[Rehabilitation of lung cancer patients]. / Rehabilitation bei Patienten mit Lungenkarzinom.

In the industrial world incidence and prevalence of lung cancer are increasing. At the same time new drugs and new therapies can improve cure rates, prolong survival and procure better quality of life. Nowadays, oncology provides multimodal therapies which may cause psychological and physical stress in the often multimorbid patients. Furthermore, the tumour itself may cause pain and bring about special nutritional and coping problems. Patients may face fear and depression, nicotine withdrawal, socioeconomic problems and the risk of permanent disability. The sequelae of multimodal therapies can vary according to the chosen procedure such as surgery, radiotherapy, chemotherapy, and hormone or immune treatment. After the end of treatment, rehabilitation needs to address the never-ending fear of disease relapse, dyspnoea and suffocation feelings as well as the psychological problems associated with lung cancer. At the initiation of rehabilitation, physical performance is usually limited by the underlying disease as well as the different therapeutic modalities. In Germany, rehabilitation is mainly carried out as in-patient rehabilitation in specialised oncological or pneumological rehabilitation centres. The analysis of published data shows that in-patient rehabilitation has not been evaluated sufficiently for its efficiency so far. This also applies to out-patient rehabilitation, which is largely unavailable in Germany. Oncologists, pneumologists and patient groups agree that rehabilitation should be offered or even strongly recommended to all lung cancer patients.

Preclinical experiences with magnetic drug targeting: tolerance and efficacy.

Although site-specific direction of drugs within an organism would benefit patients with many diseases, active drug targeting is clinically not yet possible. To overcome some of the problems associated with active drug targeting, we have developed a magnetic fluid to which drugs, cytokines, and other molecules can be chemically bound to enable those agents to be directed within an organism by high-energy magnetic fields. In the first part of this study, various concentrations of the magnetic fluid were tested in rats and immunosuppressed nude mice with regard to subjective and objective tolerance. In the second part, the same parameters were evaluated after administration of the ferrofluid to which epirubicin (4'-epidoxorubicin) was chemically bound. Finally, two forms of therapy with the magnetic fluid were tested: tumor treatment by mechanical occlusion with the ferrofluid in high concentrations; and magnetic drug targeting, using small amounts of the ferrofluid as a vehicle to concentrate epirubicin locally in tumors. As a result, the ferrofluid did not cause major laboratory abnormalities; there was no LD50. With very high concentrations of the ferrofluid, animals showed lethargy for 1-2 days. There were no intolerances with the epirubicin-bound ferrofluid as well. Both forms of treatment led to complete tumor responses in an experimental human kidney as well as in a xenotransplanted colon carcinoma model. Thus, the magnetic fluid is a safe agent, which can be used in different ways for local forms of cancer treatment in conjunction with high-energy magnetic fields.

Locoregional cancer treatment with magnetic drug targeting.

The specific delivery of chemotherapeutic agents to their desired targets with a minimum of systemic side effects is an important, ongoing challenge of chemotherapy. One approach, developed in the past to address this problem, is the i.v. injection of magnetic particles [ferrofluids (FFs)] bound to anticancer agents that are then concentrated in the desired area (e.g., the tumor) by an external magnetic field. In the present study, we treated squamous cell carcinoma in rabbits with FFs bound to mitoxantrone (FF-MTX) that was concentrated with a magnetic field. Experimental VX-2 squamous cell carcinoma was implanted in the median portion of the hind limb of New Zealand White rabbits (n = 26). When the tumor had reached a volume of approximately 3500 mm3, FF-MTX was injected intraarterially (i.a.; femoral artery) or i.v. (ear vein), whereas an external magnetic field was focused on the tumor. FF-MTX i.a. application with the external magnetic field resulted in a significant (P < 0.05), complete, and permanent remission of the squamous cell carcinoma compared with the control group (no treatment) and the i.v. FF-MTX group, with no signs of toxicity. The intratumoral accumulation of FFs was visualized both histologically and by magnetic resonance imaging. Thus, our data show that i.a. application of FF-MTX is successful in treating experimental squamous cell carcinoma. This "magnetic drug targeting" offers a unique opportunity to treat malignant tumors locoregionally without systemic toxicity. Furthermore, it may be possible to use these magnetic particles as a "carrier system" for a variety of anticancer agents, e.g., radionuclides, cancer-specific antibodies, and genes.

Clinical experiences with magnetic drug targeting: a phase I study with 4'-epidoxorubicin in 14 patients with advanced solid tumors.

