Chemotherapy-induced peripheral neuropathy in cancer patients: a four-arm randomized trial on the effectiveness of electroacupuncture.

Purpose. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting side effect of cytostatic drugs. Since there are no proven therapeutic procedures against CIPN, we were interested to define the role of electroacupuncture (EA) from which preliminary data showed promising results. Methods. In a randomized trial with a group sequential adaptive design in patients with CIPN, we compared EA (LV3, SP9, GB41, GB34, LI4, LI11, SI3, and HT3; n = 14) with hydroelectric baths (HB, n = 14), vitamin B1/B6 capsules (300/300 mg daily; VitB, n = 15), and placebo capsules (n = 17). The statistical power in this trial was primarily calculated for proving EA only, so results of HB and VitB are pilot data. Results. CIPN complaints improved by 0.8 ± 1.2 (EA), 1.7 ± 1.7 (HB), 1.6 ± 2.0 (VitB), and 1.3 ± 1.3 points (placebo) on a 10-point numeric rating scale without significant difference between treatment groups or placebo. In addition no significant differences in sensory nerve conduction studies or quality of life (EORTC QLQ-C30) were found. Conclusions. The used EA concept, HB, and VitB were not superior to placebo. Since, contrary to our results, studies with different acupuncture concepts showed a positive effect on CIPN, the effect of acupuncture on CIPN remains unclear. Further randomized, placebo controlled studies seem necessary. This trial is registered with DRKS00004448.

Characteristics of cancer patients using homeopathy compared with those in conventional care: a cross-sectional study.

BACKGROUND: There are only few studies on cancer patients who are treated in complementary and alternative medicine clinics and comparing them with patients in conventional care. We will present the comparison of characteristics of two patient cohorts: one was treated in a homeopathic cancer care clinic and one was treated in a conventional oncology care (CC) outpatient clinic. PATIENTS AND METHODS: Six-hundred and forty-seven patients were included in this cross-sectional cohort study and had to fill in questionnaires [health-related quality of life (QoL) (Functional Assessment of Cancer Therapy-General Scale), depression and anxiety (Hospital Anxiety and Depression Scale), fatigue (Multidimensional Fatigue Inventory) and expectancies toward treatment]. Clinical data were extracted from medical records. This study presents the comparison of both cohorts. RESULTS: Patients in the homeopathy cohort are younger, better educated and more often employed than patients in the CC cohort. The most pronounced differences indicate longer disease histories and different diagnostic and clinical pretreatment variables. Despite the clinical differences, QoL as well as anxiety, depression and fatigue was similar in both the groups. CONCLUSIONS: Homeopathic treatment is sought by cancer patients at a different phase during the course of the disease, which has particular implications for research. However, expectancies toward the benefit of the treatment as well as QoL data are similar.

Effects of specific neuropsychological training programs for breast cancer patients after adjuvant chemotherapy.

Neuropsychological deficits are among the negative side effects of adjuvant chemotherapy for breast cancer. We compared the effects of two types of neuropsychological interventions against a control group with no specific training in a total of 96 female in-patients undergoing oncological rehabilitation. Most results of a comprehensive neuropsychological test battery improved significantly during the patients' oncological rehabilitation in all three groups; we identified no specific intervention effects. We observed little overall correlation between the neuropsychological test results and the patients' own appraisals of their mental capacity. Clinically relevant neuropsychological deficits were still evident 6 months later in a small subgroup of patients.

Cognitive deficits as long-term side-effects of adjuvant therapy in breast cancer patients: 'subjective' complaints and 'objective' neuropsychological test results.

OBJECTIVE: Various studies have demonstrated that neuropsychological deficits are potential side-effects of adjuvant therapy in breast cancer patients. To date, little is known about the long-term development of these deficits and their implications for patients' everyday life. METHODS: Within the framework of an intervention study, 90 breast cancer patients after adjuvant chemotherapy were examined at three measurement points. The focus of this article is on the cognitive status at the last measurement point (on average, 9 months after the end of oncological therapy) and, in particular, on the correlations between subjective self-appraisal and neuropsychological test results. RESULTS: Although the prevalence of neuropsychological deficits significantly decreased as time elapsed after the end of oncological therapy, 21% of our sample group still displayed indications of clinically relevant long-term cognitive deficits. A sub-group of severely affected patients showed specific deficits in verbal-semantic memory and judged their everyday cognitive performance as being extremely poor. CONCLUSION: The identification of verbal-semantic memory as a specific problem area has important implications on the planning of future studies with regard to both the examination of underlying pathophysiological mechanisms and the specific effects of these deficits on patients' self-appraisal.

