Current pediatric cancer survivorship practices: a report from the Children's Oncology Group.

PURPOSE: The purpose of this study is to describe current survivor services provided by COG institutions. METHODS: A 190-question online survey was distributed to 209 COG member institutions over a 5-month period in 2017. Descriptive statistics were used to describe survivor services and explore their changes between 2007 and 2017. RESULTS: Representatives from 153 (73%) institutions completed the survey. Of these, 96% of institutions reported that they provide pediatric cancer survivor care either in a specialized late effects program (75%) or a regular pediatric oncology clinic (24%). However, only 29.8% of institutions reported that > 75% of eligible patients were seen in a survivorship clinic. The most prevalent reported barriers to survivor care were lack of dedicated time (58%) and lack of funding for program development (41%). In 2017, 88% of institutions provided a treatment summary compared to 31% in 2007. CONCLUSION: The majority of COG institutions have dedicated care for pediatric and young adult survivors of childhood cancer; however, at most institutions, < 75% of eligible patients access this care. Research into more efficient technology strategies is needed to ensure all survivors the opportunity to receive appropriate follow-up care. IMPLICATIONS FOR CANCER SURVIVORS: This survey provides a snapshot of the status of late effects services within COG institutions and provides information on residual gaps in services. Next steps should focus on the importance of attendance in a survivorship clinic on the physical health and psychosocial outcomes in cancer survivors.

CAD/CAM-produced surgical guides: Optimizing the treatment workflow.

The increased availability of devices for 3D radiological diagnosis allows the more frequent use of CAD/CAM-produced surgical guides for implant placement. The conventional workflow requires a complex logistic chain which is time-consuming and costly. In a pilot study, the workflow of directly milled surgical guides was evaluated. These surgical guides were designed based on the fusion of an optical impression and the radiological data. The clinical use showed that the surgical guides could be accurately placed on the residual dentition without tipping movements. The conventional surgical guides were used as a control for the manual check of the deviation of the implant axis. The direct transfer of the digital planning data allows the fabrication of surgical guides in an external center without the need of physical transport, which reduces the logistic effort and expense of the central fabrication of surgical guides.

A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice.

Chemotherapy-induced central nervous system (CNS) neurotoxicity presents an unmet medical need. Patients often report a cognitive decline in temporal correlation to chemotherapy, particularly for hippocampus-dependent verbal and visuo-spatial abilities. We treated adult C57Bl/6 mice with 12 × 20 mg kg-1 paclitaxel (PTX), mimicking clinical conditions of dose-dense chemotherapy, followed by a pulse of bromodesoxyuridine (BrdU) to label dividing cells. In this model, mice developed visuo-spatial memory impairments, and we measured peak PTX concentrations in the hippocampus of 230 nm l-1, which was sevenfold higher compared with the neocortex. Histologic analysis revealed a reduced hippocampal cell proliferation. In vitro, we observed severe toxicity in slowly proliferating neural stem cells (NSC) as well as human neuronal progenitor cells after 2 h exposure to low nanomolar concentrations of PTX. In comparison, mature post-mitotic hippocampal neurons and cell lines of malignant cells were less vulnerable. In PTX-treated NSC, we observed an increase of intracellular calcium levels, as well as an increased activity of calpain- and caspase 3/7, suggesting a calcium-dependent mechanism. This cell death pathway could be specifically inhibited with lithium, but not glycogen synthase kinase 3 inhibitors, which protected NSC in vitro. In vivo, preemptive treatment of mice with lithium prevented PTX-induced memory deficits and abnormal adult hippocampal neurogenesis. In summary, we identified a molecular pathomechanism, which invokes PTX-induced cytotoxicity in NSC independent of cell cycle status. This pathway could be pharmacologically inhibited with lithium without impairing paclitaxel's tubulin-dependent cytostatic mode of action, enabling a potential translational clinical approach.

Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2A-receptor-dependent and potentiated under hyperthermia.

