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Overview of some fundamental designs for clinical trials and studies. Some tentative definitions are given in order to stimulate questions and perspectives for further research., (Copyright 2004 S. Karger GmbH, Freiburg)

Using placebos in day-to-day practice is an ethical problem. This paper summarises the available epidemiological evidence to support this difficult decision. Based on these data we propose to differentiate between placebo and "knowledge framing". While the use of placebo should be confined to experimental settings in clinical trials, knowledge framing--which is only conceptually different from placebo--is a desired, expected and necessary component of any doctor-patient encounter. Examples from daily practice demonstrate both, the need to investigate the effects of knowledge framing and its impact on ethical, medical, economical and legal decisions.

Although effective conventional therapies are available to treat basal cell carcinoma (BCC), undesirable side effects, including scarring, and in some cases permanent damage, often occur in problematic areas of the body, especially around the eyes, mouth, and cartilage of the nose and ears. In previous studies, intratumoural injection of recombinant interferon beta-1a (rIFN-beta-1a) has been shown to result in complete remission (CR) in 47% to 86% of patients with BETACC. The primary objective of the study was to determine the response rate to rIFN-beta-1a, in a larger BETACC patient population. Secondary objectives included evaluating the effect of tumour type/size on response as well as residues, cosmetic results, and relapse rate after CR. The safety profile of intratumoural rIFN-beta-1a in BETACC patients was also evaluated. This was an open-label, multicentre study involving 139 patients with BETACC (diameter between 5.0 and 20 mm). Intratumoural injections of rIFN-beta-1a (1.0 x 106 IU) were administered three times a week for 3 weeks. The response was determined 16 weeks after start of treatment and the status of patients was followed for up to 5 years. At 16 weeks, the response rate to intratumoural rIFN-beta-1a was 66.9% (95% CI, range 58.2-74.8%). There was no significant difference between the response rates for patients with solid or other BETACC tumour types. Similarly, tumour size did not significantly affect the response rate. The cosmetic result of treatment was rated as good or very good in 83% of responders. The relapse rate after CR was 4.5% (median follow-up 2 years). All patients showed local inflammatory reactions, which were generally considered to be the adverse drug reactions (ADRs). Systemic ADRs mostly consisted of flu-like symptoms and occurred in 32/139 patients. No ADRs were considered to be the serious. These results show that intratumoural injections of rIFN-beta-1a are effective in the treatment of BETACC in the majority of patients. In addition, rIFN-beta-1a is safe and generally well tolerated. rIFN-beta-1a represents an effective alternative treatment for BETACC.

New therapies in rehabilitation medicine have to be evaluated with clinical trials. For drug approval the methodology of clinical trials is standardized world wide and the results of these studies are widely accepted. This standard should be achieved in clinical trials in rehabilitation research, too. One of the standards is the existence of a control group, comparing the effect of the new intervention against controls. In addition, the investigational and control groups must be equal in terms of the structure of possible confounders. Randomisation is the best possibility to distribute the patients to the therapy-groups, confounders will be equally distributed by chance. Other procedures for assignment to the study groups can result in confounding and lead into biased results. In spite of these advantages, randomisation is not generally accepted in rehabilitation research up to now. There are some reservations, mostly ethical, organisational and methodological ones. However, randomised clinical trials should be conducted in rehabilitation research in order to obtain more convincing results. Our intention is to bring some input in this debate and to present basics and practical aspects of randomisation.

Background: Perioperative antibiotic prophylaxis surely reduces surgical infection rate. Pharmacokinetic data of oral ofloxacin in combination with its antibacterial spectrum suggest effective protection against perioperative infection. In addition, costs, adverse effects, and induction of microbial resistance are low. Therefore we performed a controlled randomized study comparing oral and intravenous single dose prophylaxis., Methods: A total of 61 patients undergoing colonic or pancreatic resection randomly received either a single dose standard intravenous prophylaxis or ofloxacin 400 mg and metronidazole 500 mg orally 2 h before surgery. Postoperative infections were recorded for 3 weeks., Results: Groups were very well comparable regarding age, overweight, concomitant disease, type and duration of surgery, blood loss, and volume support. Infectious complications occurred in 14.8% after parenteral and 3.3% after enteral antibiotic prophylaxis. There was no difference in post-operative hospital stay., Conclusion: The data demonstrate that single-dose oral ofloxacin is at least as effective as a standard intravenous prophylaxis in patients with colonic or pancreatic resection. It offers significant advantages regarding costs and ease of administration.

