paphies australis , a bivalve known to accumulate TTX in the wild. The TTX-containing microcapsules were fed to P. australis every second day for 13 days. Ten P. australis (including five controls fed non-toxic microalgae) were harvested after 7 days and ten after 13 days. Paphies australis accumulated TTX, reaching concentrations of up to 103 µg kg -1 by day 13, exceeding the European Food Safety Authority recommended concentration of 44 μg kg -1 in shellfish. This novel method will allow future studies to explore the effects, accumulation and depuration rates of TTX in different animals and document how it is transferred through food webs.

The cyanobacterium Microcoleus autumnalis grows as thick benthic mats in rivers and is becoming increasingly prevalent around the world. M. autumnalis can produce high concentrations of anatoxins and ingestion of benthic mats has led to multiple dog deaths over the past two decades. M. autumnalis produces a suite of different anatoxin congeners including anatoxin-a (ATX), dihydroanatoxin-a, (dhATX), homoanatoxin-a and dihydrohomoanatoxin-a. Benthic mat samples often contain high levels of dhATX, but there is little toxicology information on this congener. In the present study, natural versions of dhATX and ATX were purified from cyanobacteria to determine the acute toxicity by different routes of administration using mice. Nuclear magnetic resonance spectroscopy was used to confirm the putative structure of dhATX. By intraperitoneal (ip) injection, the median lethal dose (LD 50 ) for dhATX was 0.73 mg/kg, indicating a reduced toxicity compared to ATX (LD 50 of 0.23 mg/kg). However, by oral administration (both gavage and feeding), dhATX was more toxic than ATX (gavage LD 50 of 2.5 mg/kg for dhATX and 10.6 mg/kg for ATX; feeding LD 50 of 8 mg/kg for dhATX and 25 mg/kg for ATX). The relative nicotinic acetylcholine receptor-binding affinities of ATX and dhATX were determined using the Torpedo electroplaque assay which showed consistency with the relative toxicity determined by ip injection. This work highlights that toxicity studies based solely on ip injection may not yield LD 50 values that are relevant to those derived via oral administration, and hence, do not provide a good estimate of the risk posed to human and animal health in situations where oral ingestion is the likely route of exposure. The high acute oral toxicity of dhATX, and its abundance in M. autumnalis proliferations, demonstrates that it is an important environmental contaminant that warrants further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The goal of this retrospective observational study was to determine the impact of the extent of peritoneal disease on 1-year healthcare costs in patients with colorectal peritoneal metastases (PM) who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). The extent of peritoneal disease, expressed by the Peritoneal Cancer Index (PCI), directly affects the complexity of CRS + HIPEC and ultimately survival outcomes. The impact of the PCI on treatment-related healthcare costs remains unknown., Methods: Data from patients with colorectal PM who underwent CRS + HIPEC between January 2012 and November 2017 were extracted retrospectively from an institutional database. Patients were divided into four subgroups with PCI scores ranging from 0 to 20. Treatment-related costs up to 1 year after CRS + HIPEC were obtained from the financial department. Differences in costs and survival outcomes were compared using the χ 2 test and Kruskal-Wallis H test., Results: Seventy-three patients were included (PCI 0-5, 22 patients; PCI 6-10, 19 patients; PCI 11-15, 17 patients; PCI 16-20, 15 patients). Median (i.q.r.) costs were significantly increased for the PCI 11-15 and PCI 16-20 groups (€51 029 (42 500-58 575) and €46 548 (35 194-60 533) respectively) compared with those for the PCI 0-5 and PCI 6-10 groups (€33 856 (25 293-42 235) and €39 013 (30 519-51 334) respectively) (P = 0·009)., Conclusion: Treatment-related healthcare costs are significantly increased among patients with extensive tumour burden (PCI score 10 or above) who undergo CRS + HIPEC for the treatment of colorectal PM., (© 2020 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of British Journal of Surgery Society.)