Studies on 3,4-methylenedioxymethamphetamine ("ecstasy")-induced neurotoxicity mainly focus on damage of serotonergic terminals. Less attention has been given to neuronal cell death produced by 3,4-methylenedioxymethamphetamine and other amphetamines in areas including the cortex, striatum and thalamus. In the present study we investigated 3,4-methylenedioxymethamphetamine-induced neurotoxicity in neuronal serum free cultures from rat cortex. Since 3,4-methylenedioxymethamphetamine intake induces hyperthermia in both animals and humans, the experiments were performed under normal (36.5 degrees C) and hyperthermic conditions (40 degrees C). Our findings showed a dose-, time- and temperature-dependent apoptotic cell death induced by 3,4-methylenedioxymethamphetamine in cortical neurons. 3,4-Methylenedioxymethamphetamine-induced damage was potentiated under hyperthermia. The neurotoxicity was reduced by the serotonin 2A-receptor antagonists, ketanserin and (2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrolidinol hydrochloride, in both normothermic and hyperthermic conditions. (+/-)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride, a model agonist for the serotonin 2A-receptor, also induced a dose- and time-dependent apoptotic cell death. Again, protection was provided by ketanserin and (2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrolidinol hydrochloride against (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride-induced neurotoxicity, thereby indicating that the 3,4-methylenedioxymethamphetamine stimulation of the serotonin 2A-receptor leads to neurotoxicity. This study provides for the first time evidence that direct 3,4-methylenedioxymethamphetamine serotonin 2A-receptor stimulation leads to neuronal cortical death. alpha-Phenyl-N-tert-butyl nitrone a free radical scavenger and the nitric oxide synthase inhibitor Nomega-nitro-L-arginine as well as the NMDA-receptor antagonist MK-801 provided protection under normothermia and hyperthermia, thereby suggesting the participation of free radicals in 3,4-methylenedioxymethamphetamine-induced cell death. Since 3,4-methylenedioxymethamphetamine serotonin 2A-receptor agonistic properties lead to neuronal death, clinically available atypical antipsychotic drugs with serotonin 2A-antagonistic properties could be a valuable therapeutic tool against 3,4-methylenedioxymethamphetamine-induced neurodegeneration.

Early injury to cortical and cancellous bone from induction chemotherapy for adolescents and young adults treated for acute lymphoblastic leukemia.

Diminished bone density and skeletal fractures are common morbidities during and following therapy for acute lymphoblastic leukemia (ALL). While cumulative doses of osteotoxic chemotherapy for ALL have been reported to adversely impact bone density, the timing of onset of this effect as well as other changes to bone structure is not well characterized. We therefore conducted a prospective cohort study in pre-adolescent and adolescent patients (10-21years) newly diagnosed with ALL (n=38) to explore leukemia-related changes to bone at diagnosis and the subsequent impact of the first phase of chemotherapy ("Induction"). Using quantitative computerized tomography (QCT), we found that pre-chemotherapy bone properties were similar to age- and sex-matched controls. Subsequently over the one month Induction period, however, cancellous volumetric bone mineral density (vBMD) decreased markedly (-26.8%, p<0.001) with sparing of cortical vBMD (tibia -0.0%, p=0.860, femur -0.7%, p=0.290). The tibia underwent significant cortical thinning (average cortical thickness-1.2%, p<0.001; cortical area-0.4%, p=0.014), while the femur was less affected. Areal BMD (aBMD) concurrently measured by dual-energy X-ray absorptiometry (DXA) underestimated changes from baseline as compared to vBMD. Biochemical evidence revealed prevalent Vitamin D insufficiency and a net resorptive state at start and end of Induction. Our findings demonstrate for the first time that significant alterations to cancellous and cortical bone develop during the first month of treatment, far earlier during ALL therapy than previously considered. Given that osteotoxic chemotherapy is integral to curative regimens for ALL, these results provide reason to re-evaluate traditional approaches toward chemotherapy-associated bone toxicity and highlight the urgent need for investigation into interventions to mitigate this common adverse effect.

Differential mechanisms of neuroprotection by 17 beta-estradiol in apoptotic versus necrotic neurodegeneration.

