What are essential elements of high-quality palliative care at home? An interview study among patients and relatives faced with advanced cancer.

BACKGROUND: In the Netherlands, general practitioners (GPs) and community nurses play a central role in the palliative care for home-dwelling patients with advanced cancer and their relatives. To optimize the palliative care provision at home, it is important to have insight in the elements that patients and relatives consider essential for high-quality palliative care, and whether these essentials are present in the actual care they receive. METHODS: Qualitative semi-structured interviews were conducted with 13 patients with advanced cancer and 14 relatives. The participants discussed their experiences with the care and support they received from the GP and community nurses, and their views on met and unmet needs. Interview data were analysed according to the principles of thematic analysis. RESULTS: Patients as well as relatives considered it important that their GP and community nursing staff are medically proficient, available, person-focused and proactive. Also, proper information transfer between care professionals and clear procedures when asking for certain resources or services were considered essential for good palliative care at home. Most interviewees indicated that these essential elements were generally present in the care they received. However, the requirements of 'proper information transfer between professionals' and 'clear and rapid procedures' were mentioned as more difficult to meet in actual practice. Patients and relatives also emphasized that an alert and assertive attitude on their own part was vital in ensuring they received the care they need. They expressed worries about other people who are less vigilant regarding the care they receive, or who have no family to support them in this. CONCLUSIONS: Medical proficiency, availability, a focus on the person, proper information transfer between professionals, clear procedures and proactivity on the part of GPs and community nursing staff are considered essential for good palliative care at home. Improvements are particularly warranted with regard to collaboration and information transfer between professionals, and current bureaucratic procedures. It is important for care professionals to ensure that the identified essential elements for high-quality palliative care at home are met, particularly for patients and relatives who are not so alert and assertive.

Effect of the partner's health and support on cancer patients' use of general practitioner care.

OBJECTIVE: Cancer and its treatment often have a profound impact on patients, leading to increased health care use in the years after diagnosis. Social support is an important determinant of health care use. Partners of cancer patients may not always be able to provide all support patients need and patients may then revert to professional health care. We examined whether partners' health and the support they provide affect the use of general practitioner (GP) care in cancer patients. METHODS: Cancer patients aged ≥18, diagnosed <20 years ago with a cancer type with a 5-year survival rate >20% and no distant metastases were sent a questionnaire, along with their partners. Patients' self-reported recent use of GP care, i.e. whether they had discussed health problems with the GP in the past year, was assessed. Partner support as perceived by the patient was measured on three scales: Active engagement, protective buffering and overprotection. RESULTS: We included 219 patients and partners. Many patients discussed physical and emotional problems with their GP (60% and 28% of patients, respectively). Patients were less likely to discuss physical problems when they experienced active engagement and protective buffering, the latter only for females. CONCLUSION: Partner support affects use of GP care in cancer patients. GPs should therefore pay attention to the support style of the partner. GPs could ask about the support provided by the partner and inform both patients and partners about support groups where they can share experiences.

The combined effect of cancer and chronic diseases on general practitioner consultation rates.

AIM: More than two-thirds of cancer patients have one or more chronic diseases besides cancer. The purpose of this study was to get detailed insight into the combined effect of cancer and chronic diseases on general practitioner (GP) consultation rates. METHODS: From the NIVEL Primary Care Database we identified cancer patients with diabetes mellitus (n=629), osteoarthritis (n=425), coronary artery disease (n=466), COPD (n=383) or without a chronic disease (n=1507), diagnosed with cancer between 2002 and 2010. They were matched on sex, age, practice and chronic disease to 6645 non-cancer controls. RESULTS: 2-5 years after diagnosis, cancer patients without a chronic disease had on average 6.5 GP contacts per year, those with a comorbid disease almost twice as many (ranging from 10 for osteoarthritis to 12.4 for COPD). A similar difference was seen in non-cancer controls. The number of GP contacts for chronic diseases did not differ between cancer patients and controls. The increase in the number of GP consultations with age and number of chronic diseases was similar in cancer patients and controls. Consultation rates were similar in cancer patients and controls if they were stratified by number of chronic diseases while counting cancer as a chronic disease. CONCLUSIONS: Two to five years after diagnosis, cancer leads to an increase in GP contacts that is similar to having a chronic disease. This increase does not differ between those with and without a chronic disease and cancer does not seem to increase the impact of having a chronic disease.

