[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.

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.

Health-related quality of life and pulmonary function in lung cancer patients undergoing medical rehabilitation treatment.

Treatment for lung cancer results in reduced Quality of Life (QoL) and limited lung function are well-known. Yet, there are no results available concerning the interaction of objective lung function tests and QoL parameters for lung cancer patients during in-patient cancer rehabilitation. This is also true for outcome parameters in medical rehabilitation. The aim was to study the impact of lung and cardiopulmonary function on QoL (EORTC-QLQ C-30 and SF-36 Health Survey) and to identify possible outcome parameters for a rehab program. 56 lung cancer patients participated. Inpatient rehabilitation consisted of individual aerobic exercise and physical, psychological, social, educational and recreational components and only led to a gain of QoL by SF-36 Health Survey sub scales "Vitality" and "Mental Health". Lung function parameters improved; yet the correlation between lung function and health-related QoL questionnaires was not significant. Multivariate analysis for groups with high and low performance in lung functioning showed differences in the SF-36 Health Survey "Vitality" and "Mental Health" sub-scales. However, patients with high and low functional performance of the lungs did not differ in their QoL over time. Health-related QoL and pulmonary function therefore seem to be independent dimensions. Thus, for judging the outcome and success of medical rehabilitation of lung cancer patients, both, QoL and pulmonary function have to be taken into account.

Clinical applications of magnetic drug targeting.

Cancer patients often present with localized disease. Yet, surgical eradication or radiation treatment is not always possible or meaningful. Site-directed drug targeting is one way of local or regional antitumor treatment. Magnetically controlled drug targeting is one of the various possibilities of drug targeting. This technology is based on binding established anticancer drugs with ferrofluids that concentrate the drug in the area of interest (tumor site) by means of magnetic fields. Then, the drug desorbs from the ferrofluid and enfolds its mechanism of action. This paper gives the reader an overview of current applications of ferrofluids (magnetic liquids) in conjunction with magnetic fields as they relate to the latest advances in medical applications and in particular to anticancer treatment.

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.

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.

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.

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.

Hyperthermia decreases cytokine-mediated adhesion molecule expression on human umbilical vein endothelial cells.

Although hyperthermia has been used as an effective cancer treatment modality, its effects on metastasis of tumour cells are not clear. Since adhesion molecules play a key role in metastasis, we evaluated how the expression of adhesion molecules is influenced by hyperthermia. Human umbilical vein endothelial cells were incubated in vitro for 1 h. at 39, 42, 43 and 44 degrees C with and without addition of tumour-necrosis factor (TNF) or interferon-gamma (IFN-gamma) and the expression of endothelial cell leukocyte adhesion molecule-1 (ELAM-1), intercellular adhesion molecule-1 (ICAM-1) and major histocompatibility complex (MHC) class-II molecule was measured. Expression of MHC class-II molecules and expression of unstimulated constituent ICAM-1's was not reduced by heat treatment. In contrast, expression of cytokine-induced ELAM-1's and ICAM-1's was significantly lower after heat treatment. The adhesion to HUVEC in vitro of HL-60 leukemia cells, which express sialyl-Lewis-x antigen as a ligand to ELAM-1, was diminished after incubation at 42 degrees C and totally lost after treatment at 44 degrees C. This suggests that any decrease in metastasis formation after heat treatment, which is occasionally observed, could be due to a reduced action of TNF or related cytokines on adhesion molecule induction and subsequent membrane expression by the endothelial cell. A possible underlying mechanism involved is a heat-induced alteration or blockage of the biosynthetic pathways required for synthesis of ELAM-1 and ICAM-1 proteins.

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.

Endothelium-dependent microvascular responses to activated complement.

Infusion of Escherichia coli bacteria to cause high cardiac output bacteremia produces a differential microvascular response with constriction of large arterioles and dilation of small arterioles in skeletal muscle of rats. An important component to host-defense mechanisms during bacteremia is activation of the complement system. One part of this study explored the possibility that microvascular responses to bacteremia could be mediated by activation of the alternative complement cascade to alter skeletal muscle blood flow during sepsis. Complement activation by iv zymosan into unanesthetized (decerebrate) Sprague-Dawley rats caused constriction of large arterioles and dilation of small arterioles in cremaster muscle, while cardiac output stayed normal or was elevated. These microvascular responses mimic those during bacteremia, suggesting that components of the complement system mediate skeletal muscle microcirculatory responses to live E. coli sepsis. The vasodilation response of small arterioles in skeletal muscle during bacteremia is endothelium-dependent and is mediated at least partially by endothelial-derived relaxing factor (EDRF). Complement activation gives products which interact with endothelial cells. Thus, a second part of this study explored the role of EDRF in the vasodilation of skeletal muscle small arterioles during activation of the alternate complement pathway. Blockade of EDRF action by hydroquinone totally abolished small arteriole dilation and large arteriole constriction responses to complement activation by zymosan infusion.