Biomedical subjects

Valentin Djonov

Publications and source records attributed to Valentin Djonov.

At least 37 records · Page 2Linked to original sources

PubMed2005

The influence of trauma and ischemia on carbohydrate metabolites monitored in hamster flap tissue.

To monitor hypoperfusion of the peripheral tissues in critical illness caused by injury, we measured the concentrations of glucose, pyruvate, and lactate in traumatized and ischemic hamster flap tissue with the use of microdialysis. The interruption of the anatomic blood supply led to a drastic decrease in microvascular blood flow (laser Doppler flowmetry) and partial tissue oxygen tension (dye fluorescence quenching technique) in the ischemic part of the flap (both P < 0.01). In the traumatized area, blood flow, oxygen tension, and pyruvate were similar to the healthy control tissue throughout the experiments, whereas pyruvate was reduced in the ischemic tissue (P < 0.05 versus baseline and other tissues). Lactate was increased in both parts of the flap (P < 0.01 versus baseline and other groups for ischemic, not significant for traumatized). The sensitivity to detect ischemic hypoxia was 62% for lactate and 93% for lactate/pyruvate ratio (L/P) (P < 0.01). The specificity to discern ischemia-related from trauma-related changes was 71% for lactate and 70% for L/P (not significant). Our results suggest that L/P is more accurate than lactate for monitoring ischemia-related hypoxia after trauma. However, the rate of increased values originating from normally perfused but traumatized tissue was high for both markers.

Animals↗

PubMed2004

Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter?

BACKGROUND: Hypoxia-inducible factor 1 alpha (hif-1alpha) furnishes tumor cells with the means of adapting to stress parameters like tumor hypoxia and promotes critical steps in tumor progression and aggressiveness. We investigated the role of hif-1alpha expression in patients with node-positive breast cancer. METHODS: Tumor samples from 77 patients were available for immunohistochemistry. The impact of hif-1alpha immunoreactivity on survival endpoints was determined by univariate and multivariate analyses, and correlations to clinicopathological characteristics were determined by cross-tabulations. RESULTS: hif-1alpha was expressed in 56% (n = 43/77) of the patients. Its expression correlated with progesterone receptor negativity (P = 0.002). The Kaplan-Meier curves revealed significantly shorter distant metastasis-free survival (DMFS) (P = 0.04, log-rank) and disease-free survival (DFS) (P = 0.04, log-rank) in patients with increased hif-1alpha expression. The difference in overall survival (OS) did not attain statistical significance (5-year OS, 66% without hif-1alpha expression and 55% with hif-1alpha expression; P = 0.21). The multivariate analysis failed to reveal an independent prognostic value for hif-1alpha expression in the whole patient group. The only significant parameter for all endpoints was the T stage (T3/T4 versus T1/T2: DMFS, relative risk = 3.16, P = 0.01; DFS, relative risk = 2.57, P = 0.03; OS, relative risk = 3.03, P = 0.03). Restricting the univariate and multivariate analyses to T1/T2 tumors, hif-1alpha expression was a significant parameter for DFS and DMFS. CONCLUSIONS: hif-1alpha is expressed in the majority of patients with node-positive breast cancer. It can serve as a prognostic marker for an unfavorable outcome in those with T1/T2 tumors and positive axillary lymph nodes.

Adult↗

PubMed2004

Intussusceptive angiogenesis: its emergence, its characteristics, and its significance.

This review shall familiarize the reader with the various aspects of intussusceptive angiogenesis (IA). The basic event in IA is the formation of transvascular tissue pillars. Depending on location, timing, and frequency of pillar emergence, the IA process has different outcomes. In capillaries, a primary IA function is to expand the capillary bed in size and complexity (intussusceptive microvascular growth). It represents an alternative to capillary sprouting. Highly ordered pillar formation in a developing capillary network leads to the formation of vascular trees (intussusceptive arborization). In small arteries and veins, pillar formation at the vessels' branching angles leads either to remodeling of the branching geometry or even to vascular pruning (intussusceptive branching remodeling). It appears essential that future angiogenic research considers always both phenomena, sprouting and intussusception. Vascularization of tissues, organs, and tumors rely heavily on both mechanisms; neglecting one or the other would obscure our understanding of the angiogenesis process.

Animals↗

PubMed2004

Heterophilic interactions between cell adhesion molecule L1 and alphavbeta3-integrin induce HUVEC process extension in vitro and angiogenesis in vivo.