EGFR-inhibition enhances apoptosis in irradiated human head and neck xenograft tumors independent of effects on DNA repair.

Epidermal growth factor receptor (EGFR) inhibition using cetuximab improves the efficacy of radiotherapy in only a subgroup of head and neck squamous cell carcinoma (HNSCC) patients. Therefore, to improve patient selection a better understanding of tumor characteristics that affect treatment is necessary. Here, we investigated the effect of cetuximab on repair of radiation-induced DNA damage in a HNSCC xenograft model, which shows a synergistic effect to cetuximab and radiotherapy (SCCNij185) and a HNSCC model, which shows no additive effect of cetuximab to radiotherapy (SCCNij153). In both tumor models, clear increases were seen in the number of 53BP1 and Rad51 foci after irradiation. 53BP1 foci were present at comparable levels in hypoxic and normoxic tumor areas of the tumor xenografts, while the number of Rad51 foci was significantly higher in normoxic areas compared to hypoxic areas (P < 0.05). In both SCCNij185 and SCCNij153 xenografts an increased number of 53BP1 foci was observed in tumors treated with cetuximab and radiotherapy compared to radiotherapy alone. In SCCNij185 this increase was statistically significant in normoxic tumor areas (P = 0.04) and in SCCNij153 in both hypoxic and normoxic areas (P = 0.007 and P = 0.02, respectively). The number of Rad51 foci was not significantly different when cetuximab was added to radiotherapy compared to radiotherapy alone. Levels of pEGFR and pERK1/2 were decreased when cetuximab was added to radiotherapy in SCCNij185, but not in SCCNij153. Apoptosis was also only increased in SCCNij185 tumors at 4 days after cetuximab and radiotherapy treatment (P < 0.01). In conclusion, cetuximab inhibited DNA repair in both HNSCC models, but this effect was not predictive for the radiosensitizing effect of cetuximab in vivo. This lack of correlation may be related to differential effects of cetuximab and radiotherapy on ERK1/2 signaling and a decreased induction of apoptosis by cetuximab and radiotherapy in the resistant model.

For which health problems do cancer survivors visit their General Practitioner?

Primary health care use of cancer patients is increased, even years after active treatment. Insight into the reasons for this could help in developing and improving guidelines and planning of health care, which is important given the expected increase in cancer survivors. Using data from the Netherlands Information Network of Primary Care, we selected 1256 adult breast cancer, 503 prostate cancer and 487 colorectal cancer patients diagnosed between 2001 and 2006. We compared diseases and complaints for which they contacted their General Practitioner (GP) 2-5 years after diagnosis to age and sex matched non-cancer controls from the same practice. Cancer patients consulted their GP more often than controls for acute symptoms such as abdominal pain and fatigue (18% more in breast cancer, 26% more in prostate cancer) and infections, such as cystitis or respiratory infections (45% in breast cancer and 17% in colorectal cancer). Consultations for chronic diseases and psychosocial problems were slightly increased: breast cancer patients had more contacts related to diabetes (55%), sleep disturbance (60%) and depression (64%), prostate cancer patients had more contacts related to hypertension (53) and chronic obstructive pulmonary disease (COPD, 34%). Adverse drug effects were almost twice as often observed in prostate and colorectal cancer patients than in controls. Fear of cancer recurrence was noted as the reason for consulting the GP in only 20 patients. Concluding, increased primary health care use in cancer survivors is mostly related to common infections and acute symptoms, which may be due to direct effects of cancer treatment or increased health concerns.

Assessment of Blood Hemodynamics by USPIO-Induced R(1) Changes in MRI of Murine Colon Carcinoma.