Rehabilitation of therapy-related cognitive deficits in patients after hematopoietic stem cell transplantation.

Neuropsychological deficits are potential side effects of hematopoietic stem cell therapy (HSCT). Systematic data on the long-term course of and therapeutic options for these consequences are limited. One hundred fifty-seven patients were screened for cognitive deficits following HSCT for malignant diseases at an in-patient oncologic rehabilitation clinic. Patients showing evidence of impairment were randomly assigned to one of two training groups: individualized PC-supported training or neuropsychological group therapy. The control group consisted of patients who received no specific training. During in-patient rehabilitation, the results of a comprehensive neuropsychological test battery improved significantly in all three groups, and no specific intervention effects were identified. Neuropsychological deficits were still evident in a subgroup of patients 6 months later. Correlation between neuropsychological testing and patients' self-evaluation of cognitive functioning in daily life was generally low. Sustained attention and verbal-semantic memory played the main role for self-appraisal and in the designation as 'neuropsychologically impaired'. In conclusion, a substantial number of patients revealed evidence of cognitive deficits a long time after HSCT. There is a need for more studies and for the development of differentiated rehabilitative measures for such therapeutic consequences.

Cognitive dysfunction and subjective complaints of cancer patients. a cross-sectional study in a cancer rehabilitation centre.

Although the neurotoxicity of many anticancer therapies is well documented, the impact of cancer treatment on cognitive functioning has been studied less frequently. The present study examines deficits in cognitive functioning and their correlation with medical data as well as with psychosocial variables. A standardised neuropsychological test battery and several questionnaires were administered to a random sample of 119 patients. 24% of our patients fulfilled our criterion for cognitive impairment. There were no significant associations between the results of the neuropsychological testing and the current affective status or self-reports of attentional deficits in daily life. Cognitive impairment occurs in a clinically relevant percentage of cancer patients and cannot be explained exclusively due to depression or anxiety. Since subjective and objective cognitive impairment data showed little correlation, neuropsychological evaluation should not only be based on subjectively-reported complaints, but also on objective measurements.

Cancer-related fatigue in patients attending oncological rehabilitation programs: prevalence, patterns and predictors.

BACKGROUND: Fatigue is one of the most frequent symptoms in cancer patients. It is the aim of medical and psychosocial rehabilitation programs to reduce physical impairments and psychosocial distress. There are no reliable data on the prevalence or the pattern of fatigue in patients attending such rehabilitation programs. We therefore initiated a cross-sectional study to evaluate this phenomenon. PATIENTS AND METHODS: Using the EORTC QLQ-C30, HADS and MFI questionnaires in 144 patients with different malignant diseases the incidence, patterns and necessity of treatment of fatigue were evaluated. RESULTS: One third of the patients were diagnosed with breast cancer, 27% with gastrointestinal cancers and 20% suffered from haematologic/lymphatic diseases. There was a good correlation between fatigue levels in the 3 instruments used. 22% of all patients showed significant symptoms of fatigue. The univariate analysis did not reflect any significant differences in severity of fatigue with respect to diagnosis, haemoglobin levels, medical and therapeutic history or sociodemographic data. However, using cluster analysis we could identify 3 groups of patients that differ significantly in fatigue and quality-of-life measurements. CONCLUSION: We conclude from our data that fatigue is an important phenomenon in cancer patients who attend medical and psychosocial rehabilitation programs. This has an impact on the ability and degree to reintegrate these patients into everyday life.

[What is the benefit of oncological rehabilitation programs for cancer patients in palliative care?]. / Was können onkologische Rehabilitationsstrategien für Tumorpatienten in palliativen Erkrankungssituationen leisten?

Medical and psychosocial rehabilitation of cancer patients is deeply integrated into the German health system. In contrast to the majority of other European countries and the United States of America, rehabilitation is mainly done as inpatient care and only rarely in outpatient units. In curative treated cancer patients the main goals of rehabilitation include recovery from physical impairments, adaptation to functional disabilities and improvement of psychosocial functioning, including the ability to go back to work. In palliative cancer patients the improvement of health adjusted quality of life, the avoidance of permanent supportive care and the social integration are the major goals. Cancer rehabilitation needs an interdisciplinary strategy between medical, psychooncologic, physiotherapeutical and educational professionals. To attain a benefit for the individual cancer patient as well as for the medical system it is important to clearly define the rehabilitation needs and design a most individual rehabilitation program adjusted to the personal needs of the patient. A systematic quality management since 1995 of German rehabilitation clinics and rehabilitation programs did significantly improve this part of the professional health system. However it is necessary to add more outpatient units for cancer rehabilitation to reach more flexibility and satisfy the demand of patients for more home located support.

