Patient reported outcomes in randomized controlled cancer trials in advanced disease: a structured literature review.

INTRODUCTION: In advanced cancer quality of life (QoL) is the most important goal of care. It is measured by patient-reported-outcomes (PRO). This structured review evaluated how randomized controlled trials (RCTs) on anti-cancer therapy in advanced cancer reported PRO. METHODS: Search was performed in MEDLINE via PubMed for RCTs with median patient survival of ≤2 years. Reporting was rated with the Consolidated Standards of Reporting Trials (CONSORT) PRO extension. RESULTS: Of 370 retrieved publications, 117 were eligible, but only 30/117 (26%) reported PRO. QoL was most frequently measured (29/30). On average, 4.4 (SD 2.5) of the 14 CONSORT items were met. CONCLUSION: PRO are insufficiently reported in advanced cancer trials. Yet, this is paramount to enable an informed and patient-oriented decision making process.

Complement activation contributes to ventilator-induced lung injury in rats.

The complement system contributes to ventilator induced lung injury (VILI). We hypothesized that pretreatment with the C1 esterase inhibitor (C1INH) Berinert® constrains complement activation consecutively inducing improvements in arterial oxygenation and histological pulmonary damage. At baseline, male Sprague-Dawley rats underwent mechanical ventilation in a conventional mode (PIP 13 cm H2O, PEEP 3 cm H2O). In the Control group, the ventilator setting was maintained (Control, n = 15). The other animals randomly received intravenous pretreatment with either 100 units/kg of the C1-INH Berinert® (VILI-C1INH group, n = 15) or 1 ml saline solution (VILI-C group, n = 15). VILI was induced by invasive ventilation (PIP 35 cm H2O, PEEP 0 cm H2O). After two hours of mechanical ventilation, the complement component C3a remained low in the Control group (258 ± 82 ng/ml) but increased in both VILI groups (VILI-C: 1017 ± 283 ng/ml; VILIC1INH: 817 ± 293 ng/ml; P < 0.05 for both VILI groups versus Control). VILI caused a profound deterioration of arterial oxygen tension (VILI-C: 193 ± 167 mmHg; VILI/C1-INH: 154 ± 115 mmHg), whereas arterial oxygen tension remained unaltered in the Control group (569 ± 26 mmHg; P < 0.05 versus both VILI groups). Histological investigation revealed prominent overdistension and interstitial edema in both VILI groups compared to the Control group. C3a plasma level in the VILI group were inversely correlated with arterial oxygen tension (R = -0.734; P < 0.001). We conclude that in our animal model of VILI the complement system was activated in parallel with the impairment in arterial oxygenation and that pretreatment with 100 units/kg Berinert® did neither prevent systemic complement activation nor lung injury.

[Palliative medicine and advanced incurable illness]. / Palliativmedizin und fortgeschrittene, nicht heilbare Erkrankungen.

Advanced incurable and life-threatening diseases of internal organs such as chronic obstructive pulmonary disease (COPD), heart failure, and terminal kidney failure are associated with considerable burden for the patients caused by pronounced symptoms (e.g., dyspnea, anxiety, depression) and unmet psychosocial needs. Nevertheless, in Germany addressing palliative medicine in the context of these disorders and co-treatment of these patients by cross-sector partnership with specialized palliative care physicians are not very developed. Against the background of an international perspective and current guidelines, general aspects of palliative care needs (symptom control, communication, advance care planning, etc.) are discussed together with the resultant implications for potential cooperation between internal medicine and palliative care as well as special aspects of the individual diseases (e.g., prognosis or implications of certain treatment options such as "automatic implantable cardioverter-defibrillator", AICD). Timely involvement of the specific expertise of palliative care medicine can ensure that the workload of the primary providers (and their teams) is reduced and better cross-sector management (hospital and home) of the severely ill patients and their families is achieved.

Effects of thiopental on endothelium-dependent relaxation in porcine coronary arteries.