The objective of this study is to assess whether ultrasmall superparamagnetic iron oxide (USPIO)-induced changes of the water proton longitudinal relaxation rate (R(1)) provide a means to assess blood hemodynamics of tumors. Two types of murine colon tumors (C26a and C38) were investigated prior to and following administration of USPIO blood-pool contrast agent with fast R(1) measurements. In a subpopulation of mice, R(1) was measured following administration of hydralazine, a well-known blood hemodynamic modifier. USPIO-induced R(1) increase in C38 tumors (DeltaR(1) = 0.072 +/- 0.0081 s(-1)) was significantly larger than in C26a tumors (DeltaR(1) = 0.032 +/- 0.0018 s(-1), N = 9, t test, P < 0.001). This was in agreement with the immunohistochemical data that showed higher values of relative vascular area (RVA) in C38 tumors than in C26a tumors (RVA = 0.059 +/- 0.015 vs. 0.020 +/- 0.011; P < 0.05). Following administration of hydralazine, a decrease in R(1) value was observed. This was consistent with the vasoconstriction induced by the steal effect mechanism. In conclusion, R(1) changes induced by USPIO are sensitive to tumor vascular morphology and to blood hemodynamics. Thus, R(1) measurements following USPIO administration can give novel insight into the effects of blood hemodynamic modifiers, non-invasively and with a high temporal resolution.

Bioavailability of phenolic compounds from olive oil and oxidative/antioxidant status at postprandial state in healthy humans.

Olive oil phenolic compounds are generally believed to have beneficial antioxidant effects, but little is known about characteristics of their postprandial bioavailability in natural olive oil at real-life doses. The aim of the present study was to determine the concentrations of olive oil phenolic compounds in urine collected over 24 h (24-h urine) after a bolus ingestion of 25 ml of olive oil with different phenolic content, and to demonstrate the effect of this real-life olive oil dose on postprandial levels of blood lipids and oxidative stress biomarkers, as well as to examine the beneficial effects of olive oil phenols. Oral fat loads of 25 ml olive oil with high, moderate, and low phenolic content were administered to 12 healthy male volunteers in a randomized, controlled, crossover trial. Tyrosol and hydroxytyrosol were absorbed in a dose-dependent manner according to the phenolic content of the olive oil administered. The administered dose of 25 ml, which is close to that used daily in Mediterranean countries, did not induce significant postprandial lipemia nor did it promote an increase of in vivo oxidation markers. With regard to plasma antioxidant enzymes, glutathione peroxidase activity decreased postprandially after low phenolic content olive oil ingestion; however this was not observed after intake of moderate and high phenolic content olive oils. The phenolic content of the olive oils administered may account for the protection of the endogenous antioxidant defenses at postprandial state after ingestion of moderate and high phenolic content olive oils.

Pimonidazole binding in C6 rat brain glioma: relation with lipid droplet detection.

In C6 rat brain glioma, we have investigated the relation between hypoxia and the presence of lipid droplets in the cytoplasm of viable cells adjacent to necrosis. For this purpose, rats were stereotaxically implanted with C6 cells. Experiments were carried out by the end of the tumour development. A multifluorescence staining protocol combined with digital image analysis was used to quantitatively study the spatial distribution of hypoxic cells (pimonidazole), blood perfusion (Hoechst 33342), total vascular bed (collagen type IV) and lipid droplets (Red Oil) in single frozen sections. All tumours (n=6) showed necrosis, pimonidazole binding and lipid droplets. Pimonidazole binding occurred at a mean distance of 114 microm from perfused vessels mainly around necrosis. Lipid droplets were principally located in the necrotic tissue. Some smaller droplets were also observed in part of the pimonidazole-binding cells surrounding necrosis. Hence, lipid droplets appeared only in hypoxic cells adjacent to necrosis, at an approximate distance of 181 microm from perfused vessels. In conclusion, our results show that severe hypoxic cells accumulated small lipid droplets. However, a 100% colocalisation of hypoxia and lipid droplets does not exist. Thus, lipid droplets cannot be considered as a surrogate marker of hypoxia, but rather of severe, prenecrotic hypoxia.

Influence of dietary components associated with high or low risk of colon cancer on apoptosis in the rat colon.