Object: Failed-back syndrome is still an unsolved problem. Use of ADCON-L gel, already commercially available, has been proven to reduce postoperative scarring in animal experiments. The authors of two controlled clinical studies have also shown positive results when applying the gel. They did not, however, establish patient-oriented endpoints. The authors report a study of ADCON-L in which they focus on patient-oriented endpoints., Methods: Patients with lumbar disc herniation were randomized to an ADCON-L-treated or control group. Therapeutic success was evaluated using the validated Hannover Questionnaire on Activities of Daily Living (FFbH) 6 months after surgery. The study took place between November 14. 1996, and April 20, 1998, in eight neurosurgical centers in Germany. A total of 398 patients was recruited; 41 patients dropped out during follow up. The mean functional FFbH score (100 points = all activities are possible without problem; 0 points = no activity is possible) was 78.5 points in the ADCON-L-treated group compared with 80 points in the control group. Furthermore, in terms of secondary outcome variables, the ADCON-L group did not have an advantage over the control group. Only the mean magnetic resonance imaging score showed a slight advantage of ADCON-L over the control group., Conclusions: The authors found no positive effect of treatment with ADCON-L gel in patients in whom one-level lumbar microdiscectomy was performed. Because of its rather large sample size and its homogeneity, the study had sufficient power to detect even small differences between the two groups.

For efficient rehabilitation it is important to identify, as early as possible, the patients likely to be successfully returned to work after rehabilitation. The aim of this pilot study was to develop a statistical model for predicting this return as reliably as possible. The model uses only information readily available at the beginning of rehabilitation. A multiple regression analysis with backward elimination was used from a routine data base and identified 8 variables of prognostic value. The model offers a comfortable possibility to predict the probability of return to work of a patient on the basis of routinely registered data. The prognosis was found correct in 68% of those returning to work after rehabilitation (sensitivity) and in 80% of those who did not (specificity). Further work to improve the model for prognosis in rehabilitation research is considered reasonable.

Methodology of clinical studies is highly sophisticated in drug research. But clinical trials are also necessary to demonstrate efficacy and safety of rehabilitation treatment. The call for evidence based medicine has also reached rehabilitation. However, in rehabilitation medicine it is much more difficult to design and conduct clinical trials with a high methodological standard. Among the reasons are: A comparable control group is necessary because spontaneous healing and unspecific measures contribute to therapeutic success, too. But what could "placebo rehabilitation" look like? The masking of therapies (blinded studies) will hardly ever be possible. Therefore, it is more difficult to achieve the same treatment and observation for the treatment and control group. Treatments in rehabilitation take longer to become effective than a drug and maybe the success will disappear after some time. Therefore, long-term trials and follow-ups are necessary. Such studies are expensive, need a strong organisation, and drop-outs are unavoidable. An appropriate outcome variable does not always exist. "Return to work" is an important, reliable and valid variable, but it delivers only one bit of information per patient. As a consequence, smaller progress in rehabilitation can only be demonstrated with large sample sizes. Outcome variables based on time enable studies with reasonable sample sizes. Sometimes it is more difficult to obtain acceptance of randomisation in rehabilitation patients than in acute patients. Some rehabilitation hospitals have only recently begun to take an interest in controlled clinical trials, hence are not so experienced. Nevertheless, controlled clinical trials delivering convincing results are possible in rehabilitation medicine as well. But biometrical consultation is necessary e.g. for study design, study conduction and evaluation. Most important points are the methodology of the study design and its practicability. Especially in these topics rehabilitation physicians and biometrician have to cooperate.

Background: The pharmacological inhibition of exocrine pancreatic secretion with the somatostatin analogue octreotide has been advocated as a specific treatment of acute pancreatitis., Aim: To investigate the efficacy of octreotide in acute pancreatitis in a randomised, placebo controlled trial., Methods: 302 patients from 32 hospitals, fulfilling the criteria for moderate to severe acute pancreatitis within 96 hours of the onset of symptoms, were randomly assigned to one of three treatment groups: group P (n=103) received placebo, while groups O1 (n=98) and O2 (n=101) received 100 and 200 microg of octreotide, respectively, by subcutaneous injection three times daily for seven days. The primary outcome variable was a score composed of mortality and 15 typical complications of acute pancreatitis., Results: The three groups were well matched with respect to pretreatment characteristics. An intent to treat analysis of all 302 patients revealed no significant differences among treatment groups with respect to mortality (P: 16%; O1: 15%; O2: 12%), the rate of newly developed complications, the duration of pain, surgical interventions, or the length of the hospital stay. A valid for efficacy analysis (251 patients) also revealed no significant differences., Conclusions: This trial shows no benefit of octreotide in the treatment of acute pancreatitis.