This study investigated the effects of thiopental on endothelium-dependent relaxation (EDR), and especially the effects on nitric oxide- and prostacyclin-independent EDR. Fresh porcine coronary artery rings (4 mm long), were consecutively tested with and without 20 microg/ml thiopental in Krebs-Henseleit solution. Indomethacin (10 micromol/l) was used in all experiments to eliminate prostacyclin effects. Prostaglandin F(2alpha) (10 micromol/l) was used to induce contractions and bradykinin (10(-10) - 10(-5) M) was used to induce EDR. Experiments were also carried out using 300 micromol/l N-nitro-L-arginine to block nitric oxide production and to assess the influence of thiopental on nitric oxide- and prostacyclin-independent EDR. Thiopental induced statistically significant increases in EDR at concentrations of 10(-6) - 10(-5) M bradykinin. Following nitric oxide production block, thiopental significantly reduced the relaxation response at concentrations of 10(-8) - 10(-5) M bradykinin. At a clinically relevant concentration of 20 microg/ml thiopental, a significant increase in EDR and a significant reduction in nitric oxide- and prostacyclin-independent relaxation was observed in porcine epicardial coronary arteries.

[Influence of changes to daily dose of opioids on aspects of cognitive and psychomotor performance involved in driving]. / Einfluss von Anderungen der Opioidtagesdosis auf fahrrelevante kognitive und psychomotorische Leistungen.

INTRODUCTION: It has been shown that long-term treatment with opioids does not necessarily impair driving ability in patients suffering from chronic pain. However, few studies are so far available on how increases in daily opioid dosage affect driving ability. METHODS: A prospective trial was conducted in patients suffering from chronic noncancer pain, to examine the effects of the daily dose of opioids on psychomotor and cognitive functions. A computerized test system was administered to patients before and 7 days after alteration of their opioid therapy, to determine performance affecting driving ability at each time point. The test design was based on both international and national recommendations for the examination of driving safety. RESULTS: Raising the daily dose of opioids and/or changing to an opioid at a higher WHO level had no effect on the functions relevant to driving ability in the group context. Pain intensity and serum concentrations of morphine influenced only few items in the test battery. CONCLUSION: Seven days after an increase in the daily dose of an opioid or after the initiation of opioid therapy there was no general deterioration in patients' driving ability at group level.

Rapidly progressive vanishing white matter disease in a child with previously inconspicuous brain MRI.

In this pediatric case of vanishing white matter disease with early onset, rapidly progressive course, and fatal outcome, the white matter vanishing process in patient was for the first time documented morphologically in detail: An initial magnetic resonance imaging documented a normal appearing brain maturation. Rapid progressive brain lesions initiated morphologically DE NOVO in the former well myelinated deep white matter were observed six months later after disease onset, including concentric ongoing signs of restricted proton diffusion cytotoxic edema on diffusion weighted imaging. Cyst-like defects at the lesion center of the deep white matter were detected more clearly on MRI ten months later. A pathomechanism like tumor necrosis factor induced oligodendrocyte apoptosis and primary demyelination was postulated. The case demonstrates that in the presence of clinically progressive symptoms, the development of VWM is possible even if first MRI findings are negative.

[Pain and symptom management in palliative care]. / Schmerztherapie und symptomorientierte Behandlung in der Palliativmedizin.

Physical complaints, especially severe pain, result in a massive restriction of a patient's quality of life, especially in the late stages of their disease. The patient's needs and wishes should be the primary goal of any symptom-aimed therapeutic measure. Before initiating or continuing any antineoplastic procedure (e.g., radiation, chemotherapy), it is essential to thoroughly consider their benefits and side effects, since some patients benefit considerably more from quality of life oriented symptom control. This review article describes the basics of cancer pain therapy and symptom management, which are based on the guidelines published by the World Health Organization (WHO).

Assessing cognition and psychomotor function under long-term treatment with controlled release oxycodone in non-cancer pain patients.

BACKGROUND: The therapeutic use of opioids can be associated with altered cognition and impaired psychomotor function. Several studies have demonstrated the impact of opioid therapy on psychomotor performance and cognition, but no data exist about the effect of long-term treatment with controlled release oxycodone (CRO) on driving ability. METHODS: Thirty patients suffering from chronic non-cancer pain who had been treated with stable doses of CRO where included in a prospective trial and compared with 90 healthy volunteers (matched pairs). A computerized test battery that was developed to assess the driving ability of traffic delinquents in Germany was employed. Attention reaction, visual orientation, motor coordination and vigilance were evaluated. The data from a total of 11 parameters were assessed and for each test a relevant score was defined. As the primary endpoint the sum score of the three relevant scores was determined. A weaker statistical means to assess the patients' performance is to compare the test results with an age-independent control group. Individuals performing worse than the 16th percentile of this control group are considered to be unable to drive according to German legislation. RESULTS: Significant non-inferiority could not be demonstrated for the primary endpoint. However, driving ability as defined as a result above the 16th percentile did not differ significantly between the patients receiving CRO and the age-independent control group. CONCLUSION: The use of CRO does not prohibit driving, but individual assessment is necessary.