Background: Measles is an infectious disease providing lifelong immunity. Epidemics periodically occur among unvaccinated orthodox Protestants in the Netherlands. During the 2013/2014 epidemic, 17% of the reported patients was over 14 years old. Apparently, they did not catch measles during the previous 1999/2000 epidemic and remained susceptible. We wanted to identify risk factors for this so-called persisting measles susceptibility, and thus risk factors for acquiring measles at older age with increased risk of complications., Methods: A case-control study was performed among unvaccinated orthodox Protestants born between 1988 and 1998; cases had measles in 2013/2014, controls during or before 1999/2000. Associations between demographic, geographical and religion-related determinants and persisting measles susceptibility were determined using univariate and multivariable logistic regression. Analyses were stratified in two age-groups: infants/toddlers and primary school-aged children during the 1999/2000 measles epidemic., Results: In total, 204 cases and 563 controls were included. Risk factors for persisting measles susceptibility for infants/toddlers in 1999/2000 were belonging to a moderately conservative church, absence of older siblings and residency outside low vaccination coverage (LVC)-municipalities. Risk factors for primary school-aged children were residency outside LVC-municipalities and attendance of non-orthodox Protestant primary school., Conclusion: Unvaccinated orthodox Protestant adolescents and adults who resided outside the LVC-municipalities, did not attend an orthodox Protestant primary school, had no older siblings and belonged to a moderately conservative church were at risk for persisting measles susceptibility and, thus, for acquiring measles at older age with increased risk of complications. For this subgroup of orthodox Protestants targeted information on vaccination is recommended.

In fisheries management-as in environmental governance more generally-regulatory arrangements that are thought to be helpful in some contexts frequently become panaceas or, in other words, simple formulaic policy prescriptions believed to solve a given problem in a wide range of contexts, regardless of their actual consequences. When this happens, management is likely to fail, and negative side effects are common. We focus on the case of individual transferable quotas to explore the panacea mindset, a set of factors that promote the spread and persistence of panaceas. These include conceptual narratives that make easy answers like panaceas seem plausible, power disconnects that create vested interests in panaceas, and heuristics and biases that prevent people from accurately assessing panaceas. Analysts have suggested many approaches to avoiding panaceas, but most fail to conquer the underlying panacea mindset. Here, we suggest the codevelopment of an institutional diagnostics toolkit to distill the vast amount of information on fisheries governance into an easily accessible, open, on-line database of checklists, case studies, and related resources. Toolkits like this could be used in many governance settings to challenge users' understandings of a policy's impacts and help them develop solutions better tailored to their particular context. They would not replace the more comprehensive approaches found in the literature but would rather be an intermediate step away from the problem of panaceas., Competing Interests: The authors declare no conflict of interest.

Three patients presented some decades after severe traumatic injury with atypical bowel symptoms which were caused by a giant myelolipoma of the adrenal gland. The aetiology of this rare, benign and generally asymptomatic tumour is virtually unknown at present and several hypotheses have been devised. This report describes a possible association between high-energy trauma and the development of giant myelolipomas, further contributing to the hypothesis that severe systemic stress could be an aetiological factor in the development of an adrenal myelolipoma., (2014 BMJ Publishing Group Ltd.)

Public health authorities are required to prepare for future threats and need predictions of the likely impact of climate change on public health risks. They may get overwhelmed by the volume of heterogeneous information in scientific articles and risk relying purely on the public opinion articles which focus mainly on global warming trends, and leave out many other relevant factors. In the current paper, we discuss various scientific approaches investigating climate change and its possible impact on public health and discuss their different roles and functions in unraveling the complexity of the subject. It is not our objective to review the available literature or to make predictions for certain diseases or countries, but rather to evaluate the applicability of scientific research articles on climate change to evidence-based public health decisions. In the context of mosquito borne diseases, we identify common pitfalls to watch out for when assessing scientific research on the impact of climate change on human health. We aim to provide guidance through the plethora of scientific papers and views on the impact of climate change on human health to those new to the subject, as well as to remind public health experts of its multifactorial and multidisciplinary character.