The total costs of the hospital treatment of patients with secondary peritonitis were investigated with a prospective, randomized, multicenter study. Moreover, the cost-effectiveness of an initial therapy with Imipenem/Cilastatin was compared to selected alternative antibiotic regimens. Altogether 154 patients (77 Imipenem/Cilastatin group, 77 alternative group) that displayed Mannheim Peritonitis Scores between 16 and 26 (average 20.8) were analyzed. The average total cost of treatment was DM 11,140 per patient (range DM 2794-45,526). Patients receiving an initial therapy with Imipenem/Cilastatin incurred average costs of DM 10,455, while patients with alternative regimens caused average costs of DM 11,826. The difference between the two treatment groups was statistically significant (P = 0.037).

Objective: To confirm significant improvement of the skin score in systemic sclerosis by treatment with interferon gamma in a larger group of patients and to investigate on a molecular level the influence of interferon gamma on collagen type I messenger RNA expression., Design: Open, noncontrolled multicenter study., Setting: Five outpatient clinics specializing in the care of systemic scleroderma., Patients: Thirty-two patients suffering from the diffuse or limited form of systemic sclerosis and progressive disease were recruited; 20 patients finished the study., Intervention: Each patient received interferon gamma, 50 micrograms subcutaneously 3 times a week for 1 year., Main Outcome Measure: Skin score, collagen type I messenger RNA in skin biopsy specimens., Results: The patients who completed the study showed an unchanged median skin score after 1 year of therapy. In addition, similar collagen type I messenger RNA levels were detected in skin biopsy specimens taken from involved skin before and after therapy in these patients., Conclusions: Treatment of systemic scleroderma with interferon gamma is associated with stabilization of the skin score and lack of worsening of visceral involvement.

Pentoxifylline (POF) may suppress overproduction of tumor necrosis factor alpha (TNF alpha), which is thought to contribute to complications of human falciparum malaria. However, POF is believed to improve impaired capillary blood flow, which can be impaired in falciparum malaria. To test whether POF affects TNF alpha serum levels or other variables in this disease, we administered POF (20 mg/kg/day intravenously in 150 ml of saline for five days) randomized versus placebo (150 ml of saline without POF) in addition to standard antimalarial therapy. After recruitment of 51 patients with Plasmodium falciparum malaria, those receiving POF had more nausea and abdominal discomfort than the placebo group, as expected. Eleven of 27 patients receiving POF and three of 24 patients receiving placebo requested termination of the study medication (P < 0.05). Pentoxifylline did not change the decrease of TNF alpha levels or affect the clinical course in a significant way. Since POF failed to improve the clinical situation or to impact numerous laboratory parameters (including TNF alpha, thrombin-antithrombin III, thrombomodulin, and human neutrophil elastase), the study was terminated earlier than planned. While this study does not specifically address cerebral complications of malaria, the results suggest that POF is not useful as a routine adjunct to the standard therapy of falciparum malaria.

Aim of the Study: The present study assessed the total cost involved in the therapy of nosocomial pneumonia. Cost for patients receiving Imipenem as initial antibiotic therapy was compared with that for patients treated by selected alternative regimens. Secondary objectives included the evaluation of fever days, days of antibiotic therapy, days at ICU and days of overall hospitalisation required for the treatment of the nosocomial pneumonia for both methods of treatment., Methods: A prospective randomised open study involving multiple study sites was conducted. Total cost, efficacy and safety of an initial therapy with Imipenem were compared to results achieved with selected other antibiotic regimens. Altogether 109 patients were enrolled into the study; 85 patients could be assessed., Results: Both treatment methods showed equal clinical efficacy. Total cost of the therapy of nosocomial pneumonia for all patients was in the range between 1,616 DM and 82,141 DM, the arithmetic mean was calculated to be 11,307 DM and the median was found to be 6,507 DM. Imipenem-treated patients incurred lower cost (median 5,649 DM, mean 10,009 DM) than patients treated with other antibiotics (median 9,334 DM, mean 12,701 DM)., Conclusion: The total cost of treatment of nosocomial pneumonia was lower for Imipenem-treated patients than for patients receiving initially other selected antibiotic regimens. The savings are apparently due to a faster recovery of the patients resulting in reduced duration of therapy. The study shows that assessment of cost of therapy per day might be misleading in the economic analysis of antimicrobial chemotherapy.