The major goal of this study was to compare mechanisms of the neuroprotective potential of 17 beta-estradiol in two models for oxidative stress-independent apoptotic neuronal cell death with that in necrotic neuronal cell death in primary neuronal cultures derived from rat hippocampus, septum, or cortex. Neuronal apoptosis was induced either by staurosporine or ethylcholine aziridinium (AF64A), as models for necrotic cell death glutamate exposure or oxygen-glucose deprivation (OGD) were applied. Long-term (20 hr) pretreatment (0.1 microm 17 beta-estradiol) was neuroprotective in apoptotic neuronal cell death induced by AF64A (40 microm) only in hippocampal and septal neuronal cultures and not in cortical cultures. The neuroprotective effect was blocked by the estrogen antagonists ICI 182,780 and tamoxifen and the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002. In glutamate and OGD-induced neuronal damage, long-term pretreatment was not effective. In contrast, short-term (1 hr) pretreatment with 17 beta-estradiol in the dose range of 0.5-1.0 microm significantly reduced the release of lactate dehydrogenase and improved morphology of cortical cultures exposed to glutamate or OGD but was not effective in the AF64A model. Staurosporine-induced apoptosis was not prevented by either long- or short-term pretreatment. The strong expression of the estrogen receptor-alpha and the modulation of Bcl proteins by 17 beta-estradiol in hippocampal and septal but not in cortical cultures indicates that the prevention of apoptotic, but not of necrotic, neuronal cell death by 17 beta-estradiol possibly depends on the induction of Bcl proteins and the density of estrogen receptor-alpha.

Induced hypothermia in experimental pneumococcal meningitis.

Pneumococcal meningitis resulting from Streptococcus pneumoniae has a death rate of 28% in adults. In severe head injury and stroke, inflammatory changes and intracranial hypertension are improved by induced hypothermia, which also is neuroprotective. We hypothesized that moderate hypothermia ameliorates inflammatory changes in experimental pneumococcal meningitis. Wistar rats were cooled systemically, and meningitis was induced by pneumococcal cell wall components. The increase of regional cerebral blood flow in the meningitis animals was blocked by hypothermia at 6 hours. The reduction of intracranial pressure correlated with temperature. The influx of leukocytes into the cerebrospinal fluid and levels of tumor necrosis factor alpha in the cerebrospinal fluid were decreased. Cooling the animals 2 hours after meningitis induction to 30.5 degrees C was also protective. We conclude that hypothermia is a new adjuvant approach to reduce meningitis-induced changes, in particular intracranial pressure, in the early phase of the disease.

Global cerebral ischemia in the rat: online monitoring of oxygen free radical production using chemiluminescence in vivo.

Using online in vivo chemiluminescence (CL), we studied for the first time continuously the production of reactive oxygen species (ROS) after global cerebral ischemia and the relationship of ROS production to CBF. In anesthetized rats equipped with a closed cranial window, the CL enhancer, lucigenin (1 mM), was superfused onto the brain topically. CL was measured through the cranial window with a cooled photomultiplier, and CBF was measured simultaneously with laser-Doppler flowmetry. Reperfusion after 10 min (n = 8) of global cerebral ischemia led to a CL peak to 188 +/- 77% (baseline = 100%) within 10 +/- 4 min. After 2 h of reperfusion, CL had returned to 102 +/- 28%. Reperfusion after 20 min (n = 8) of ischemia increased CL to 225 +/- 48% within 12 +/- 3 min. After 2 h, CL was still increased (150 +/- 44%, p < 0.05 compared with 10 min of ischemia). CL after 10 min of ischemia was neither affected by brain topical free CuZn-superoxide dismutase (SOD) (100 U/ml, n = 3) nor by i.v. administration of free CuZn-SOD (104 U/kg, followed by 104 U/kg/h, n = 3). The CBF hyperfusion peak on reperfusion preceded the CL peak in all experiments by several minutes. In additional in vitro experiments we investigated the source of CL: Intracellular loading of lucigenin was demonstrated in cultured CNS cells, and a very similar pattern of CL as in the in vivo preparation after ischemia developed in rat brain slices after 15 min of hypoxia, which was unaffected by free CuZn-SOD (100 U/ml) but strongly attenuated by liposome-entrapped CuZn-SOD. We conclude that lucigenin-enhanced CL is a promising tool to study ROS production continuously from the in vivo brain of experimental animals and brain slices, and that the CL signal most likely derives from the intracellular production of superoxide. The production of ROS is preceded by reperfusion, is burst-like, and is dependent on the duration of the ischemic interval.

Heparin inhibits leukocyte rolling in pial vessels and attenuates inflammatory changes in a rat model of experimental bacterial meningitis.