Although there is much epidemiological evidence for an interaction between diet and colorectal cancer risk, the mechanisms by which diet might protect against colorectal cancer are still unclear. Here we report the significant up-regulation of carcinogen-induced apoptosis in the colon of rats fed a diet containing low-risk factors for colon cancer, namely low fat content, high calcium and high non-digestible carbohydrate. The dose-dependent induction of apoptosis in colonic crypts by the carcinogen 1,2-dimethylhydrazine (DMH) was significantly greater in rats receiving the low-risk compared with a high-risk (high fat, low calcium, low non-digestible carbohydrate) diet (P<0.001). There were also significant interactions of colon region with DMH dose and region by diet, with the greatest increases in apoptosis occurring in the mid and distal regions of the colon compared with the proximal region. Since we have previously shown the low-risk diet to be non-toxic, these new results suggest a diet-induced up-regulation of apoptosis, which may represent a mechanism of protection against the early stages of carcinogenesis in the colon.

Quantitative analysis of varying profiles of hypoxia in relation to functional vessels in different human glioma xenograft lines.

Tissue oxygenation influences the radiation response of tumors. To further investigate the underlying mechanisms of tumor hypoxia, the spatial distribution of hypoxic cells in relation to the vasculature was studied. In a panel of three human glioma xenograft lines (E2, E102, E106) with different growth characteristics, tumor line-specific patterns of hypoxia (pimonidazole) and (functional) vasculature (Hoechst 33342) were observed. Two of the three glioma lines showed a more homogeneous distribution of perfused vessels (E102 and E106) than the third glioma line (E2). Although all tumors showed hypoxia, the distance at which the steepest part of the gradient of the hypoxia marker was found varied significantly among the different glioma lines. The faster-growing E102 tumors had the longest distance (>300 microm). These results indicate that tumor line-specific factors, rather than vascular geometry alone, may determine the oxygenation status of a tumor. As a consequence, vascular density cannot be used as a surrogate parameter for tumor hypoxia when comparing different tumors. Additional hypoxia and perfusion markers will further improve our understanding of changes in tumor physiology at the microregional level explaining the relationship between the low oxygen levels and the response of tumors to treatment.

Changes in tumor hypoxia measured with a double hypoxic marker technique.

PURPOSE: Development of a double hypoxic cell marker assay, using the bioreductive nitroimidazole derivatives CCI-103F and pimonidazole, to study changes in tumor hypoxia after treatments that modify tumor oxygenation. METHODS AND MATERIALS: Both hypoxic markers were visualized by immunohistochemical techniques to detect changes in hypoxic fraction induced by carbogen breathing (95% O(2) and 5% CO(2)) or hydralazine injection. The protocol was tested in a human laryngeal squamous cell carcinoma xenograft line. Quantitative measurements were derived from consecutive tissue sections that were analyzed by a semiautomatic image analysis system. Qualitative analysis was obtained by double staining of the two hypoxic markers on the same tissue section. RESULTS: A significant correlation between the hypoxic fractions for the two markers, CCI-103F and pimonidazole, was found in air breathing animals. After carbogen breathing, the hypoxic fraction decreased significantly from 0.07 to 0.03, and after hydralazine treatment, the hypoxic fraction increased significantly. Reduction of hypoxia after carbogen breathing was most pronounced close to well-perfused tumor regions. CONCLUSIONS: With this method, employing two consecutively injected bioreductive markers, changes in tumor hypoxia can be studied. A significant reduction in hypoxia after carbogen breathing and a significant increase in hypoxia after hydralazine administration was demonstrated.

Hypoxia in a human intracerebral glioma model.

OBJECT: The development of hypoxia in human gliomas is closely related to functional vasculature and the presence of hypoxia has important biological and therapeutic consequences. Assessment of hypoxia is necessary to understand its role in treatment response and to evaluate treatment strategies to improve tumor oxygenation. In this study, the authors report findings of their analysis of the degree of hypoxia in relation to other vascular parameters in a human intracerebral glioma xenograft. METHODS: In sections of tumor, hypoxic regions were identified immunohistochemically by using the hypoxic marker pimonidazole. The S-phase marker bromodeoxyuridine was used to detect cell proliferation, and the perfusion marker Hoechst 33342 was used to delineate perfused vessels. Vascular structures were stained with an endothelial marker. Hypoxic tumor regions were clearly present in this human intracerebral glioma model. Hypoxic areas were usually found in nonperfused regions, whereas tumor cell proliferation was especially marked in perfused tumor areas. Furthermore, by using in situ hybridization the authors identified infiltrating tumor cells in the normal brain. This feature is often observed in gliomas in patients. CONCLUSIONS: This model is a representative human glioma model that provides the researcher with the opportunity to analyze the relationship between the degree of hypoxia and vascular parameters, as well as to examine the effects of treatments aimed at modification of the oxygenation status of a tumor.