Dried plant herbarium specimens are potentially a valuable source of DNA. Efforts to obtain genetic information from this source are often hindered by an inability to obtain amplifiable DNA as herbarium DNA is typically highly degraded. DNA post-mortem damage may not only reduce the number of amplifiable template molecules, but may also lead to the generation of erroneous sequence information. A qualitative and quantitative assessment of DNA post-mortem damage is essential to determine the accuracy of molecular data from herbarium specimens. In this study we present an assessment of DNA damage as miscoding lesions in herbarium specimens using 454-sequencing of amplicons derived from plastid, mitochondrial, and nuclear DNA. In addition, we assess DNA degradation as a result of strand breaks and other types of polymerase non-bypassable damage by quantitative real-time PCR. Comparing four pairs of fresh and herbarium specimens of the same individuals we quantitatively assess post-mortem DNA damage, directly after specimen preparation, as well as after long-term herbarium storage. After specimen preparation we estimate the proportion of gene copy numbers of plastid, mitochondrial, and nuclear DNA to be 2.4-3.8% of fresh control DNA and 1.0-1.3% after long-term herbarium storage, indicating that nearly all DNA damage occurs on specimen preparation. In addition, there is no evidence of preferential degradation of organelle versus nuclear genomes. Increased levels of C→T/G→A transitions were observed in old herbarium plastid DNA, representing 21.8% of observed miscoding lesions. We interpret this type of post-mortem DNA damage-derived modification to have arisen from the hydrolytic deamination of cytosine during long-term herbarium storage. Our results suggest that reliable sequence data can be obtained from herbarium specimens.

Background & Aims: Functional nonretentive fecal incontinence (FNRFI), incontinence in the absence of signs of fecal retention, is a frustrating phenomenon in children. No data on long-term outcome are available. The aim was to investigate the long-term outcome of FNRFI patients after intensive medical treatment., Methods: Between 1990 and 1999, 119 patients (96 boys) with FNRFI were enrolled in 2 prospective, randomized trials investigating the effect of biofeedback training and/or laxative treatment. Follow-up (FU) was performed at 6 months, 1 year, and thereafter annually until September 2004. A standardized questionnaire was used to evaluate symptoms. Success was defined as a fecal incontinence frequency <1 per 2 weeks., Results: Median age (25th-75th percentiles) was 9.2 years (range, 7.9-11.6 years). A 90% FU was achieved at all stages of the study. After 2 years of intensive therapy, 33 of 112 (29.5%) patients were successfully treated. The cumulative success percentage after 7 years of FU was 80%. At the biologic ages of 12 and 18 years, 49.4% (40/81) and 15.5% (9/58), respectively, of the patients still had fecal incontinence. Duration of fecal incontinence, with 4 years of age as the starting age for fecal incontinence (when a child should be toilet trained), was not related to successful outcome or relapse. Relapse occurred in 37% of patients., Conclusions: Only 29% of the patients with FNRFI were successfully treated after 2 years of intensive treatment. Despite recovery in the majority of patients beyond puberty, at age 18 years, 15% continued to have fecal incontinence.

Background & Aims: Sparse data exist about the prognosis of childhood constipation and its possible persistence into adulthood., Methods: A total of 418 constipated patients older than 5 years at intake (279 boys; median age, 8.0 yr) participated in studies evaluating therapeutic modalities for constipation. All children subsequently were enrolled in this follow-up study with prospective data collection after an initial 6-week intensive treatment protocol, at 6 months, and thereafter annually, using a standardized questionnaire., Results: Follow-up was obtained in more than 95% of the children. The median duration of the follow-up period was 5 years (range, 1-8 yr). The cumulative percentage of children who were treated successfully during follow-up was 60% at 1 year, increasing to 80% at 8 years. Successful treatment was more frequent in children without encopresis and in children with an age of onset of defecation difficulty older than 4 years. In the group of children treated successfully, 50% experienced at least one period of relapse. Relapses occurred more frequently in boys than in girls (relative risk 1.73; 95% confidence interval, 1.15-2.62). In the subset of children aged 16 years and older, constipation still was present in 30%., Conclusions: After intensive initial medical and behavioral treatment, 60% of all children referred to a tertiary medical center for chronic constipation were treated successfully at 1 year of follow-up. One third of the children followed-up beyond puberty continued to have severe complaints of constipation. This finding contradicts the general belief that childhood constipation gradually disappears before or during puberty.