Heparin is a natural proteoglycan that was first described in 1916. In addition to its well characterized effect on blood coagulation, it is becoming clear that heparin also modulates inflammatory processes on several levels, including the interference with leukocyte-endothelium interaction. Anecdotal observations suggest a better clinical outcome of heparin-treated patients with bacterial meningitis. The authors demonstrate that heparin, a glycosaminoglycan, inhibits significantly in the early phase of experimental pneumococcal meningitis the increase of 1) regional cerebral blood flow (125 +/- 18 versus 247 +/- 42%), 2) intracranial pressure (4.5 +/- 2.0 versus 12.1 +/- 2.2 mm Hg), 3) brain edema (brain water content: 78.23 +/- 0.33 versus 79.49 +/- 0.46%), and 4) influx of leukocytes (571 +/- 397 versus 2400 +/- 875 cells/microL) to the cerebrospinal fluid compared with untreated rats. To elucidate the possible mechanism of this observation, the authors investigated for the first time leukocyte rolling in an inflammatory model in brain venules by confocal laser scanning microscopy in vivo. Heparin significantly attenuates leukocyte rolling at 2, 3, and 4 hours (2.8 +/- 1.3 versus 7.9 +/- 3.2/100 microm/min), as well as leukocyte sticking at 4 hours (2.1 +/- 0.4 versus 3.5 +/- 1.0/100 microm/min) after meningitis induction compared with untreated animals. The authors conclude that heparin can modulate acute central nervous system inflammation and, in particular, leukocyte-endothelium interaction, a key process in the cascade of injury in bacterial meningitis. They propose to evaluate further the potential of heparin in central nervous system inflammation in basic and clinical studies.

Metastatic metanephric adenoma in a child.

Metanephric adenoma is a recently characterized renal tumor that generally occurs in adults and has an excellent prognosis. To date, only one atypical metanephric adenoma has been reported to metastasize. The authors report a case of typical metanephric adenoma that arose in the left kidney of a 7-year-old girl that was associated with metastases to the para-aortic, hilar, and aortic bifurcation lymph nodes. The tumor was 9.5 cm and was composed entirely of epithelial elements arranged in tubules, short papillae, and glomeruloid bodies with scattered psammoma bodies. No atypia and only rare mitotic activity were present. Immunohistochemically, the tumor was negative for epithelial membrane antigen, negative for keratin AE1, and focally positive for both keratin CAM5.2 and cytokeratin 7. Tumor cytogenetics revealed a normal diploid karyotype, and disomy of chromosomes 7 and 17 was confirmed by fluorescence in situ hybridization. The authors conclude that tumors with histologic, immunohistochemical, and genetic features characteristic of typical metanephric adenoma can present with metastatic disease.

Tumour necrosis factor alpha induces only minor inflammatory changes in the central nervous system, but augments experimental meningitis.

Although tumour necrosis factor alpha is said to play a key role in bacterial meningitis and other CNS diseases, the effects of this pro-inflammatory cytokine have only been studied in part and are incompletely understood. In a rat model, we investigated the effect of intracisternal injection of recombinant rat-specific tumour necrosis factor alpha (5, 35, 70 and 280 microg tumour necrosis factor alpha) (i) alone, (ii) combined with pneumococcal cell wall components, on regional cerebral blood flow, intracranial pressure, white blood cell count in the cerebrospinal fluid, and brain water content. Tumour necrosis factor a dose-dependently caused an increase in regional cerebral blood flow (up to 221 +/- 43% of baseline values) over the six hour observation period and mild cerebrospinal fluid leukocytosis; intracranial pressure and brain water content were unchanged. Hypothesizing that regional cerebral blood flow changes are dependent on nitric oxide, tumour necrosis factor alpha-induced regional cerebral blood flow increase was abolished by Aminoguanidine, a selective inhibitor of inducible nitric oxide synthase. Combination of the lowest tumour necrosis factor alpha dose and a low dose pneumococcal cell wall preparation magnified the inflammatory effect of both. We conclude that intrathecally injected tumour necrosis factor alpha alone results in only minor inflammatory changes, whereas it dramatically augments experimental meningitis.

Role of nitric oxide in the ethylcholine aziridinium model of delayed apoptotic neurodegeneration in vivo and in vitro.