[Pharmaceutical comparability of different therapeutic Echinacea preperations]. / Zur pharmazeutischen Vergleichbarkeit von therapeutisch verwendeten Echinacea-Präparaten.

Cichoric acid and Dodeca 2E, 4E, 8Z, 10E/Z-tetraenoic acid isobutylamide (alkamides 8, 9) are described as immunomodulating active components of Echinacea. We quantified both substances in 25 Echinacea-containing remedies customary in trade. Concerning both active components, we found highly concentrated remedies as well as remedies without any detectable cichoric acid or alkamides. The concentration of both active components varied extremely depending on the type of remedy (homeopathic mother tincture, pressed juice, tablets, spagyric tincture), on the Echinacea-species (Echinacea angustifolia, Echinacea pallida, Echinacea purpurea) and on the part of the plant (root, herb, whole plant). Moreover, we found large differences between comparable drugs of different manufacturers and between different charges of the same remedy. We recommend that preclinical and clinical studies with Echinacea-containing drugs should always include the quantification of the potentially active components. We are convinced, that in the long term this will help to clarify how the different active components contribute to the immunomodulating effect of Echinacea.

[Process quality in oncologic rehabilitation. Viewpoint of the Professional Committee of Rehabilitation, After-care and Social Medicine of the German Cancer Society]. / Zur Prozessqualität in der onkologischen Rehabilitation. Die Sichtweise der Arbeitsgemeinschaft für Rehabilitation, Nachsorge und Sozialmedizin in der Deutschen Krebsgesellschaft (ARNS).

The article concerns itself with the issue of process quality in inpatient institutions for oncological rehabilitation and expresses the viewpoint of the German Cancer Society's Section for Rehabilitation, Aftercare and Social Medicine (ARNS). Standards for the organization of patients' access to the rehabilitation clinic, for the design of oncological-rehabilitational diagnostics, for the formation of therapeutic strategies and the rehabilitative services offered will be described.

Cytokine production in leukocyte cultures during therapy with Echinacea extract.

We measured the levels of the cytokines IL-1-alpha, IL-1-beta, IL-2, IL-6, TNF-alpha, and IFN-gamma in culture supernatants of stimulated whole blood cells derived from 23 tumor patients undergoing a 4-week oral treatment with a spagyric extract from Echinacea angustifolia, Eupatorium perfoliatum, and Thuja occidentalis (Echinacea complex). All patients had had curative surgery for a localized solid malignant tumor. Blood was taken before treatment and after 2 and 4 weeks of therapy. Twelve untreated tumor patients at the same clinical stage, also after curative surgery, served as a control group. In the blood cell cultures of all patients, a rather wide range of cytokine levels was found. After therapy with Echinacea complex, no significant alteration in the production of the cytokines could be seen in comparison to the controls, and also the leukocyte populations remained constant. We conclude that at this application and dosage, the therapy with Echinacea complex has no detectable effect on tumor patients' lymphocytes activity as measured by their cytokine production.

Accuracy and precision in protein crystal structure analysis: two independent refinements of the structure of poplar plastocyanin at 173 K.