Spatial relationship between hypoxia and the (perfused) vascular network in a human glioma xenograft: a quantitative multi-parameter analysis.

PURPOSE: To quantitatively study the spatial distribution of tumor hypoxia in relation to the perfused vasculature. METHODS AND MATERIALS: Using a human glioma xenograft model, nude mice were administered two different hypoxia markers (NITP or pimonidazole) and the perfusion marker Hoechst 33342. Frozen tumor sections were sequentially scanned for perfusion, hypoxia, and vasculature, respectively, to quantitate perfusion, vasculature, and hypoxia parameters in the same section. RESULTS: All tumors showed incomplete perfusion. Both NITP and pimonidazole stained the same hypoxic tumor areas. No statistically significant differences between the two markers were observed. The density of the perfused vessels was inversely related to the hypoxic fraction. At critical distances from perfused vessels, hypoxia occurred. These data suggest that predominantly diffusion-limited hypoxia was detected, based on the spatial distribution of nearby vessels. Also, the proportion of hypoxia distributed over arbitrary zones of 50 microm around perfused vessels was calculated. The largest proportion of hypoxia was found at distances beyond 100 microm from perfused vessels. CONCLUSION: With the multiple staining and functional microscopic imaging technique described here, the spatial relationship between perfused vessels and hypoxia was quantified in whole tumor cross-sections. The usefulness of this histologically-based method to quantitate morphological and physiological aspects of the tumor microenvironment was evaluated.

Vascular architecture and hypoxic profiles in human head and neck squamous cell carcinomas.

Tumour oxygenation and vasculature are determinants for radiation treatment outcome and prognosis in patients with squamous cell carcinomas of the head and neck. In this study we visualized and quantified these factors which may provide a predictive tool for new treatments. Twenty-one patients with stage III-IV squamous cell carcinomas of the head and neck were intravenously injected with pimonidazole, a bioreductive hypoxic marker. Tumour biopsies were taken 2 h later. Frozen tissue sections were stained for vessels and hypoxia by fluorescent immunohistochemistry. Twenty-two sections of biopsies of different head and neck sites were scanned and analysed with a computerized image analysis system. The hypoxic fractions varied from 0.02 to 0.29 and were independent from T- and N-classification, localization and differentiation grade. No significant correlation between hypoxic fraction and vascular density was observed. As a first attempt to categorize tumours based on their hypoxic profile, three different hypoxia patterns are described. The first category comprised tumours with large hypoxic, but viable, areas at distances even greater than 200 micrometer from the vessels. The second category showed a typical band-like distribution of hypoxia at an intermediate distance (50-200 micrometer) from the vessels with necrosis at greater distances. The third category demonstrated hypoxia already within 50 micrometer from the vessels, suggestive for acute hypoxia. This method of multiparameter analysis proved to be clinically feasible. The information on architectural patterns and the differences that exist between tumours can improve our understanding of the tumour micro-environment and may in the future be of assistance with the selection of (oxygenation modifying) treatment strategies.

Noninvasive assessment of the functional neovasculature in 9L-glioma growing in rat brain by dynamic 1H magnetic resonance imaging of gadolinium uptake.

Pathophysiologic parameters of the functional neovasculature and the blood-brain barrier of 9L-glioma in rat brain were measured noninvasively by dynamic 1H magnetic resonance imaging studies of gadolinium (Gd)-DTPA uptake. Changes of apparent [Gd-DTPA] uptake in time (CT[t]) were analyzed in a slice through the center of 10 9L-gliomas using fast T1 measurements. The distribution of the contrast agent was spatially correlated with the distribution of perfused microvessels as determined by immunohistochemical analysis. This method permits a distinction between perfused and nonperfused microvessels with a disrupted blood-brain barrier. In transverse slices of the whole tumor, a spatial correlation was observed between CT maps and the two-dimensional distribution of perfused microvessels. In the next step, Gd-DTPA uptake rates were spatially related to the perfused microvessel density (Np) or vascular surface area (Sp). In tumor voxels with perfused microvessels, a linear correlation was found between Gd-DTPA uptake rate constants (k values) and Np or Sp. No correlation was observed between k values and the total microvessel density. These are the first data that show a relation between Gd-DTPA uptake rates and parameters of the functional neovasculature in 9L-glioma growing in rat brain. Now that Gd-DTPA uptake studies can be related to parameters of the functional neovasculature, they may be used more efficiently as a prognostic tool before or during therapy.