The involvement of nitric oxide in neurodegenerative processes still remains incompletely characterized. Although nitric oxide has been reported to be an important mediator in neuronal degeneration in different models of cell death involving NMDA-receptor activation, increasing evidence for protective mechanisms has been obtained. In this study the role of nitric oxide was investigated in a model of NMDA-independent, delayed apoptotic cell death, induced by the neurotoxin ethylcholine aziridinium ethylcholine aziridinium both in vivo and in vitro. For the in vivo evaluation rats received bilateral intracerebroventricular injections of ethylcholine aziridinium (2nmol/ventricle) or vehicle. In the hippocampus a transient decrease in nitric oxide synthase activity occurred, reaching its lowest levels three days after ethylcholine aziridinium treatment (51.7+/-9.8% of controls). The decrease coincided with the maximal reduction in choline acetyltransferase activity as marker for the extent of cholinergic lesion. The effect of pharmacological inhibition of nitric oxide synthase was tested by application of various nitric oxide synthase inhibitors with different selectivity for the nitric oxide synthase-isoforms. Unspecific nitric oxide synthase inhibition resulted in a significant potentiation of the loss of choline acetyltransferase activity in the hippocampus measured seven days after ethylcholine aziridinium application, whereas the specific inhibition of neuronal or inducible nitric oxide synthase was ineffective. These pharmacological data are suggestive for a neuroprotective role of nitric oxide generated by endothelial nitric oxide synthase. In vitro experiments were performed using serum-free primary neuronal cell cultures from hippocampus, cortex and septum of E15-17 Wistar rat embryos. Ethylcholine aziridinium-application in a range of 5-80microM resulted in delayed apoptotic neurodegeneration with a maximum after three days as confirmed by morphological criteria, life-death assays and DNA laddering. Nitric oxide synthase activity in harvested cells decreased in a dose- and time-dependent manner. Nitric oxide production as determined by measurement of the accumulated metabolite nitrite in the medium was equally low in controls and in ethylcholine aziridinium treated cells (range 0.77-1.86microM nitrite). An expression of inducible nitric oxide synthase messenger RNA could not be detected by semiquantitative RT-PCR 13h after ethylcholine aziridinium application. The present data indicate that in a model of delayed apoptotic neurodegeneration as induced by ethylcholine aziridinium neuronal cell death in vitro and in vivo is independent of the cytotoxic potential of nitric oxide. This is confirmed by a decrease in nitric oxide synthase activity, absence of nitric oxide production and absence of inducible nitric oxide synthase expression. In contrast, evidence for a neuroprotective role of nitric oxide was obtained in vivo as indicated by the exaggeration of the cholinergic lesion after unspecific nitric oxide synthase inhibition by N-nitro-L-arginine methylester.

Rapid Ca2+-dependent NO-production from central nervous system cells in culture measured by NO-nitrite/ozone chemoluminescence.

We have established simple and reliable measurement of constitutive nitric oxide (NO) synthase-dependent nitrite formation in supernatants from primary central nervous system (CNS) cells in culture using NO-ozone chemoluminescence. We found that: (1) astrocytes, endothelial cells and cerebellar granule cells produce NO upon stimulation with the calcium ionophore A23187 (1 microM); (2) application of 100 microM glutamate for 2 min results in NO-production in cerebellar granule cells and cortical neurons. NO-formation upon application of 50 mM KCl was found in cortical neurons; (3) in cultivated cerebral endothelial cells, an inducible form of NO-synthase (iNOS) is found under standard culture conditions. This induction was blocked by dexamethasone applied for at least 48 h and stimulation of constitutive NOS was detectable while iNOS was inhibited. The activity of iNOS was selectively inhibited by application of aminoguanidine for 48 h. Our results suggest that all major CNS cells implied in cerebral blood flow regulation and neurovascular coupling are capable of rapidly producing the vasodilator NO upon intracellular increases of the universal second messenger calcium.

The CD11/CD18 leukocyte glycoprotein deficiency.

CD11/CD18 leukocyte glycoprotein deficiency is a rare, inherited disorder of leukocyte function, manifested by recurrent severe bacterial infections. A deficiency in the expression of a family of leukocyte membrane glycoproteins (the CD11/CD18 glycoproteins) represents the molecular basis for this disease.

Fucoidin, a polysaccharide inhibiting leukocyte rolling, attenuates inflammatory responses in experimental pneumococcal meningitis in rats.

It is presumed that adjuvant therapy rather than new antibiotics will improve the prognosis of pneumococcal meningitis. We investigated the effect of fucoidin, a polysaccharide inhibiting leukocyte rolling, on inflammatory changes in experimental meningitis in rats. After induction of meningitis by pneumococcal cell wall components, regional cerebral blood flow and intracranial pressure increased over the observation period of 6 h. At the end of the experiments, cerebrospinal fluid pleocytosis and brain water content were higher in animals with meningitis than without. Fucoidin treatment in the meningitis group reduced all inflammatory changes, whereas fucoidin treatment of animals without meningitis increased blood white cell count, but had no effect on any other parameter. Our results confirm that selectins are involved in the early phase of pneumococcal meningitis and possibly are a target for adjunctive therapy.