Cell adhesion molecule L1 was implicated in angiogenic processes, tumor formation and metastasis. Here, we provide evidence that the sixth Ig-like domain of L1 (L1Ig6) interacts with alpha(v)beta3 to induce process extension of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. HUVECs formed network-like structures on full-length L1 or L1Ig6 substrates comparable to structures found on matrigel. In the presence of mab alpha(v)beta3 or cyclic RGD, apoptosis was induced. In fibrin matrices where L1Ig6 was covalently incorporated, HUVECs formed multicellular and hollow processes through interactions between cell-surface alpha(v)beta3 and RGD-sites of matrix-immobilized L1Ig6. No such processes were induced by L1Ig6 having non-functional RDG-sites, or in the presence of mab alpha(v)beta3 or cyclic RGD. In those matrices, increased apoptosis was found. Co-immunoprecipitation of L1 or L1Ig6 with alpha(v)beta3 suggests close interactions. Furthermore, L1Ig6 stimulated HUVECs showed increased tyrosine phosphorylation of alpha(v)beta3 and phosphorylation of MAP kinases (ERK1 and ERK2) but not AKT indicating specific activation of alpha(v) and alpha(v)beta3 followed by activation of downstream kinases. Application of L1Ig6-modified fibrin matrices on CAMs induced 50-60% increased alpha(v) and alpha(v)beta3 protein expression and in vivo angiogenesis indicated by approximately 50% increased mean vascular length density. The results demonstrate angiogenic potential of L1Ig6 involving ligation and activation of alpha(v)beta3.

Antibodies, Monoclonal↗

PubMed2004

Engineered fibrin matrices for functional display of cell membrane-bound growth factor-like activities: study of angiogenic signaling by ephrin-B2.

With the rapid increase in approaches to pro- or anti-angiogenic therapy, new and effective methodologies for administration of cell-bound growth factors will be required. We sought to develop the natural hydrogel matrix fibrin as platform for extensive interactions and continuous signaling by the vascular morphogen ephrin-B2 that normally resides in the plasma membrane and requires multivalent presentation for ligation and activation of Eph receptors on apposing endothelial cell surfaces. Using fibrin and protein engineering technology to induce multivalent ligand presentation, a recombinant mutant ephrin-B2 receptor binding domain was covalently coupled to fibrin networks at variably high densities. The ability of fibrin-bound ephrin-B2 to act as ligand for endothelial cells was preserved, as demonstrated by a concomitant, dose-dependent increase of endothelial cell binding to engineered ephrin-B2-fibrin substrates in vitro. The therapeutic relevance of ephrin-B2-fibrin implant matrices was demonstrated by a local angiogenic response in the chick embryo chorioallontoic membrane evoked by the local and prolonged presentation of matrix-bound ephrin-B2 to tissue adjacing the implant. This new knowledge on biomimetic fibrin vehicles for precise local delivery of membrane-bound growth factor signals may help to elucidate specific biological growth factor function, and serve as starting point for development of new treatment strategies.

Angiogenesis Inducing Agents↗

PubMed2003

Flow regulates arterial-venous differentiation in the chick embryo yolk sac.

Formation of the yolk sac vascular system and its connection to the embryonic circulation is crucial for embryo survival in both mammals and birds. Most mice with mutations in genes involved in vascular development die because of a failure to establish this circulatory loop. Surprisingly, formation of yolk sac arteries and veins has not been well described in the recent literature. Using time-lapse video-microscopy, we have studied arterial-venous differentiation in the yolk sac of chick embryos. Immediately after the onset of perfusion, the yolk sac exhibits a posterior arterial and an anterior venous pole, which are connected to each other by cis-cis endothelial interactions. To form the paired and interlaced arterial-venous pattern characteristic of mature yolk sac vessels, small caliber vessels of the arterial domain are selectively disconnected from the growing arterial tree and subsequently reconnected to the venous system, implying that endothelial plasticity is needed to fashion normal growth of veins. Arterial-venous differentiation and patterning are controlled by hemodynamic forces, as shown by flow manipulation and in situ hybridization with arterial markers ephrinB2 and neuropilin 1, which show that expression of both mRNAs is not genetically determined but plastic and regulated by flow. In vivo application of ephrinB2 or EphB4 in the developing yolk sac failed to produce any morphological effects. By contrast, ephrinB2 and EphB4 application in the allantois of older embryos resulted in the rapid formation of arterial-venous shunts. In conclusion, we show that flow shapes the global patterning of the arterial tree and regulates the activation of the arterial markers ephrinB2 and neuropilin 1.