As the goals of palliative cancer treatments have not always been clearly specified, this paper describes how frequently the goals of palliative cancer treatment can be specified according to a given definition and how frequently those specified goals can be achieved. The clinical problems of 171 cancer patients were discussed in the Interdisciplinary Oncologic Conference (IOC) of the Cancer Centre University of Ulm (CCUU) and recommendations concerning further diagnostic treatments and/or therapy were provided. These recommendations had been documented and analysed retrospectively. The goals were classified as either cure or palliation or further investigation. If the goal was palliation, it was investigated whether or not the goal was specified as either alleviation of existing problems or prevention of impending problems. The achievement of the specified goals was assessed. Palliation was the goal of treatment in 119 (71%) of the 168 evaluable recommendations. In 83 of the 119 cases (70%), immediate treatment was recommended. The goal was specified in 57 (69%) of the 83 recommendations and could be realized in 24 of 57 specified cases (42%). Patients in this group survived longer (p < 0.01) than patients in whom the goals could not be achieved. Impending problems could be prevented more often (p = 0.001) in 14 out of 18 cases, while existing problems could be alleviated in only 10 out of 34 cases. It is concluded that specification of the goals of palliation is necessary because it is impossible to decide if a goal of treatment could be achieved or not unless the goal of treatment has been defined (as existing/impending problem). The prevention of impending problems could be investigated in prospectively controlled clinical trials.

Many unconventional therapies (e.g. dietary, phytotherapy, acupuncture, homeopathy) are well known and often applied, but their efficacy has hardly been proven. New trial designs and study components must be found to meet the specific demands of the particular unconventional therapy on one hand and keep the high methodological standard of controlled clinical trials on the other hand. Biometricians and unconventional therapists are challenged to develop such designs. Typical problems in designing studies of unconventional therapies include that placebo is not possible, therapies cannot be masked, outcome variables are not reliable, therapy is highly individualized, and studies on the efficacy of soft therapies require many patients and long treatment periods. Studies with unconventional therapies should be performed by practitioners (because they use these therapies), but this leads to further problems. Some solutions are given in examples: A study is described investigating the herbal remedy Kava-Kava for patients in the state of anxiety, tension and restlessness; a study on classical homeopathy for chronical headaches is specified; some designs for dietary studies in patients with rheumatoid arthritis are compared. A design called "cross-allocation of patients to two treatments with randomization option" and the "N-of-1 design", also called "single case design" are described and discussed. The "change-to-open-label design" could be useful to investigate soft and natural therapies which require studies with many patients and long-term treatment.

The "Change-to-Open-Label Design" (COLA-design) is proposed to overcome some of the ethical and organizational problems of the usual double-masked design in certain situations while preserving its scientific rigor. Patients are randomized on a doubled-masked basis into treatment groups. During the trial the patient or the treating physician may ask for a change from the masked treatment to any open-label treatment of their choice (experimental or not), if the masked treatment is thought to be unsatisfactory. It seems to be easier to obtain a patient's informed consent to participate in placebo controlled double-masked trials especially for long term studies. The main outcome variable in COLA-design is the time until a patient demands for such a change. "Survival analysis" is a powerful statistical method to evaluate this outcome variable. Even patients lost from observation can be included in the evaluation: they still deliver censored outcome values. Evidently, in trials with a COLA-design the patient's personal impression of the therapy is the most important factor in its assessment. Therapeutical success is mingled with undesirable effects into the outcome measure; therefore this design is especially applicable to investigate treatments supposed to increase quality of life.

Background: A multicenter controlled study was performed to evaluate the effect of high doses of the low molecular weight protease inhibitor gabexate mesilate on mortality and complications associated with moderate and severe acute pancreatitis., Methods: Two hundred twenty-three patients from 29 hospitals were entered in the randomized, double-blind trial. Admission to the study was based on strict criteria excluding mild acute pancreatitis. The patients received placebo or 4 g gabexate mesilate per day intravenously for 7 days. All patients were followed up for 90 days after randomization. The analysis was based on 14 complications, including death., Results: There was no statistical difference in either mortality or complications associated with acute pancreatitis between the placebo and gabexate mesilate groups., Conclusions: The results show that gabexate mesilate was not effective in preventing complications and mortality in acute pancreatitis.