Chemiluminescence detection of nitric oxide production from rat cerebral cortical endothelial cells in culture.

Cultured brain microvascular endothelial cells have been used to study blood-brain barrier properties in vitro. Among several endothelial derived factors the gaseous free radical nitric oxide (NO) has been shown to regulate both vascular tone and blood-brain barrier permeability. Due to its short half-life and high reactivity with many other molecules, effects of NO have preferentially been investigated using NO synthase inhibitors, NO donors or, more recently, in NO synthase knock-out animals. In the present study we describe a rapid, sensitive and reliable protocol for chemiluminescence detection of NO2-, the stable oxydation product of NO, from the supernatant of rat cortical endothelial cells in culture. After suppression of inducible NOS activity brain endothelial cells showed low basal NO levels. After stimulation with calcium ionophore NO levels increased and were attenuated again by NOS blockade. NO release was also elicited by bradykinin or acetylcholine, albeit to a lesser extent. This protocol might prove useful to investigate calcium-dependent NO formation in cerebral endothelial cells and blood-brain barrier models in vitro. In principle, the same protocol can be applied to virtually any cell type in culture.

Surface Mo1 (CD11b/CD18) glycoprotein is up-modulated by neutrophils recruited to sites of inflammation in vivo.

Inasmuch as the recruitment of polymorphonuclear leukocytes (PMNs) to inflammatory foci in vivo involves adhesion-dependent events (e.g., margination, diapedesis, and directed migration), we sought to characterize the relationship between the local accumulation of PMNs in sterile peritonitis and their surface expression of the adhesion-promoting plasma membrane glycoprotein, Mo1 (CD11b/CD18). In an immunofluorescence analysis of PMNs isolated from rats injected intraperitoneally with sterile 1% glycogen solution, we detected a significant enhancement of surface Mo1 expression by exudative peritoneal PMNs. In contrast, no significant rise in Mo1 expression was noted over time by circulating intravascular PMNs (isolated simultaneously). However, these intravascular PMNs had the capacity to increase their surface Mo1 density upon exposure to peritoneal fluid supernatant at 37 degrees C. These results demonstrate that PMNs at sites of inflammation in vivo do up-modulate their surface expression of the adhesion-promoting Mo1 glycoprotein during their recruitment from the circulating, intravascular leukocyte pool.

Non-ossifying fibromas and giant cell reparative granulomas in a child with ocular-ectodermal syndrome.

We report on a patient with ocular-ectodermal syndrome who was previously described in 1993 [Am J Med Genet (1993) 45:764-766]. This boy has now developed additional manifestations, including giant cell granulomas and non-ossifying fibromas. This adds to the list of phenotypic manifestations of this condition.

The evidence for the use of growth factors and active skin substitutes for the treatment of non-infected diabetic foot ulcers (DFU): a health technology assessment (HTA).

AIMS: Assessment of the safety, efficacy and effectiveness of growth factors alone or in combination with other technologies in the treatment of DFU including medical, economical, social, ethical and juridical aspects. METHODS: We systematically searched relevant data bases limited to English and German language and publications since 1990. Review and assessment of the quality of publications followed methods conforming to widely accepted standards for evidence-based medicine and health economics. RESULTS: We identified 25 studies comparing becaplermin, rhEGF, bFGF and the metabolically active skin grafts Dermagraft and Apligraf with standard wound care (SWC) alone or extracellular wound matrix. Study duration ranged from 12 to 20 weeks and the study population comprised between 17 and 382 patients. Treatment with becaplermin, rhEGF, Dermagraft and Apligraf resulted in a higher incidence of complete wound closure and shorter time to complete wound healing with statistically significant differences. Regarding the proportion of adverse events there was no difference between treatment groups. The methodological quality of the studies was affected by significant deficiencies. Economic evaluations showed becaplermin being cost-effective. CONCLUSIONS: Add-on therapy with growth factors and active skin substitutes for treating uncomplicated DFU could be an alternative to SWC alone. For explicit recommendations further studies with stronger evidence are necessary.