Animals↗

PubMed2003

Vascular remodeling by intussusceptive angiogenesis.

Intussusception (growth within itself) is an alternative to the sprouting mode of angiogenesis. The protrusion of opposing microvascular walls into the capillary lumen creates a contact zone between endothelial cells. The endothelial bilayer is perforated, intercellular contacts are reorganized, and a transluminal pillar with an interstitial core is formed, which is soon invaded by myofibroblasts and pericytes leading to its rapid enlargement by the deposition of collagen fibrils. Intussusception has been implicated in three processes of vascular growth and remodeling. (1) Intussusceptive microvascular growth permits rapid expansion of the capillary plexus, furnishing a large endothelial surface for metabolic exchange. (2) Intussusceptive arborization causes changes in the size, position, and form of preferentially perfused capillary segments, creating a hierarchical tree. (3) Intussusceptive branching remodeling (IBR) leads to modification of the branching geometry of supplying vessels, optimizing pre- and postcapillary flow properties. IBR can also lead to the removal of branches by pruning in response to changes in metabolic needs. None of the three modes requires the immediate proliferation of endothelial cells but rather the rearrangement and plastic remodeling of existing ones. Intussusception appears to be triggered immediately after the formation of the primitive capillary plexus by vasculogenesis or sprouting. The advantage of this mechanism of growth over sprouting is that blood vessels are generated more rapidly in an energetically and metabolically more economic manner, as extensive cell proliferation, basement membrane degradation, and invasion of the surrounding tissue are not required; the capillaries thereby formed are less leaky. This process occurs without disrupting organ function. Improvements in our understanding of the process should enable the development of novel pro- and anti-angiogenic therapeutic treatments.

Allantois↗

PubMed2003

Cell-demanded release of VEGF from synthetic, biointeractive cell ingrowth matrices for vascularized tissue growth.

Local, controlled induction of angiogenesis remains a challenge that limits tissue engineering approaches to replace or restore diseased tissues. We present a new class of bioactive synthetic hydrogel matrices based on poly(ethylene glycol) (PEG) and synthetic peptides that exploits the activity of vascular endothelial growth factor (VEGF) alongside the base matrix functionality for cellular ingrowth, that is, induction of cell adhesion by pendant RGD-containing peptides and provision of cell-mediated remodeling by cross-linking matrix metalloproteinase substrate peptides. By using a Michael-type addition reaction, we incorporated variants of VEGF121 and VEGF165 covalently within the matrix, available for cells as they invade and locally remodel the material. The functionality of the matrix-conjugated VEGF was preserved and was critical for in vitro endothelial cell survival and migration within the matrix environment. Consistent with a scheme of locally restricted availability of VEGF, grafting of these VEGF-modified hydrogel matrices atop the chick chorioallontoic membrane evoked strong new blood vessel formation precisely at the area of graft-membrane contact. When implanted subcutaneously in rats, these VEGF-containing matrices were completely remodeled into native, vascularized tissue. This type of synthetic, biointeractive matrix with integrated angiogenic growth factor activity, presented and released only upon local cellular demand, could become highly useful in a number of clinical healing applications of local therapeutic angiogenesis.

Animals↗

PubMed2003

Conditional human VEGF-mediated vascularization in chicken embryos using a novel temperature-inducible gene regulation (TIGR) system.

Advanced heterologous transcription control systems for adjusting desired transgene expression are essential for gene function assignments, drug discovery, manufacturing of difficult to produce protein pharmaceuticals and precise dosing of gene-based therapeutic interventions. Conversion of the Streptomyces albus heat shock response regulator (RheA) into an artificial eukaryotic transcription factor resulted in a vertebrate thermosensor (CTA; cold-inducible transactivator), which is able to adjust transcription initiation from chimeric target promoters (P(CTA)) in a low-temperature- inducible manner. Evaluation of the temperature-dependent CTA-P(CTA) interaction using a tailored ELISA-like cell-free assay correlated increased affinity of CTA for P(CTA) with temperature downshift. The temperature-inducible gene regulation (TIGR) system enabled tight repression in the chicken bursal B-cell line DT40 at 41 degrees C as well as precise titration of model product proteins up to maximum expression at or below 37 degrees C. Implantation of microencapsulated DT40 cells engineered for TIGR-controlled expression of the human vascular endothelial growth factor A (hVEGF121) provided low-temperature-induced VEGF-mediated vascularization in chicken embryos.