Anticancer drugs reversibly bound to magnetic fluids (ferrofluids) could be concentrated in locally advanced tumors by magnetic fields that are arranged at the tumor surface outside of the organism. If certain requirements are met, systemic toxicity might be minimized, and local tumor efficacy might be increased. We have conducted a Phase I clinical trial using this approach in patients with advanced and unsuccessfully pretreated cancers or sarcomas. Nine such patients received two treatment courses, 3 patients received one course, and 2 patients received three courses of magnetic drug targeting consisting of the infusion of epirubicin in increasing doses (from 5 to 100 mg/m2) that had been chemically bound to a magnetic fluid and the application of magnetic fields to the tumors for 60-120 min. In 2 of 14 patients, the same dose of epirubicin not bound to a magnetic fluid was administered systemically 3 weeks after drug targeting for intraindividual comparisons. Magnetic drug targeting with epirubicin was well tolerated. In one case, a planned second treatment was withdrawn, because of an episode of chills 130 min after infusion of the magnetic drug. Two patients received a third treatment because of good responses after the first two therapies. Based on magnetic resonance tomographic techniques, pharmacokinetics, and the histological detection of magnetites, it was shown that the ferrofluid could be successfully directed to the tumors in about one-half of the patients. Organ toxicity did not increase with the treatment, but epirubicin-associated toxicity appeared at doses greater than 50 mg/m2. Although treatment with magnetic drug targeting seems safe, improvements are necessary to make it more effective and independent of patient- or disease-related problems. A study design to compare conventional treatments with the new treatment form within one patient seems crucial to eliminate interindividual differences.

Heat shock attenuates endothelium-dependent vasodilation in skeletal muscle microcirculation.

Endothelium-derived relaxing factors (EDRFs) mediate vasodilation of small arterioles in skeletal muscle under various (patho)physiological conditions: Escherichia coli sepsis, systemic hypoxia, and topical acetylcholine (ACH) application. To test if heat shock changes EDRF-dependent reactivity of arterioles to ACH, we used closed-circuit videomicroscopy in the in vivo cremaster muscle of rats whose systemic temperatures had been slowly raised to and maintained at 41 degrees C. We also tested for ACH responses after increasing cremaster muscle temperatures and maintaining those at 40 degrees C. The experiments showed that EDRF-dependent vasodilation of small arterioles to acetylcholine was substantially attenuated in response to systemic and local heat treatment. In two other animal groups, concentration-dependent vasodilation of small arterioles to sodium-nitroprusside was not as much attenuated in the response to local tissue temperature elevation. This suggests that locally elevated tissue or systemically elevated body temperatures can change generation or efficacy of EDRFs in the post-hyperthermia phase in the skeletal muscle microcirculation.

Differential microvascular response to cyclooxygenase blockade in the rat small intestine during acute bacteremia.

To determine whether arachidonic acid metabolites are mediators of regional blood flow changes during sepsis, we examined the effects of cyclooxygenase blockade on intestinal microvascular diameters and blood flow during acute bacteremia, induced in the rat by the intravenous injection of 10(9) live Escherichia coli. Mean arterial pressure, cardiac output, intestinal microvascular diameters, and blood flow were measured in the presence or absence of a topically applied selective cyclooxygenase inhibitor (mefenamate). Bacteremia caused a diffuse constriction of both arterioles and venules and a concomitant 50% decrease in blood flow. Treatment with mefenamate did not affect baseline intestinal microvascular tone or bacteremia-induced arteriolar constriction and hypoperfusion, but did reverse an intense venular constriction. Our results suggest that the small intestinal microcirculation has a differential response to cyclooxygenase products of arachidonic acid metabolism during acute bacteremia. They appear not to be mediators of the intestinal arteriolar constriction and hypoperfusion observed during acute E. coli bacteremia, but profoundly influence the mesenteric venular constriction. These observations support the concept that microvascular control mechanisms are different not only between but within organ specific vascular beds.

Altered microvascular responses of the small intestine to sepsis during renovascular hypertension.