[Efficacy of opioid analgesia at the superior cervical ganglion in neuropathic head and facial pain]. / Opioidwirksamkeit am Ganglion cervicale superius bei neuropathischen Schmerzen im Kopf- und Gesichtsbereich.

The efficacy of ganglionic local opioid analgesia (GLOA) at the superior cervical ganglion (SCG) was retrospectively investigated in 74 consecutive patients with neuropathic pain in the head and face region. It was possible to retrospectively analyze the short-term and medium-term treatment results in 64 of 74 patients. The long-term effect was subsequently determined using a standardized questionnaire. The short-term analgesic effect of the first blockade by GLOA was significant with a mean pain reduction of 52% (p < 0.001). Within a span of 20 min the mean pain intensity decreased from 65 to 28 on a visual analogue scale. A clinically relevant pain reduction (> or = 30%) was observed in 73% of the patients. The proportion of responders (pain reduction > or = 50%) was 59% after the first blockade. Patients with zoster or trigeminal neuralgia experienced greater pain relief than patients with atypical facial pain or longer lasting postzoster neuralgia. During the course of the blockade series with an average duration of 33 days, a significant medium-term pain reduction of 30% was noted. In the first 3 treatment days, the level of continuous pain declined from 6.3 to 4.3 on a numerical rating scale. Short-term responders reported a better medium-term pain reduction than nonresponders. After 3 years (range: 5 months to 6 years), 21% of 52 patients remained free of pain. The other patients reported often only minimal residual pain or a decrease of pain severity and duration. According to these results, GLOA at the SCG can represent a suitable and simple treatment option for neuropathic facial pain.

[Oral controlled-release oxycodone for the treatment of chronic pain. Data from 4196 patients]. / Therapie chronischer Schmerzen mit oralem retardiertem Oxycodon. Behandlungsdaten von 4196 Patienten.

Oral controlled-release oxycodone has been available for the treatment of chronic pain in Germany since 1998. Controlled trials have shown good clinical efficacy and tolerability. This survey reports results from six open prospective multicenter trials. In these trials 4196 patients suffering from cancer pain and non-cancer-related pain with inadequate pain relief were treated with oral controlled-release oxycodone for 3-4 weeks. Only a few participating physicians were pain specialists. A total of 356 patients suffering from pain of the musculoskeletal system and receiving oxycodone therapy were monitored for 6 months. Exclusion from the studies was due mainly to inadequate analgesia, side effects, and noncompliance. The efficacy of oxycodone was rated to be better than moderate by most of the patients, quality of life parameters increased significantly, and patient satisfaction was high. The treatment with oral controlled-release oxycodone was a safe and effective option even when used by nonspecialized physicians.

Intravenous versus subcutaneous morphine titration in patients with persisting exacerbation of cancer pain.

BACKGROUND: Patients with cancer pain with initially adequate analgesia under oral sustained-release opioid medication may suffer from persisting pain exacerbations. Sometimes even fast help is needed and then optimally performed by intravenous application (IVA) of immediate-release (IR) opioids. This IVA, however, may only be performed by physicians in Germany. OBJECTIVE: We wanted to find out if subcutaneous application of IR-opioids might be an adequate alternative to IVA in persisting pain exacerbations of patients with cancer pain because this could be performed by the nursing staff in Germany as well. DESIGN: An open randomized controlled trial was used to compare intravenous versus subcutaneous morphine titration in persisting pain exacerbations in patients with cancer pain. SETTING/SUBJECTS: Thirty-nine patients with cancer (21 intravenously, 18 subcutaneously) of the pain management department of the university hospital of Cologne, Germany were included into the study. MEASUREMENTS: Calculated from preexisting analgesic medication boli of morphine were given every 5 minutes (intravenously) or 30 minutes (subcutaneously) up to adequate analgesia or intolerable side effects. Pain intensity, nausea, sedation, and some vital parameters were documented before the start, after each application and at the end of titration. RESULTS: Thirty-five patients were pretreated with oral opioids, 4 patients with nonopioid analgesics. Six patients stopped titration because of intolerable side effects (sedation, vomiting). Thirty patients (77%) reported at least sufficient pain reduction, 3 patients were free of pain (intravenously). Mean pain intensity decreased on a visual analogue scale (VAS, 0-100) from 83 to 32 (intravenously) and from 68 to 42 (subcutaneously). Morphine doses ranged from 4 mg to 32 mg (intravenously; mean, 18.5 +/- 9.2 mg) and from 10 mg to 200 mg (subcutaneously mean, 57.9 +/- 59.6 mg). Mean time up to adequate analgesia was 53 (intravenously) 77 min (subcutaneously), respectively. There was no change in vital parameters but an increase of sedation in both groups. The adaptation of the continuous analgesic medication resulted in a stable and lasting pain relief after 4 days in both groups. CONCLUSIONS: Intravenous and subcutaneous-morphine titration are adequate to antagonize persisting pain exacerbations in cancer pain patients quickly and to adapt the continuous opioid analgesic medication.