Animals↗

PubMed2003

Significant correlation of hypoxia-inducible factor-1alpha with treatment outcome in cervical cancer treated with radical radiotherapy.

PURPOSE: In the early stages of cervical cancer treated with surgery alone, hypoxia-inducible factor-1alpha (hif-1alpha) expression is prognostic for overall survival. Because hypoxia plays an important role in radiation resistance, we investigated hif-1alpha expression in cervical cancer treated with local radical radiotherapy (RT). METHODS AND MATERIALS: Between 1990 and 1998, 91 patients with squamous cell or adenocarcinoma of the uterine cervix were treated with external beam RT with and without brachytherapy. Biopsies from 78 patients were available for immunohistochemistry. The impact of the immunoreactivity of hif-1alpha in regard to survival end points was determined by univariate and multivariate analyses. Correlations with clinicopathologic characteristics were determined by cross-tabulations. RESULTS: Hif-1alpha was expressed in 73 (94%) of 78 patients. It was closely linked to the pretreatment hemoglobin level (p = 0.04, r = -0.22, Spearman correlation test). The Kaplan-Meier curves showed a significantly shorter local progression-free survival (p = 0.04, log-rank) and overall survival (p = 0.01, log-rank) and a trend for shorter disease-free survival (p = 0.15) for patients with increased hif-1alpha expression. The multivariate analyses revealed hif-1alpha expression to be an independent factor for overall survival (p = 0.02). CONCLUSION: Hif-1alpha is expressed in the vast majority of patients with advanced cervical cancer and had a prognostic significance. A weak but significant correlation was noted with pretreatment hemoglobin level.

Adenocarcinoma↗

PubMed2003

EphB4 receptor tyrosine kinase transgenic mice develop glomerulopathies reminiscent of aglomerular vascular shunts.

We have established transgenic mice over-expressing the EphB4 receptor tyrosine kinase in the kidney. The EphB4 protein was localised to the developing tubular system of both control and transgenic newborn mice. In transgenic adults, transgene expression persisted in the proximal tubules and the Bowman's capsules, structures, which were not stained in control kidneys. The glomeruli of control animals consisted of regular, round vascular baskets with clearly discernable afferent and efferent arterioles. In contrast, approximately 40% of the transgenic glomeruli had an irregular shrivelled appearance and many exhibited fused, horse shoe-like afferent and efferent arterioles bypassing the glomerulus. These abnormal glomerular structures are very reminiscent of aglomerular vascular shunts, a human degenerative glomerulopathy of unknown aetiology.

Animals↗

PubMed2003

Making vascular networks in the adult: branching morphogenesis without a roadmap.

The vascular system is unique in that extensive branching morphogenesis may take place in the adult. Developmental neovascularization is guided by precise spatial cues but vessel formation in the adult is not genetically programmed. Here, we review different adult modes for branch patterning, acquiring artery or vein identity and allocating vascular progenitor cells. The endothelium shows a remarkable degree of self-organization into a treelike network and hemodynamic forces are important in rectifying abnormal branching. This discussion is in the context of a contemplated therapy for improving organ perfusion by creating new vascular loops properly integrated within the existing network.

Aging↗

PubMed2003

Induction of vascular networks in adult organs: implications to proangiogenic therapy.

Most therapeutic proangiogenic approaches rely on the premise that a single factor (e.g., VEGF) can induce new vascular loops properly connected to the existing vasculature of an ill-perfused organ (e.g., the ischemic myocardium). To gain insights into VEGF-driven neovascularization in the adult, in general, and to uncover inherent obstacles in VEGF-based therapeutic angiogenesis, we have used a transgenic system for conditional "on" and "off" switching of VEGF expression in selected adult organs and analytical methods for three-dimensional visualization of the induced vascular network. VEGF induces massive accumulation of endothelial progenitor cells and their subsequent coalescence into new vascular loops. Continual ramification of the vasculature and fusion of adjacent vessels culminate in formation of hemangioma-like vessels. In the absence of guiding cues, abnormal branching patterns and random connections with the existing network are formed. Following cessation of the VEGF stimulus, the acquired network undergoes extensive hemodynamic remodeling acting to "normalize" its architecture. Premature withdrawal of VEGF leads to regression of most acquired vessels, thus challenging the utility of therapeutic approaches relying on short stimulus duration. Overproduction of VEGF leads also to highly disruptive edema, thereby emphasizing the need to uncouple VEGF-induced permeability from its angiogenic activity. This genetic switch system thus highlights remaining problems critical for the implementation of proangiogenic therapy.