The structure of the copper protein plastocyanin from poplar leaves (Populus nigra var. italica) at 173 K has been subjected to two independent refinements, using a single set of synchrotron X-ray data at 1.6 A resolution. Energy-restrained refinement using the program EREF resulted in lower root-mean-square deviations from ideal geometry (e.g. 0.011 A for bond lengths) but a higher residual R (0.153) than restrained least-squares refinement using the program PROLSQ (0.014 A, 0.132). Electron-density difference maps in both refinements provided evidence for disorder at some side chains and solvent atoms, and the PROLSQ refinement made allowance for this disorder. The number of solvent sites identified at the 4sigma(rho) level was 171 in the EREF refinement and 189 in the PROLSQ refinement; 159 of the solvent sites are common to both refinements within 1 A. The root-mean-square differences between the atomic positions produced by the two refinements are 0.08 A for C(alpha) atoms, 0.08 A for backbone atoms and 0.12 A for all non-H atoms (excluding six obvious outliers) of the protein molecule. The two sets of Cu-ligand bond lengths differ by up to 0.07 A, and the ligand-Cu-ligand angles by up to 7 degrees. At 173 K the volume of the unit cell is 4.2% smaller than at 295 K. Greater order in the solvent region is indicated by the location of 79 more solvent sites, the identification of extensive networks of hydrogen-bonded rings of solvent molecules, and a general decrease in the thermal parameters. Within the unit cell, the protein molecules are significantly translated and rotated from their positions at ambient temperature. An important structural change at low temperature is a 180 degrees flip of the peptide group at Ser48-Gly49. Nearly all other significant differences between the structures of the protein at 173 and 295 K occur at exposed side chains. If the backbone atoms in the 173 and 295 K structures are superposed, excluding atoms involved in the peptide flip, the root-mean- square difference between the positions of 393 atoms is 0.25 A. Two internal water molecules, not included in previous descriptions of poplar plastocyanin, have been located. The plastocyanin Cu-site geometry at 173 K is not significantly different from that at 295 K. If plastocyanin undergoes a change in Cu-site geometry at low temperature, as has been suggested on the basis of resonance Raman spectroscopic evidence, then the change is not detected within the limits of precision of the present results.

Accuracy in Laue X-ray diffraction analysis of protein structures.

The accuracy in protein structure analysis based on Laue X-ray diffraction has been investigated for the example of two orthorhombic structures of bovine pancreatic trypsin (BPT). The precision in the Laue structure factors and the contrast in electron-density maps were used as criteria. A comparison with the results of previous analyses based on conventional crystal rotation methods showed that high resolution around 1.4 A may be reached with both monochromatic and polychromatic techniques. Electron-density maps exhibited significantly lower contrast when calculated on the basis of Laue structure amplitudes, due to inefficient exploration of reciprocal space at low resolution by the Laue method even in the case of a broad bandwidth and inclusion of exposures from several different crystal orientations. Laue data were recorded on photographic film and processed using the program LAUEMAD [Bartunik & Borchert (1989). Acta Cryst. A45, 718-726]. The empirically derived wavelength scaling factors based on a comparison of equivalent reflection intensities were in good agreement with theoretical estimates over a broad wavelength range. One BPT structure was refined on the basis of Laue structure amplitudes (current R factor 24% at 1.8 A resolution).

Treatment of gastrointestinal endocrine tumours with interferon-alpha and octreotide.

This paper reports on the results of two controlled therapeutic trials on patients with endocrine tumours of the gastrointestinal tract. Seventeen patients were treated up to 18 months with recombinant interferon-alpha 2c (2 x 10(6) IU/m2 s.c. daily) and 16 patients are treated in an ongoing study with octreotide (3 x 200 micrograms daily). Objective response (greater than 50% reduction of hormone secretion) was observed in one of 15 evaluable patients on IFN-alpha and in 12 of 16 patients on octreotide. Reduction of tumour size was not observed in these two trials. However, the majority of patients had stable tumour size during IFN-alpha and octreotide treatment despite progressive disease before. Subjective improvement due to reduction of symptoms such as flushing, diarrhea, and dermatitis was significantly more frequent after octreotide than after IFN-alpha. Of five endocrine tumour patients with progressive disease on IFN-alpha, three responded to subsequent treatment with octreotide while one had stable disease and one progressed. Two cases are reported from the authors' series of patients treated with octreotide before start of these trials. Complete remission of the tumour by low-dose (2 x 100 micrograms daily) octreotide was observed in one carcinoid patient. This remission has now lasted for four years. In one patient with liver metastasis of a VIPoma, who had become resistant to streptozotocin, his watery diarrhoea is now completely controlled with 100 micrograms octreotide s.c. every second day.

Interleukin-2 in combination with interferon-alpha in disseminated malignant melanoma and advanced renal cell carcinoma. A phase I/II study.