Renovascular hypertension alters endothelial-dependent mechanisms to affect the response of small arterioles in skeletal muscle to sepsis. Small arteriole responses to sepsis differ between skeletal muscle and small intestine in normotensives. Our study now shows that renovascular (1K1C) hypertension alters small arteriole responses in the small intestine to Escherichia coli sepsis. Large arterioles (A1, A2) constricted by 10-20% in the small intestine of both normotensive and hypertensive rats during both high and low cardiac output sepsis. Small arterioles (premucosal A3 and preserosal A4) constricted during high cardiac output sepsis in normotensive but not hypertensive rats. Small A3 and A4 arterioles dilated (20-40%) during low cardiac output sepsis in hypertensives; but only A3 and not A4 arterioles dilated in normotensives during low cardiac output sepsis. Acetylcholine, which releases endothelial-derived relaxing factor in skeletal muscle, dilated both premucosal A3 and preserosal A4 in both normotensive and hypertensive rats. Thus, hypertension alters small arteriole responses to sepsis in both skeletal muscle and small intestine, but apparently by different mechanisms.

Venules and arterioles in xenotransplanted human colon adenocarcinoma critically constrict with hyperthermia and serotonin.

Local and regional hyperthermia for treatment of cancer is often combined with radio- and chemotherapy. In this study we tested whether topically applied serotonin (5-HT) modulates tumor blood flow during local hyperthermia. The surgically unprepared ear microcirculation of anesthetized (75 mg/kg pentobarbital sodium) female nude athymic (nu/nu) mice (18-25 g) was used. Between 5 and 10 days after passaged pieces of human colon adenocarcinoma cells (1 microliter) had been implanted under the dorsal epidermis of the ear, that ear (tumor diameter 1.5 mm) was fixed on a temperature-regulated stage for measurement (via closed-circuit videomicroscopy) of the diameters of large and small (A1-3) arterioles and venules (V1-4), and capillaries, during local hyperthermia (28 degrees C-45 degrees C) and during local hyperthermia plus 1 mmol/l 5-HT. In the hyperthermia-alone group all skin vessels dilated, whereas all tumor vessels constricted with increasing temperatures. Hyperthermia combined with 5-HT caused dilation of skin arterioles, but skin venules constricted. In contrast, we observed constriction of all microvessels in human tumor xenografts with the combination of hyperthermia and 5-HT. We conclude that hyperthermia and 5-HT, applied intratumorally, could be clinically effective, since normal skin microcirculation is best protected with this treatment, while tumor blood flow is widely reduced.

Growth, microvessel density and tumor cell invasion of human colon adenocarcinoma under repeated treatment with hyperthermia and serotonin.

The intratumoral microvessel density of malignant breast cancer has been shown to be an important prognostic marker. In this study, we tested whether repeated treatment with hyperthermia and serotonin (5-hydroxytryptamine) reduces tumor growth and alters tumor histology of a colon adenocarcinoma, and whether capillary density in this tumor can also be regarded as an important prognostic marker. Previously we have shown that acute treatment of colon adenocarcinoma with hyperthermia, alone or in combination with serotonin, selectively constricted tumor microvessels, which could reduce blood flow and inhibit tumor growth. Fourteen days after human colon adenocarcinoma had been transplanted under the dorsal epidermis of the ear of athymic nude mice, the surgically unprepared tumor-bearing ear of the sodium-pentobarbital-anesthetized animal was treated with hyperthermia alone (group 1, 43 degrees C for 45 min), or with hyperthermia plus topically applied serotonin (1 mM/l, 43 degrees C for 45 min, group 2) twice per week for 5 weeks. Control animals were not treated (group 3). Histological slides (stained with hematoxylin/eosin) were prepared 42 days after implantation, for analysis of tumor grading, tumor cell invasion into the surrounding tissue and microvessels, and the number of intratumoral microvessels. Repeated hyperthermia inhibited tumor growth, reduced the number of intratumoral microvessels, did not change tumor cell invasion and increased the necrotic area. Hyperthermia and serotonin did not influence tumor growth, but strongly reduced cell invasion and the number of microvessels. The area of necrosis was very large. Thus, analysis of microvessel density in colon adenocarcinoma seems not to be an important tool for predicting therapeutic efficacy.

Doxorubicin and local hyperthermia in the microcirculation of skeletal muscle.