Macroscopic and radiological grading of osteoarthritis correlates inadequately with cartilage height and histologically demonstrable damage to cartilage structure.

INTRODUCTION: The aim of the present study was to investigate different methods for determining osteoarthritis-related (OA) cartilaginous changes. MATERIALS AND METHODS: Human tibial heads were investigated radiologically, macroscopically and microscopically. The height of the hyaline cartilage was measured with the aid of a computerised digital image analysis system. RESULTS: The comparison of the different evaluation systems revealed, in part, appreciable variations in severity and produced correlations of r=-0.312-0.673. In none of the methods was a linear correlation between the histomorphometrically measured decrease in cartilage height and the increasing grade of OA evident. DISCUSSION: The microscopic scores are superior, since they provide the most precise description of cartilaginous structure. The variation in cartilage height with increasing OA is not a linear process; measurement of the cartilage height alone is not a valid parameter for determining the grade of OA.

Material properties of trabecular bone structures.

The transplantation of human allograft for restoration and filling of cortical bone defects is well known. Our aim was an experimental investigation of the mechanical stability of the often used femoral head spongiosa depending on the caliber and extent of the allograft. To evaluate the orientation of the trabecular structures of the femoral head and relate this data to its mechanical properties, morphometric studies were combined with mechanical tests of cancellous bone specimens. The mechanical examination of the allograft was done following the compression test according to DIN 50106. We examined 36 human unfixed hip joint spongiosa cylinders with a height of 11 mm and a diameter of 24 mm. We took three specimens from each femoral head. We compressed the allograft at a constant velocity of 0.017 mm/sec. We calculated the maximum compression strength, the yield point and the Young's modulus. We also examined 12 parallelepipedic specimens with (17 x 17 x 51 mm) for morphometric analysis and loading in the direction of the primary compressive group (PCG), as well as perpendicular loading and at an angle of 45 degrees. We found divergent mechanical stabilities. None of the femoral heads showed comparable compressive strength. There was no position dependency of the strength of the samples. No relation between optical appearance and strength was found. We found a value for the lower compressive strength, which can be used for calculation as a basic value for safe constructions. Furthermore we tested the well known dependence of strength on the direction of the trabecular structure. We found a strong relationship between strength and load direction on the preferred direction of the trabecular structure. The sole recommendation resulting from our investigations is to rely on the lowest compressive strength for all preoperative planning. Relying on higher compressive strength by using the theoretical predicted areas of higher strength is hazardous since we found no correlation between position of sampling and strength. The size of our samples is important, because of the fact that different sizes of the samples might cause different failure mechanisms in the samples. The preparation of the femoral head spongiosa should be done according to the primary compressive group of the trabecular structure.

Interactive computer aided shift scheduling.

This paper starts with a discussion of computer aided shift scheduling. After a brief review of earlier approaches, two conceptualizations of this field are introduced: First, shift scheduling as a field that ranges from extremely stable rosters at one pole to rather market-like approaches on the other pole. Unfortunately, already small alterations of a scheduling problem (e.g., the number of groups, the number of shifts) may call for rather different approaches and tools. Second, their environment shapes scheduling problems and scheduling has to be done within idiosyncratic organizational settings. This calls for the amalgamation of scheduling with other tasks (e.g., accounting) and for reflections whether better solutions might become possible by changes in the problem definition (e.g., other service levels, organizational changes). Therefore shift scheduling should be understood as a highly connected problem. Building upon these two conceptualizations, a few examples of software that ease scheduling in some areas of this field are given and future research questions are outlined.

Balancing flexibility for the employer and the employee: a case study of the development of annualized hours employment contracts.