The efficacy of classic homeopathic therapy is scientifically not well proven. Few of the studies available are acceptable from a scientific point of view. In this paper we will describe a study protocol for a trial of classic homeopathy in chronic headache, which not only is in accordance with currently accepted scientific research standards but also accounts for the special needs of homeopathic therapy. The prescribing practioners are allowed to use any homeopathic drug at any potency or dosage, this enables them to ful fill the homeopathic principle of individuality. At the same time, the study is strictly controlled, randomized and double blind. The prescribing physician sends the homeopathic medication selected for a patient to a notary public, who either forwards it to the patient or substitute placebo, according to the randomization plan. Hence, the trial is not testing a specific drug, but the rationale of individual homeopathic drug selection and the efficacy of the selected drugs in headache patients in general. Patients suffering from chronic headaches for at least 1 year and with headaches at least once a week on average are eligible for the study. Exclusion criteria follow the generally accepted standards and account for the special needs of homeopathic therapy. Data are to be recorded in a patient's diary containing the outcome variables occurrence, duration, intensity of headaches and use of analgesic drugs. After a baseline period of at least 6 weeks the first consultation will take place, with the proper remedy selected and sent to the patient via the notary. After 6 weeks a first follow-up will allow the physician to modify the treatment if necessary. After another 6 weeks the final examination will take place. The duration of the homeopathic treatment, then, is 12 weeks. A total of 100 patients in two groups of 50 are to be treated in the study. The study started in the later part of 1991, and is scheduled to last for 2 1/2 years. We expect a critical discussion of the results from conventional medicine or from homeopathy, depending on the outcome of the study. The study protocol is being published in advance to enable the reviewers of the study to check the original study design and the a priori hypotheses adopted.

Experimental situations are considered, in which t different treatments are administered to n cases (volunteers, patients, animals etc.) during p periods (p less than or equal to t) in a way that each of these cases receives p different treatments in sequence (crossover designs). In order to minimize the influence of carry-over effects the designs of the trials are constructed with regard to three conditions of balance: (a) Each case receives the same number of treatments, (b) each treatment is applied the same number of times in each period, and (c) each possible transition between two consecutive periods appears the same number of times during the experiment. The minimal numbers of cases are given for complete (p = t) and incomplete (p less than t) designs balanced according to all the above mentioned conditions. Furthermore, the designs themselves (plans of the experiments) are also listed for the minimal number of cases for 2 less than or equal to p less than or equal to t less than or equal to 10.

In the HIV study of the German Red Cross blood banks the overall rate has remained constantly low, with less than two Western blot positive donors in 100,000 donors since 1987. However, the rate of HIV positivity tends to increase in male first time and in male repeat blood donors. Despite this fact, the overall rate stays constant since the number of young first time donors has decreased with increasing donations by women. Therefore the blood banks once again have to take newly intensified but also sophisticated measures to guarantee further as well a sufficient number of blood products as their HIV safety.

From the multicenter study of the Red Cross Blood Banks in the FRG HIV-antibody prevalences and incidences are documented since July 1985. Constantly low prevalences and incidences since 1987 of less than 2 Western blot (Wb)-positive donors and less than 1 Wb-positive donor per 100,000 donors respectively confirm our estimate of the rest risk of an HIV-infection by blood products of 1:500,000 to 1:3 million donations. In the epidemiologic details there seems to be a trend to an increase of the incidence in male repeat blood donors. The modes of HIV-infection in blood donors have changed to an increasing number of infections acquired in heterosexual contacts to persons at risk.

In a randomized study comparing cotrimoxazole plus colistin with ciprofloxacin, each in combination with nonabsorbable antimycotics, the incidence of major infections in terms of septicemias and pneumonias as well as of minor infections and episodes of unexplained fever (FUO) was higher in patients treated with ciprofloxacin. In cases of microbiologically documented infections, gram-positive cocci dominated by far. In surveillance cultures of oral washings and of feces, gram-negative enterobacteria were only rarely detected; however, large numbers of cultures were positive for Acinetobacter species. There were four cases of documented Pneumocystis carinii pneumonia in patients not receiving cotrimoxazole. The incidence of documented mycotic infections as well as the detection of fungi in surveillance cultures was similar in both treatment groups. A decrease in the number of adverse events, especially of allergic reactions, could not be achieved by the administration of ciprofloxacin. In conclusion, cotrimoxazole plus colistin in combination with nonabsorbable antimycotics remains the standard regimen for prevention of infection in patients with acute leukemia undergoing aggressive remission induction therapy. A detailed analysis of study II will be prepared for publication.

In an open, non-randomized clinical trial conducted at multiple centres, 49 patients with rheumatoid arthritis were treated with recombinant interferon-gamma for 20 days. The study was carried out in two sub-studies. In the first, the total daily dose of interferon-gamma was 50 micrograms; in the second, 100 micrograms. Of the 49 cases, 40 were evaluable for statistical analysis; 24 of these patients (60%) responded to therapy, according to the criteria of a successful outcome laid down in the study protocol, and were classified as responders. In responders, the clinical parameters investigated improved with both dosages. The lower dosage differed from the higher one in having a markedly lower incidence of side-effects. The results lead to the conclusion that a randomized double-blind phase-III clinical trial should be performed.