Changes in blood perfusion and hypoxia after irradiation of a human squamous cell carcinoma xenograft tumor line.

The effect of irradiation depends on the oxygenation status of the tissue, while irradiation itself also changes the oxygenation and perfusion status of tissues. A better understanding of the changes in tumor oxygenation and perfusion over time after irradiation will allow a better planning of fractionated radiotherapy in combination with modifiers of blood flow and oxygenation. Vascular architecture (endothelial marker), perfusion (Hoechst 33342) and oxygenation (pimonidazole) were studied in a human laryngeal squamous cell carcinoma tumor line grown as xenografts in nude mice. The effect of a single dose of 10 Gy X rays on these parameters was evaluated from 2 h to 11 days after irradiation. Shortly after irradiation, there was an 8% increase in perfused blood vessels (from 57% to 65%) followed by a significant decrease, with a minimum value of 42% at 26 h after irradiation, and a subsequent increase to control levels at 7 to 11 days after irradiation. The hypoxic fraction showed a decrease at 7 h after treatment from 13% to 5% with an increase to 19% at 11 days after irradiation. These experiments show that irradiation causes rapid changes in oxygenation and perfusion which may have consequences for the optimal timing of radiotherapy schedules employing multiple fractions per day and the introduction of oxygenation- and perfusion-modifying drugs.

Effect of vegetable and carotenoid consumption on aberrant crypt multiplicity, a surrogate end-point marker for colorectal cancer in azoxymethane-induced rats.

Epidemiological studies indicate that increased vegetable consumption reduces the risk of colorectal cancer mortality. In the present study we have investigated the effect of consumption of standard diets supplemented with freeze-dried vegetables (peas, spinach, sprouts and broccoli) and carotenoids (all-trans beta-carotene and palm oil carotenoid extract) on surrogate end-point markers for colorectal cancer in an azoxymethane-induced rat model. Mean aberrant crypt multiplicity was reduced (19%) by the pea-supplemented diet only (P < 0.05). The vegetable-induced effect was more apparent in aberrant crypt foci with higher multiplicity. Intervention with diets supplemented with peas, spinach, sprouts and a mix of all vegetables reduced the number of foci with >2 aberrant crypts/focus by 37, 26, 23 and 26%, respectively (P < 0.05). Even more pronounced effects were observed in foci with >3 aberrant crypts/focus, with reductions of approximately 50% in the pea and spinach intervention groups. All-trans beta-carotene and palm oil-derived carotenoids, supplied at similar doses to those expected in the vegetable diets, inhibited ACM only marginally. Aberrant crypt foci formation in groups fed a sprout-supplemented diet prior to or following azoxymethane treatment was similar, indicating that this effect is due to inhibition of promotion rather than initiation of colorectal carcinogenesis. Vegetable and carotenoid consumption did not affect in situ proliferation of colonic crypt cells, as assessed by semi-automated image analysis of bromodeoxyuridine (BrdU)-positive nuclei. BrdU-negative nuclei of colonic crypt cells were reduced slightly in the combined vegetable groups, as compared with the control (P < 0.05). These data: (i) are in line with epidemiological evidence regarding beneficial effects of vegetable consumption on colorectal carcinogenesis; (ii) indicate that consumption of several types of vegetables inhibits early post-initiation events in colorectal carcinogenesis; (iii) suggest that the vegetable-induced effect is more pronounced in advanced lesions; (iv) indicate that the carotenoid content of the vegetables (alpha- and beta-carotene) contributes only marginally to the vegetable-induced effects.

Global HDO uptake in human glioma xenografts is related to the perfused capillary distribution.