As with many forms of flexible working, Annualized Hours (AH) systems offer potential benefits to both the employer and the employee. However, the flexibility requirements of employers and employees often conflict. Therefore, when a large food manufacturing organization decided to redesign its AH system, it employed an independent consultancy to act as neutral third party. The consultancy provided technical expertise and assistance in developing an AH system that optimised productivity and was acceptable to the workforce. Data are presented, obtained from focus groups conducted throughout the organization, describing some of the potential difficulties of implementing an AH system. Drawing upon these data, a number of new AH systems were proposed and modelled using specialist software tools. The design process is described, together with the advantages and difficulties associated with use of the software tools. It is concluded that the key elements in the process of designing AH systems are centred around issues of trust and communication; the involvement of a broad range of interested parties, through a process of carefully managed group facilitation; and the need for adequate technical support in the development and evaluation of AH systems.

Fractional factorial study of hybridoma behavior. 1. Kinetics of growth and antibody production.

A comprehensive approach was taken toward the quantitative study of hybridoma growth and antibody production. A fractional factorial experimental method was used to identify important variables and variable interactions affecting hybridoma behavior. The variables studied include temperature, pH, dissolved oxygen, glucose, glutamine, base medium, serum, lactate, and ammonium. The growth rate was strongly affected by the levels of dissolved oxygen, pH, temperature, and base medium. Interactions between temperature, pH, and dissolved oxygen were important. The optimal pH for growth depends upon the temperature and dissolved oxygen concentration. In general, growth was fastest at low dissolved oxygen levels. The growth rate was very sensitive to low concentrations of base medium, but was relatively insensitive to the serum concentration at levels above 2.5%. Antibody production was stimulated by high concentrations of base medium and serum and inhibited by ammonium and lactate. Antibody production increased linearly with serum concentration. In general, conditions that favored a high growth rate also favored a high specific rate of antibody production. The functional dependencies of antibody production on base medium and ammonium were similar to those for cell growth; however, antibody production and cell growth exhibited different dependencies on serum. Mathematical descriptions of cell growth and antibody production were developed. These experimental results have significant implications for the optimization of hybridoma growth in bioreactors.

Fractional factorial study of hybridoma behavior. 2. Kinetics of nutrient uptake and waste production.

A fractional factorial experimental method was used to identify important variables and variable interactions which affect nutrient uptake and waste production. The variables studied include glucose, glutamine, base medium, lactate, and ammonium. Cellular glucose uptake was stimulated by glucose and glutamine and inhibited by lactate. Glucose, base medium, and glutamine all had large stimulative effects on lactate production. Glucose uptake and lactate production both exhibited Monod-type dependencies on the glucose concentration. Ammonium production was sensitive to the glucose and lactate concentrations at levels below about 8 and 20 mM, respectively. Mathematical descriptions of glucose uptake and of lactate and ammonium production were developed. These experimental results have significant implications for the optimization of hybridoma growth in bioreactors.

Target weight procedure: preventing water intoxication.

1. Prevention of water intoxication depends on early intervention for polydipsic patients who seem to be retaining fluid. The Target Weight Procedure is designed to detect early signs of fluid retention by means of weight gain and low sodium levels. 2. The use of this protocol, in addition to successfully decreasing the number of acute water intoxication episodes, has also led to increased awareness of the meaning of patient behavior, an increased sense of control of patients with water intoxication over their behavior, and an increased feeling of competence among the staff. 3. The success of the protocol seems to be based on its purpose of identifying patients at risk and those with an impending episode, as well as secondary advantages, for example, giving the patients the option to alter their behavior to be removed from the protocol.

Import of human bifunctional enzyme into peroxisomes of human hepatoma cells in vitro.

A polypeptide containing the carboxyl-terminal fragment of human peroxisomal enoyl-CoA hydratase:3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme was synthesized in vitro from its cDNA clone. This expression polypeptide was transported into purified rat liver peroxisomes. When the expression polypeptide was incubated with postnuclear supernatant fractions of human hepatoma cells and analyzed by Nycodenz gradient SDS-PAGE and fluorography, it was imported specifically into peroxisomes as indicated by its resistance to proteinase K degradation. A deletion of the last nine amino acid residues at the carboxyl-terminus of this polypeptide prevents its peroxisomal import. A tripeptide sequence, SKL, located at the carboxyl-terminus of human bifunctional enzyme appears to be the targeting signal for the peroxisomal importation of bifunctional enzyme in human cells.