A computer program specifically designed for surgical data retrieval was tested for longer than one year. By using the information contained in operation reports, with this program statistical analysis may be achieved. The reports are generated and printed using a personal computer running MS-DOS. Entering data does not cause any additional effort for the secretary. The selection of requested data is possible with any combination of criteria, and the resultant information is displayed on the computer terminal screen or printed on the computer printer. A combination of terms is used instead of a numeric code for data entry allowing far greater selectivity, with a reduced risk of data loss due to wrong numeric code entry.

The incidence of hepatitis (B and non-A, non-B) was determined in a prospective multicentre study of 1100 hospital patients during 12 months without or after surgery and with or without transfusion. The incidence was 3.6% (4 of 111 patients) after surgery and transfusion, and 0.5% (5 of 989) without transfusion - with or without surgery. The incidence of hepatitis B was significantly higher in the transfused group, while non-A, non-B hepatitis had the same incidence in all three groups. Hepatitis was clinically manifest in only three of the nine patients. The remaining six silent ones were uncovered by a careful prospective follow-up plan. Thus the incidence of hepatitis in this study was higher than has been reported in retrospective series. However, the absolute number of cases is small and the confidence limits thus rather wide: the incidence of non-A, non-B hepatitis must be interpreted with caution.

In a multicenter placebo-controlled double-blind randomized clinical study, 91 patients with rheumatoid arthritis were given 28 days' treatment with recombinant interferon-gamma (50 micrograms daily for 20 days, then 50 micrograms each second day up to day 28, given by subcutaneous injection). The aim of the study was to provide a methodologically clear demonstration of the efficacy of treatment with interferon-gamma, using criteria that could be handled by statistical tests. Evaluatable documentation was available for 79 patients, of whom 40 were treated with the active compound. The principal criterion for the statistical evaluation of the therapeutic success was improvement of the Ritchie "joint pain index" or Lansbury "joint pain index" by at least 30% within 28 days. The chi-square test showed superiority of the interferon arm over the placebo arm with an error probability of alpha less than 1%. In addition, efficacy of interferon-gamma was demonstrated in respect of practically all parameters investigated. The frequency of side-effects, including febrile reactions, was the same for the active compound and the placebo. During interferon treatment the daily maximum body temperature was raised by 0.3 degrees C on average, but was below 37.2 degrees C at all times.

Regional chemotherapy with floxuridine was undertaken in 50 patients (32 men and 18 women, mean age 57 years) with colorectal carcinoma with metastases only to the liver. In 25 patients (group I) the drug (0.2 mg/kg) was administered exclusively intraarterially into the hepatic artery, while in the remaining 25 (group II) it was given both intraarterially (0.21 mg/kg) and intravenously (0.09 mg/kg) via the inferior vena cava. The remission rate in group I was 56% (14 of 25), in group II it was 64% (16 of 25). It was subsequently discovered that 4 of the 25 in group II already had extrahepatic metastases at the time of implantation of the infusion catheter. The difference in remission rate between the two groups is not significant. Extrahepatic tumour recurrence occurred after a median period of 16 months in 17 patients of group I (68%) and six of 21 of group II (29%, P less than 0.01). Over an observation period of 34 months the survival rates of the two groups were not significantly different. However, these results suggest that over a longer period a higher survival rate is to be expected for the intraarterially plus intravenously treated group.

Until now the therapy of pollinosis with Galphimia glauca was based on individual experience. We performed a randomized, controlled, multicenter, and double-blind clinical trial to verify the effectiveness of the Galphimia glauca D4 therapy of patients with pollinosis. The average time of observation was 51/2 weeks. Galphimia was found to be more effective than placebo at a 1% level of significance. Therapeutic success was given in 34/41 (= 83%) of the patients with Galphimia and in 21/45 (= 47%) of the control patients.

Of a total of 5.6 million blood donations by 1.6 million German Red Cross donors between July, 1985 and December, 1987 tested for HIV antibodies 210 were found to be positive in at least one Western blot. Calculated per quarter, the prevalence (for first-time donors) of 10 per 100,000 in 1985 decreased to 4 per 100,000 in 1986, while the incidence (for multiple donors) was a constant 2 per 100,000 for each quarter in 1987. This indicates that new HIV infections were rare in blood donors and there was no exponential increase. Further analysis revealed that over 90% of those with confirmed Western blot positive results were members of risk groups or their direct contacts. The age and sex distribution conformed to the known pattern for AIDS cases in the Federal Republic of Germany. The data demonstrate that there is at present no indication of a rapid spread of HIV infections transmitted heterosexually among blood donors.