Doxorubicin HCl (Doxo) is an established intercalating antitumor drug. Specific side effects of Doxo primarily affect the cardiac muscle tissue to cause cardiac arrhythmias and chronic cardiomyopathies. The mechanism of action of these side effects is incompletely understood. Thus, the first objective of the present study was to test whether Doxo might have a direct effect on the microcirculation of muscular tissue. We studied large and small arterioles and large venules in the cremaster muscle of rats before and after sequential infusion of 1 (low-dose) and 10 mg/kg (high-dose) Doxo. Large arterioles showed some constriction after low Doxo doses and pronounced constriction after high Doxo doses, whereas small arterioles showed a variable response to low Doxo doses. At high Doxo doses, small arterioles dilated almost maximally (80% of the maximal response to nitroprusside). The heart rate and the diameter of large venules did not change at high Doxo doses, although the blood pressure decreased. This indicates that Doxo directly affects skeletal muscle arterioles. The second purpose of this study was to determine whether local hyperthermia would influence the microcirculation of muscular tissue such that the systemic concentration of Doxo could be reduced. In this second series of experiments, we tested whether local hyperthermia would have an effect on the skeletal muscle microvasculature and whether Doxo would change that response. Local hyperthermia alone did not alter the diameter of small arterioles or large venules, but we observed constriction of large arterioles at temperatures above 37 degrees C and during continued (60-min) hyperthermia at 40 degrees C. The low dose of Doxo did not alter these microvascular diameters at 40 degrees C. However, local hyperthermia at 40 degrees C changed the response of small arterioles to low doxo doses (no vasodilation was observed). Large arterioles continued to constrict in response to Doxo during hyperthermia. These data suggest that large arteriolar responses could be partly responsible for the toxic effect of Doxo on cardiac muscle and that local hyperthermia potentiates that response.

In vivo analysis of microcirculation following closed soft-tissue injury.

Major loss of tissue is an almost invariable consequence of severe closed soft-tissue injury. Clinically, the extent of soft-tissue trauma determines the outcome of complex injuries and significantly influences bone healing. With use of a new animal model, this study quantitatively analyzed microcirculation, i.e., nutritive perfusion and leukocyte-endothelial cell interaction, in skeletal muscle after standardized closed soft-tissue injury. By means of a computer-assisted controlled-impact technique, a severe standardized closed soft-tissue injury was induced in the left hindlimb of 28 rats. The rats were assigned to four experimental groups (n = 7 per group) that differed by time of analysis (1.5, 24, 72, and 120 hours after injury); rats that were not injured served as controls (n = 7). Intramuscular pressure was measured, and microcirculation in the rat extensor digitorum longus muscle was analyzed by in vivo fluorescence microscopy, which allowed assessment of microvascular diameters, functional capillary density, number of rolling and adherent leukocytes in venules, and microvascular permeability. Edema weight gain was quantified by the ratio of wet to dry weight of the extensor digitorum longus muscle. Microvascular perfusion of the skeletal muscle was characterized by a significant reduction in functional capillary density, which was paralleled by an increase in capillary diameter throughout the 120 hours of observation when compared with the controls. Trauma-induced inflammatory response was reflected by a markedly increased rolling and adherence of leukocytes, primarily restricted to the endothelium of postcapillary venules; this was accompanied by increased microvascular permeability, indicative of a substantial loss of endothelial integrity. The microcirculation surrounding the core of the damaged tissue area resembled that of ischemia-reperfusion injury in skeletal muscle, i.e., heterogeneous capillary perfusion, pronounced microvascular leakage, and adherence of leukocytes. Enhanced vascular leakage and leukocyte adherence (24-72 hours after injury) coincided with the maximum intramuscular pressure (which was not indicative of compartment syndrome) and edema formation. These results demonstrate that initial changes, leading to ultimate tissue death, after closed soft-tissue injury are caused on the microcirculatory level. This standardized model provides further insight into microvascular pathophysiology and cellular interactions following closed soft-tissue injury. Thus, it is an adequate tool for testing novel therapeutic interventions.

Microcirculatory responses to complement activation are blunted by hypertension.