Background & Aims: Children with chronic abdominal pain have a heterogeneous clinical presentation, but no organic cause can be identified in most of them. Some children present with symptoms of irritable bowel syndrome (IBS). We hypothesized that visceral hypersensitivity and motor abnormalities may be underlying mechanisms in these children., Methods: Rectal sensation and rectal contractile response to a meal were studied in 8 children with IBS and 8 children with functional abdominal pain (FAP) and were compared with those of 9 healthy volunteers (HVs)., Results: The threshold for pain, but not that for first sensation and urge to defecate, was significantly decreased in IBS patients (6 +/- 1 mm Hg) compared with FAP patients and HVs (17 +/- 1 and 22 +/- 2 mm Hg, respectively). In HVs and patients with FAP, ingestion of a meal induced a decrease in rectal volume with an early and late component. This motor pattern was absent in children with IBS. In IBS patients, no rapid volume waves were observed during fasting in contrast to FAP patients (2.7 +/- 0.3/10 min) and HVs (1.8 +/- 0.5/10 min)., Conclusions: Children fulfilling the Rome II criteria for IBS have a significantly lowered threshold for pain and a disturbed contractile response to a meal. Comparable to results reported in adults, sensory and motor abnormalities might play a pathophysiologic role in childhood IBS.

Unlabelled: PET with L-[1-11C]-tyrosine (TYR) was investigated in patients undergoing hyperthermic isolated limb perfusion (HILP) with recombinant tumor necrosis factor alpha (rTNF-alpha) and melphalan for locally advanced soft-tissue sarcoma and skin cancer of the lower limb., Methods: Seventeen patients (5 women, 12 men; age range 24-75 y; mean age 52 y) were studied. TYR PET studies were performed before HILP and 2 and 8 wk afterwards. The protein synthesis rates (PSRs) in nanomoles per milliliter per minute were calculated. After final PET studies, tumors were resected and pathologically examined. Patients with pathologically complete responses (pCR) showed no viable tumors after treatment. Those with pathologically partial responses (pPR) showed various amounts of viable tumors in the resected tumor specimens., Results: Six patients (35%) showed a pCR and 11 patients (65%) showed a pPR. All tumors were depicted as hot spots on PET studies before HILP. The PSR in the pCR group at 2 and 8 wk after perfusion had decreased significantly (P < 0.05) in comparison to the PSR before HILP. A significant difference was found in PSR between the pCR and pPR groups at 2 and at 8 wk (P < 0.05). Median PSR in nonviable tumor tissue was 0.62 and ranged from 0.22 to 0.91. With a threshold PSR of 0.91, sensitivity and specificity of TYR PET were 82% and 100%, respectively. The predictive value of a PSR > 0.91 for having viable tumor after HILP was 100%, whereas the predictive value of a PSR < or = 0.91 for having nonviable tumor tissue after HILP was 75%. The 2 patients in the pPR groups with a PSR < 0.91 showed microscopic islets of tumor cells surrounded by extensive necrosis on pathological examination., Conclusion: Based on the calculated PSR after HILP, TYR PET gave a good indication of the pathological outcome. Inflammatory tissue after treatment did not interfere with viable tumor on the images, suggesting that it may be worthwhile to pursue TYR PET in other therapy evaluation settings.