In a randomized multicenter study, ciprofloxacin and norfloxacin, each in two different dose regimens and in combination with non-absorbable antimycotics, were administered to 51 patients with acute leukaemia undergoing aggressive remission induction chemotherapy for infection prevention. Both drugs showed an effective elimination of gram-negative potential pathogens and Staphylococcus aureus not affecting the anaerobic flora of the gastrointestinal tract. A low incidence of side effects and a satisfactory patient compliance could be observed. A daily dosage of 1,000 mg ciprofloxacin or 800 mg norfloxacin is recommended for infection prevention in severely granulocytopenic patients.

To assess the function of the thyroid gland in premature infants of different gestational ages during the first month of life we determined simultaneously TSH, T4, T3, and rT3 serum concentrations in 116 preterm infants (gestational ages 31st to 38th week) during each of the first 30 days of life. The serum concentrations of TSH, T3, and rT3 changed significantly during this period. The TSH and rT3 values were highly increased on the first day and decreased thereafter. The T3 values, however, increased significantly during this period. During the first month of life the T4 values remained roughly unchanged independent of the age of the children. There was no significant influence on serum concentrations of thyroid hormones by gestational age. The 65 preterm infants with adaptational disorders showed no difference in their patterns of TSH and thyroid gland activity during the first month of life compared with 51 healthy premature infants. From the 4th to the 6h day of life -- a recommended period for the screening of congenital hypothyroidism -- the differences of TSH values measured were insignificant (16-18 muU/ml). The T4 values on these days remained all above 6.8 microgram/dl.

In a controlled randomized double-blind trial carried out by 47 physicians in private practice with totally 152 patients with sinusitis the therapeutic success of the following homeopathic drug preparations was investigated: Group A: combination of luffa operculata D4, kalium bicromicum D4 and cinnabaris D3. Group B: combination of kalium bicromicum D4 and cinnabaris D3. Group C: luffa operculata D4. Group D: placebo. Criteria for the therapeutic result were headache, blocked nasal breathing, trigeminal tenderness, reddening and swelling of nasal mucosa and postnasal secretion. There was no remarkable difference in the therapeutic success among the investigated homeopathic drug combinations nor between the active drugs and placebo. Averaged over all four groups 81% of the patients with acute sinusitis and 67% of the patients with chronic sinusitis recovered. In the literature comparable therapeutic results are reported for antibiotic therapy, decongestant nose drops and for the drainage of nasal cavities.

In this paper we described the results of bacteriological monitoring of oropharynx and stool samples from granulocytopenic patients with leukaemia who received oral infection prophylaxis with two different regimens for selective decontamination of the digestive tract. Patients were prospectively randomized either into a group receiving non-absorbable antimicrobial drugs for selective decontamination (polymyxin and neomycin: group A) or into a group receiving polymyxin and co-trimoxazole (group B). The oropharynx was, or became, free of gram-negative bacilli within one week of treatment in 94% and 90%, respectively, of the patients in group A and group B. The stool samples were, or became, negative after the same treatment interval in 91% and 80%, respectively, of the two patient groups. Antibiotic therapy during selective decontamination treatment significantly increased the incidence of positive cultures from the oropharynx and stools. The sensitivity of the gram-negative bacilli isolated during selective decontamination treatment to the drugs administered did not influence the average response to treatment. Both resistant and sensitive gram-negative bacteria appeared to disappear from the patients' samples, mostly within a week, without the need to adjust the selective decontamination treatment. Yeasts behaved in almost the same way as gram-negative bacilli. All patients received oral amphotericin B; some patients occasionally yielded oropharyngeal or faecal cultures which were positive for yeasts.

The pathogenicity of microorganisms isolated by surveillance cultures, the neutrophil count in the peripheral blood, and the interaction of the two factors were analyzed as risk factors for infections of the oropharynx and the respiratory tract in patients with acute leukemia being treated in strict reverse isolation under antimicrobial modulation. A statistical method was developed for the identification of bacteria, the presence of which was correlated with an increased risk of infection. A significantly increased risk was found mainly for species of Klebsiella, Enterobacter, Proteus, and Pseudomonas. The degree of neutropenia was significantly correlated with the risk of infection, which was influenced by the microbiologic state of the oropharynx. Thus, patients with gram negative bacilli had significantly more days with infection at all levels of neutropenia than patients without gram-negative bacilli. These two risks factors were additive but did not potentiate each other.