Vasodilation of small arterioles in skeletal muscle during sepsis is an endothelium-dependent response. Renovascular hypertension significantly attenuates this response. Complement activation by zymosan infusion causes small arteriole dilation in skeletal muscle similar to that seen during sepsis. This study was conducted to show whether renovascular hypertension alters the skeletal muscle microcirculatory responses in normotensive rats to systemic activation of the alternative complement system. We found that hypertension abolished the constriction of large A1 arterioles (+3 +/- 2% change at 45 min) and dilation of small A4 arterioles (-2 +/- 2% change at 45 min) in skeletal muscle. Hypertension attenuated but did not abolish (A4: +70 +/- 13% change in hypertensive vs +111 +/- 18% in normotensive rats) the ability of small arterioles to dilate to nitroprusside, an endothelium-independent vasodilator. This suggest that hypertension modifies some type of receptor-level mechanism to reduce small arteriolar dilation during complement activation. We next used hydroquinone to topically block endothelium-derived relaxing factor (EDRF) in hypertensive animals whose complement systems were activated. Hydroquinone did not change the response of large A1 arterioles (+5 +/- 4% hydroquinone change vs +3 +/- 2% non-hydroquinone at 45 min) to complement activation. However, hydroquinone allowed construction of small A4 arterioles (-12 +/- 5% hydroquinone change vs -2 +/- 2%, non-hydroquinone at 45 min) during complement activation in hypertensive rats. We conclude that during hypertension the release of EDRF in small arterioles after complement activation is counterbalanced by a constrictor-producing mechanism.

Adapting, redesigning and improving a German cancer rehabilitation centre for future challenges.

In 1996 political decisions caused significant changes within the German rehabilitation system. Rehab centers had to close down and people were laid off. Yet, new challenges came about also. At Bad Lippspringe, a 125-bed hospital for the specialized rehabilitation and supportive care of cancer patients with speech disturbances, urological incontinence, problems with reduced lung function as well as general medical disorders adapted to those current medical, financial and political challenges. This paper describes the rationale and the outcome of a three-year process in which multiple changes for and within the hospital occurred.

Microcirculation and artificial heart research.

Small blood vessels may play a more important role in artificial heart (AH) recipients than ever suspected before. Observations of elevated total peripheral resistance, low hematocrit, reduced oncotic pressure, high circulating blood volume, and arterial pulsations with nonpulsatile devices require consideration of peripheral vascular control mechanisms. Establishment of microcirculatory parameters could help in adapting cardiac output to different metabolic states. AH research offers the opportunity to evaluate pure microvascular effects of drugs without any cardiac influences. Furthermore, drugs could be developed to alter microvascular and hence, hemodynamic conditions in patients with AH. However, further development of microcirculatory techniques is imperative in order to examine small blood vessels in large animals or patients.

Microvessel diameters of human colon adenocarcinoma during acute treatment with serotonin.

Modulation of tumor blood flow could be of clinical importance, especially when it is combined with radio- or chemotherapy. Serotonin (5-HT), a naturally occurring agent, selectively reduces tumor blood flow and consecutively inhibits the growth of many animal tumors. Therefore, we introduce a new preparation that allows the study of topically applied 5-HT (10(-8) to 10(-2) mol/l) in the microcirculation of a human colon adenocarcinoma. This tumor has been xenotransplanted subcutaneously under the dorsal surface of the ear in athymic nude mice. 5-HT was also tested in the normal skin. The microvascular diameters of large and small arterioles (A1-3) and venules (V1-4) as well as capillaries were measured via closed-circuit videomicroscopy. Normal skin arterioles and venules constricted at higher doses (> 10(-7) mol/l) of 5-HT. In human colon carcinoma, doses of 5-HT higher than 10(-7) mol/l caused constriction of these microvessels; yet, tumor arterioles constricted more than skin arterioles. Thus, 5-HT could selectively reduce blood flow of human colon adenocarcinoma. Based on these findings, we suggest that 5-HT can inhibit growth of human tumors by selectively constricting tumor arterioles.

Hypertension decreases small arteriole responses to acetylcholine in skeletal muscle.

Television microscopy was used to quantitate in vivo the responses of skeletal muscle small arterioles to acetylcholine. Five groups of rats were used: normotensive and one (1K1C)- and two (2K1C)- kidney one clip renovascular hypertensive Sprague-Dawley rats (SDR), as well as WKY normotensive and spontaneously hypertensive (SHR) rats. Third-order arterioles dilated to acetylcholine with an EC50 of 3 x 10(-7) M in SDR and 10(-6) M in WKY animals. In contrast, the concentration-response curve to acetylcholine was shifted to the right (less reactive) by 100 fold in the 1K1C- and by 1000 fold in the 2K1C-hypertensives. The dose-responsive curve to acetylcholine was shifted 10-fold to the right in the SHR's compared to the WKY's. Because acetylcholine acts through endothelium-dependent mechanisms and because maximal vasodilation could be induced by an endothelium-independent vasodilator, Na-nitroprusside, in all but the 2K1C-group, we conclude that different forms of hypertension interfere to a variable degree with endothelium-dependent vasodilator mechanisms in the skeletal muscle microcirculation.