In vitro, the combination of interleukin-2 (Il-2) with interferon-alpha (IFN-alpha) seems to act synergistically on the generation of lymphokine activated killer (LAK) cells. Due to this fact two clinical trials with the combination of Il-2 and IFN-alpha were initiated in malignant melanoma (MM) and renal cell cancer (RCC). Patients with disseminated MM were treated by a sequential application of 10 x 10(6) U/m2 rIFN-alpha 2b s.c. on days 1-7 followed by continuous intravenous infusion of 3 x 10(6) U/m2 rIl-2 on days 8-13 and 15-20. After a pause of 4 weeks the cycle was repeated. In advanced or disseminated RCC, the patients were treated with a daily alternating scheme of 10 x 10(6) U/m2 rIFN-alpha and rIl-2 as 1 h infusion 1 x /day for 14 days. The rIl-2 escalates intra- and interindividually beginning with a dose of 3 x 10(6) U/m2. The cycles were repeated after a pause of 3 and 4 weeks, respectively. The preliminary results show that the schedules are practicable and that the toxicity of the combination of rIl-2 and IFN-alpha does not accumulate. Within the MM group 3/11 evaluable patients achieved partial remission and 2/11 stable disease. In the RCC-group 2/5 evaluable patients achieved partial remission and 2/5 had stable disease so far.

Crystal structure of bovine beta-trypsin at 1.5 A resolution in a crystal form with low molecular packing density. Active site geometry, ion pairs and solvent structure.

The crystal structure of bovine pancreatic beta-trypsin (BPT) has been determined from a novel orthorhombic crystal form which contains substantially more solvent (filling 57% of the volume of the unit cell) than previously determined orthorhombic (44%) and trigonal (37%) BPT structures. The native and benzamidine-inhibited crystal structures of BPT in ammonium sulphate at pH 5.3 have been determined for the new form by molecular replacement techniques. The structures have been refined at 1.5 A resolution with final R-values of 16.7% and 16.9%, respectively. Comparison with the previously refined old orthorhombic forms shows that the overall conformation of the protein backbone is highly conserved. A great number of previously undefined side-chains have been located in density. At the C terminus an extra ion pair involving lysines 87 and 107 has been revealed. A far more detailed picture of the ordered solvent structure has been derived. Thirty water clusters have been identified. A large water network extends from the calcium binding site to the activation area and the autolysis loop. There is evidence for a water channel reaching from the depth of the specificity pocket to the nearby protein surface which might be involved in the displacement of water molecules upon substrate binding. A sulphate anion which forms hydrogen bonds to the active site residues His57, Ser195 and Gly193 was for the first time positioned in clearly defined electron density. Interaction with the sulphate ion may explain the increase in the pKa value of His57 at high sulphate concentrations which was observed by nuclear magnetic resonance studies of a bacterial serine protease both in crystalline form and in solution. Thus, a His-Ser hydrogen bond will not exist in solvents containing sulphate at low pH (up to at least 6.8) where the imidazole of His57 is protonated. The new crystal form is of considerable interest for substrate binding studies. Wide solvent channels should allow diffusion of large substrates (comparable in size to, e.g. pancreatic trypsin inhibitor) into the enzyme crystal. The active site is accessible; intermolecular contact areas are further remote from the active site than in the old orthorhombic form.

[Systemic versus local therapy with recombinant tumor necrosis factor-alpha (r-TNF-alpha) in patients with advanced tumors]. / Systemische versus lokale Therapie mit rekombinantem Tumor-Nekrose-Faktor-alpha (r-TNF-alpha) bei Patienten mit fortgeschrittenen Tumoren.

44 patients with different advanced malignant tumors were treated with recombinant Tumor-necrosis factor alpha (rTNF-alpha) in two Phase-I trials. 30 patients received rTNF-alpha 3 x/week intramuscular in doses between 25-300 mcg. 14 patients were treated intra/peritumoral with rTNF-alpha in the same dose range. The maximal tolerated dose (MTD) was 150 mcg/m2 for both ways of application. The duration of therapy was 1-26 weeks for systemic application and 2-20 weeks for local treatment. 25 patients treated systemically were evaluable for response. In 2 patients a minor response (MR) and in 9 patients stable disease was observed. 5/14 patients receiving rTNF-alpha locally showed a significant tumor regression (3 PR, 2 MR). Main side effects were dose dependent fever, chills, anorexia and nausea. In doses greater than 50mcg/m2 a decrease of blood pressure according to WHO III was noted. Hematologic toxicity included a transient decrease of leucocytes and platelets without indicating a cumulative hematologic toxicity. There were no further organ toxicities. The experience from both phase-I trials indicate a definite antitumoral activity of rTNF-alpha suggesting that locoregional treatment might be superior to systemic application. The side effects observed might be a limitation for larger clinical trials.