Animals↗

PubMed2003

A paracrine loop in the vascular endothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma.

BACKGROUND AND OBJECTIVES: In tumors, vascular endothelial growth factor-A (VEGF-A) stimulates angiogenesis and vascular permeability by activating the tyrosine kinase receptor-2 (VEGFR-2 or KDR/Flk-1) and-1 (VEGFR-1 or Flt-1). DESIGN AND METHODS: The distribution and function of VEGF homologs and their receptors on bone marrow plasma cells, endothelial cells, and other stromal cells (residual stromal cells) were examined in patients with multiple myeloma (MM). RESULTS: Plasma cells secrete VEGF-A (and VEGF-B, VEGF-C and VEGF-D, albeit marginally) into their conditioned medium (CM). CM VEGF-A stimulates proliferation and chemotaxis in endothelial cells (both being mandatory for angiogenesis) via VEGF receptor-2 (VEGFR-2), and in residual stromal cells via the VEGFR-1. Residual stromal cells secrete VEGF-C and VEGF-D, but little of the other homologs. Their CM VEGF-C and VEGF-D increase in response to plasma cell CM and trigger plasma cell proliferation via VEGFR-3. Proliferation in all cell types parallels VEGFR and extracellular signal-regulated protein kinase-2 (ERK-2) phosphorylation. The homologs and receptors are weakly or inconstantly expressed in patients with monoclonal gammopathies of undetermined significance or vitamin B12/iron deficiency anemias. INTERPRETATION AND CONCLUSIONS: This study shows that the VEGF pathway is directly involved in tumor angiogenesis and growth in MM. A paracrine VEGF loop for MM progression is suggested. This, in turn, provides a further indication that the VEGF pathway and its signaling proteins may be appropriate targets in the management of MM.

Adult↗

PubMed2002

Advanced modular self-inactivating lentiviral expression vectors for multigene interventions in mammalian cells and in vivo transduction.

In recent years, lentiviral expression systems have gained an unmatched reputation among the gene therapy community for their ability to deliver therapeutic transgenes into a wide variety of difficult-to-transfect/transduce target tissues (brain, hematopoietic system, liver, lung, retina) without eliciting significant humoral immune responses. We have cloned a construction kit-like self-inactivating lentiviral expression vector family which is compatible to state-of-the-art packaging and pseudotyping technologies and contains, besides essential cis-acting lentiviral sequences, (i) unparalleled polylinkers with up to 29 unique sites for restriction endonucleases, many of which recognize 8 bp motifs, (ii) strong promoters derived from the human cytomegalovirus immediate-early promoter (P(hCMV)) or the human elongation factor 1alpha (P(hEF1)(alpha)), (iii) P(hCMV-) or P(PGK-) (phosphoglycerate kinase promoter) driven G418 resistance markers or fluorescent protein-based expression tracers and (iv) tricistronic expression cassettes for coordinated expression of up to three transgenes. In addition, we have designed a size-optimized series of highly modular lentiviral expression vectors (pLenti Module) which contain, besides the extensive central polylinker, unique restriction sites flanking any of the 5'U3, R-U5-psi+-SD, cPPT-RRE-SA and 3'LTR(DeltaU3) modules or placed within the 5'U3 (-78 bp) and 3'LTR(DeltaU3) (8666 bp). pLentiModule enables straightforward cassette-type module swapping between lentiviral expression vector family members and facilitates the design of Tat-independent (replacement of 5'LTR by heterologous promoter elements), regulated and self-excisable proviruses (insertion of responsive operators or LoxP in the 3'LTR(DeltaU3) element). We have validated our lentiviral expression vectors by transduction of a variety of insect, chicken, murine and human cell lines as well as adult rat cardiomyocytes, rat hippocampal slices and chicken embryos. The novel multi-purpose construction kit-like vector series described here is compatible with itself as well as many other (non-viral) mammalian expression vectors for straightforward exchange of key components (e.g. promoters, LTRs, resistance genes) and will assist the gene therapy and tissue engineering communities in developing lentiviral expression vectors tailored for optimal treatment of prominent human diseases.

Animals↗

PubMed2002

Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy.