Purpose. The feasibility of hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNFalpha ) and cisplatin for the management of osteosarcoma was studied in the canine model.Methods. During seven perfusions in six healthy mongrel dogs (weight 32+/-2 kg) technical aspects of HILP under mild hyperthermia (39- 40) were studied. In five experiments HILP was performed with TNFalpha alone (0.5 mg/l extremity volume), and in two experiments TNFalpha was combined with cisplatin (25 mg/l extremity volume). During the perfusions physiological parameters were monitored and TNFalpha and total cisplatin concentrations were determined.Results. Perfusion conditions (pH, PCO(2) , PO(2), flow and pressure) remained within physiological ranges.Three dogs died within 24 h despite a sublethal systemic concentration of TNFalpha that leaked from the perfusion circuit. Three dogs were terminated; one dog after the second experiment in accordance with Dutch ethical rules; one dog showed an invagination of the small bowel resulting in an ileus; one dog because of necrosis of the perfused limb.Conclusions. This feasibility study in healthy dogs demonstrated that HILP with TNFalpha and cisplatin was associated with a high mortality rate and does not allow us to treat dogs with spontaneous osteosarcoma with TNFalpha and cisplatin HILP. Therefore, an alternative model should be used in the search for the ideal combination of perfusion agents for limb sparing treatment in human osteosarcoma.

Unlabelled: We studied the potential of PET with L-[1-11C]-tyrosine (TYR) to visualize tumors outside the central nervous system and to quantify their protein synthesis rates (PSRs)., Methods: Twenty-two patients suspected of having a malignant tumor underwent a PET study with TYR before biopsy. The PSR in nanomoles per milliliter tumor tissue per minute as well as the PSR in contralateral normal tissue, standardized uptake values (SUVs) and tumor-to-nontumor-ratios (T/N ratios) were calculated., Results: Fifteen of the 16 malignancies (94%) were correctly visualized as a hot spot. A chondrosarcoma of the sacrum was not visualized. Of the six patients with benign lesions, cold spots were correctly identified in four (67%). A benign schwannoma and an intramuscular hemangioma of the forearm were visualized as hot spots. PSR in tumor tissue was higher than in the corresponding contralateral normal tissues. PSR and SUV in malignant tumors were higher than in benign tumors., Conclusion: TYR appears to be a good tracer for imaging malignancies. The PSR, which was higher in malignant tumors than in normal tissue and the studied benign lesions, could be quantified and correlated with the SUV.

This study was undertaken to determine the effects on systemic fibrinolysis of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor alpha (r-TNF-alpha) and melphalan, with or without pretreatment with recombinant IFN-gamma (r-IFN-gamma). Twenty patients were treated with r-TNF-alpha and melphalan; four patients, treated with melphalan only, served as controls. Of the twenty patients treated with both r-TNF-alpha and melphalan, eight received r-IFN-gamma for two days before the perfusion and as a bolus into the perfusion circuit. A significant leak of r-TNF-alpha from the perfusion circuit to the systemic circulation was observed in all r-TNF-alpha-treated patients (mean maximum TNF-alpha, 87,227 ng/liter versus 31 ng/liter in controls; P < 0.002). In these patients, but not in controls, there was an almost instantaneous rise in systemic tissue plasminogen activator activity (from 0.26 to 5.28 IU/ml in 90 min), causing activation of fibrinolysis. After a delay of 90 min, plasminogen activator inhibitor-1 (PAI-1) antigen rose to high levels in the r-TNF-alpha-treated group (mean maximum PAI-1, 1652 ng/ml versus 211 ng/ml in controls; P < 0.02), associated with a sharp decrease of tissue plasminogen activator activity and a slower decrease of plasminogen-antiplasminogen complexes (from 5.28 to 0.02 IU/ml in 2 h and from 1573 to 347 micrograms/liter in 22 h, respectively). No additional effect of IFN-gamma pretreatment on fibrinolysis could be demonstrated. These results suggest that in isolated limb perfusion with r-TNF-alpha and melphalan an initial activation of systemic fibrinolysis, induced by leakage of r-TNF-alpha from the perfusion circuit, is set off by a subsequent inhibition of the fibrinolytic system by PAI-1. This large increase in PAI-1 could place the patient at risk for deposition of microthrombi in the systemic circulation.