The aim of this study is to evaluate the existence of a possible relationship between global deuterium-labeled water (HDO) uptake rates and the diffusion geometry of human glioma xenografts in nude mice. HDO diffusion times in the whole extravascular tumor volume were estimated by combining quantitative (1)H-MR diffusion imaging and morphometric analysis of intercapillary distances in two tumor lines with a different perfused vascular architecture. HDO uptake was measured independently using (2)H-magnetic resonance spectroscopy. Time constants of HDO-uptake curves (tau) were compared to estimations of maximum HDO diffusion times (t(difmax)). Tumors with a homogeneously perfused capillary distribution showed a mono-exponential HDO uptake. The t(difmax) was comparable to tau values of HDO uptake curves: t(difmax) varied between 74 and 368 sec and the range of tau values was 115-370 sec. Heterogeneously perfused tumors had a bi-exponential HDO uptake with t(difmax) in between the tau values of the fast and slow uptake phase. These findings indicate that the global HDO uptake is related to the perfused capillary distribution in human glioma xenografts. That HDO uptake rates indeed can depend on the perfused capillary distribution was substantiated in experiments with two-dimensional (2D) models. In these models with a diffusion-limited HDO uptake, HDO uptake curves could be approximated by curves derived from 2D HDO diffusion simulations. Magn Reson Med 42:479-489, 1999.

Vascular architecture and microenvironmental parameters in human squamous cell carcinoma xenografts: effects of carbogen and nicotinamide.

BACKGROUND AND PURPOSE: A better understanding of the vascular architecture and the microenvironmental parameters (VAMP) will allow the identification of tumours that can be more effectively treated by intensified fractionated radiotherapy or modifiers of blood flow and oxygenation or combinations of these approaches. MATERIALS AND METHODS: Proliferation (BrdUrd), vascular architecture (endothelial marker), perfusion (Hoechst 33342) and oxygenation (NITP) were studied in two human laryngeal squamous cell carcinoma tumour lines grown as xenografts in nude mice. The effects of carbogen and nicotinamide on these parameters were evaluated. RESULTS: Carbogen treatment resulted in a decrease of the number of perfused blood vessels from 66% to 55% in one of the two tumour lines. In this tumour line nicotinamide prevented this reduction of tumour blood flow by carbogen. In both tumour lines the labelling index (LI) decreased after treatment with carbogen for 1 h, from 11-13% to 5-7%. Both tumour lines showed a drastic reduction of hypoxia by carbogen alone or by carbogen plus nicotinamide. CONCLUSIONS: In both laryngeal squamous cell carcinoma xenograft tumour lines carbogen was very effective in reducing diffusion limited hypoxia. Only in one of the two tested tumour lines carbogen also caused a reduction of tumour blood perfusion, which could be compensated for by nicotinamide. In addition, carbogen reduced tumour cell proliferation. The fact that differences in response to nicotinamide and carbogen were observed and that they can be studied in vivo provides a basis for further development of a 'predictive profile' which will guide the clinician to select the optimal treatment for individual patients or groups of patients.

A quantitative analysis of vascularization and perfusion of human glioma xenografts at different implantation sites.

The effect of tissue site of implantation of four different human gliomas on tumor vascularity and perfusion was examined. Vascular parameters of gliomas implanted subcutaneously in the nude mouse and intracerebrally in the nude rat were analyzed. Tumor vessels were stained with an antibody to collagen type IV and perfusion was investigated with the perfusion marker Hoechst 33342. Characteristic vascular patterns were observed in both intracerebral and subcutaneous xenografts belonging to the same tumor line. Major differences in vascular architecture and in the degree of vascularization were noted in comparisons of the two implantation sites for the same tumor line. Tumor perfusion was highly variable for both locations of tumor growth. Distinct differences between the implantation sites of similar tumor lines in vascular perfusion, intervascular distance, and vascular density were present. Incomplete perfusion of vascular structures, as seen in this study, may result in reduced delivery of oxygen to tumor areas. Therefore, measurements of vascular density and intervascular distance alone, without knowledge of the perfusion status, may not be sufficient to estimate the degree of tumor oxygenation. Furthermore, differences in vascular parameters may have important consequences for treatment modalities such as radiotherapy and chemotherapy. Thus, the findings in our study suggest that care has to be taken in extrapolating therapy results obtained with subcutaneous glioma tumor models to the original growth location of gliomas, the brain, due to major differences in vasculature.