To gain insight into neovascularization of adult organs and to uncover inherent obstacles in vascular endothelial growth factor (VEGF)-based therapeutic angiogenesis, a transgenic system for conditional switching of VEGF expression was devised. The system allows for a reversible induction of VEGF specifically in the heart muscle or liver at any selected schedule, thereby circumventing embryonic lethality due to developmental misexpression of VEGF. Using this system, we demonstrate a progressive, unlimited ramification of the existing vasculature. In the absence of spatial cues, however, abnormal vascular trees were produced, a consequence of chaotic connections with the existing network and formation of irregularly shaped sac-like vessels. VEGF also caused a massive and highly disruptive edema. Importantly, premature cessation of the VEGF stimulus led to regression of most acquired vessels, thus challenging the utility of therapeutic approaches relying on short stimulus duration. A critical transition point was defined beyond which remodeled new vessels persisted for months after withdrawing VEGF, conferring a long-term improvement in organ perfusion. This novel genetic system thus highlights remaining problems in the implementation of pro-angiogenic therapy.

Animals↗

PubMed2002

Intussusceptive angiogenesis--the alternative to capillary sprouting.

In contrast to sprouting angiogenesis, which is a well established mode of new blood vessel formation, intussusceptive angiogenesis (IA) is a relatively new concept in vascular biology. It was first discovered in the lung as a means of capillary network growth (intussusceptive microvascular growth). The mechanism consists in the repeated insertion of new slender transcapillary tissue pillars, which subsequently increase in size, thus allowing the capillary network to grow in itself (i.e., by intussusception). It could be shown that IA was present in all organs and species investigated so far, so that it appears to be an ubiquitous phenomenon in vertebrates at least. It was not a surprise therefore to find that IA also played a role in tumour vascularisation. Morphological analysis has yet brought evidence for 6 different modes of pillar formation. They all have in common that, at one time, two endothelial leaflets (e.g. of opposite capillary walls) come into close contact, form new junctional complexes, then thin out to finally give way to the invading interstitial tissue, particularly to fibroblasts, myofibroblasts and pericytes. Once such a transcapillary pillar is formed, it can subsequently grow to the size of a normal intercapillary mesh. The addition of collagen fibrils to the pillar core will stabilize the pillar mechanically. Recent observations allowed to extend the IA concept further: The same structural mechanism of intussusceptive pillar formation was shown to contribute also to the formation of vascular trees (arborisation) and to be involved in vascular remodeling. Although numerous growth factors and receptors have already been suggested as being active in IA, very few hard facts are at present available which would allow to get a comprehensive view of IA regulation.

Animals↗

PubMed2002

Expression of transforming growth factor-alpha, epidermal growth factor receptor and platelet-derived growth factors A and B in oropharyngeal cancers treated by curative radiation therapy.

BACKGROUND AND PURPOSE: Epidermal growth factor receptor (EGFR) has been implicated in cellular responses to ionizing radiation and represents a major target for current radiosensitizing strategies. We wished to ascertain whether a correlation existed between the expression of EGFR, transforming growth factor-alpha (TGFalpha) and platelet-derived growth factors A and B (PDGF-A and PDGF-B) and treatment outcome in a group of patients with oropharyngeal cancer who had undergone curative radiation therapy. We also assessed the relationship existing between each of the aforementioned proteins and intratumoral microvessel densities (IMD) which have been previously reported (Int J Radiat Oncol Biol Phys 2000;48:17-25. MATERIALS AND METHODS: Pretherapeutic tumor biopsies from 95 patients were immunohistochemically stained and their immunoreactivities evaluated semi-quantitatively. The statistical analyses included Cox regression for calculating risk ratios of survival endpoints and logistic regression for determining odds ratios for the development of distant metastasis. RESULTS: Local tumor control as well as disease-free and overall survival were independent of protein expression levels, whereas combined TGFalpha and EGFR immunoreactivities were closely related to IMD (P = 0.003). The expression levels of these two proteins were also correlated to each other (P = 0.015). Expression of PDGF-B occurred in 54% of cases and was associated with an increase in the risk of developing distant metastasis (P = 0.011). CONCLUSIONS: Tumoral levels of TGFalpha, EGFR and PDGF-A/B are not predictive of radioresponsiveness in oropharyngeal cancers. The association between IMD and immunoreactivity for TGFalpha and EGFR indicates the involvement of these proteins in the promotion of angiogenesis in these tumors. PDGF-B should be further evaluated as a prognostic marker for squamous cell cancer of the head and neck.

Disease-Free Survival↗