The clinical application of electroretinography has been limited until now by the lack of standardisation, especially of stimulus conditions. Normal values for the electroretinographic response parameters can only be used if patients are examined under the conditions which were given for the examination of healthy subjects. It is shown in this paper that the inexpensive apparatus designed by Kooijman and Damhof (1981) can be calibrated by any user simply and at justifiable expense. Normal values for the amplitudes and peak times for the a- and b-wave are presented. The normal range of the values has been defined with regard to the frequency distribution. According to the authors' results, methods of descriptive statistics in skewed distributions are mainly necessary at low stimulus intensities. The descriptive methods for normal distributions were regularly applied at higher stimulus intensities. In general, however, ERG parameters are normally distributed as shown by the distribution of the residuals between the linear regression of the parameter to the logarithm of the corneal illuminance and the measured values. The influence of age on the amplitude was calculated according to the results of Lehnert and Wünsche (1966) and the lower limits of the normal range are given for four age groups. The data presented here may be used as normal values provided that the simple calibration methods are applied. Thus electroretinography is no longer a method merely for the laboratory, but can be used in clinics and offices as well. However, a prerequisite is that the physician has sufficient experience in ophthalmological electrophysiology.

In a prospective study patients with acute leukemia undergoing remission induction therapy were randomized to receive either a regimen of non-absorbable antimicrobial drugs (colistin and neomycin) or of absorbable and non-absorbable drugs (trimethoprim-sulfamethoxazole [TMP-SMZ] and colistin) for antibacterial prophylaxis. For antifungal prophylaxis patients in both groups were given oral amphotericin B. The proportion of patients without acquired infections and the median of study time to the first acquired infection did not differ significantly between the two treatment groups (p greater than 0.05). Septicemias occurred in nine out of 49 recipients of colistin and neomycin and in one out of 56 patients receiving TMP-SMZ and colistin (p = 0.03). Localized infections and fever episodes without proven infections were equally distributed between the two groups. The incidence of febrile days and of days on parenteral antibiotic therapy was significantly lower in the group given TMP-SMZ and colistin (p less than 0.05). The duration of severe granulocytopenia and thrombocytopenia did not differ significantly between the two groups (p greater than 0.05).

To compare the efficacy of endoscopic paravariceal sclerotherapy and oral propranolol in the prevention of recurrent upper gastrointestinal bleeding, 78 cirrhotic patients were randomly assigned to either treatment after an endoscopically proven bleed from esophageal varices. After randomization, but before treatment had been started, a total of eight patients had to be withdrawn from the study due to early rebleeding (requiring emergency sclerotherapy) or violations of the protocol. Among the 70 patients analyzed (36 sclerotherapy, 34 propranolol), both treatment groups were comparable with respect to demographic, clinical and laboratory data. The groups also did not differ with respect to continued alcohol intake. Sclerotherapy was performed twice weekly using 1% polidocanol as the sclerosing agent until the varices were eradicated or well-covered by fibrous tissue. Propranolol was given twice daily at a dose reducing the resting heart rate by 25% (60 to 320 mg per day; mean +/- SD = 161 +/- 80 mg per day). Patients were followed for up to 2 years with visits at 3 monthly intervals (mean follow-up = sclerotherapy, 14 months; propranolol, 9.2 months). Life table analysis of patients without rebleeding from nonvariceal sites revealed a tendency in favor of propranolol; however, the difference did not reach statistical significance. No significant difference was observed between sclerotherapy and propranolol in the proportion of patients rebleeding from esophageal varices or from all sources of upper gastrointestinal bleeding. Furthermore, survival was similar in both treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

In a cooperative study, the quality of protective isolation and of antibiotic decontamination of the digestive tract was studied in patients with acute leukaemia by (bio)-typing of Enterobacteriaceae species, Pseudomonas aeruginosa and Staphylococcus aureus isolated from oral washings and faecal samples. These samples were collected before and during treatment of 82 patients who were either isolated and decontaminated for which latter purposes a combination of neomycin, polymyxin, bacitracin and nystatin was used (group A); isolated without decontamination (Group B) or treated on the ward without decontamination (Group C). The results indicated that protective isolation had only been completely successful during the entire (remission induction) treatment period in one of the 32 patients in Group B. In Group A patients, who underwent antibiotic decontamination in addition, successful isolation was achieved in 57% of 28 patients. Successful antibiotic decontamination of the digestive tract for the entire treatment period as far as all potentially pathogenic species are concerned, was realized in 4 (14%) of the 28 patients of Group A. Bacteriologically confirmed infections occurred in 50% of Group A patients, in 59% Group B patients and in 64% of Group C patients. It is concluded that the quality of isolation had in general been insufficient but that it was improved by oral nonabsorbable antibiotics and, furthermore, that the antibiotic decontamination procedure also requires improvement.

Tear film break-up time was measured on 6 consecutive workdays in 6 subjects without eye disease selected at random. The reasons for the wide range of scatter in the values measured were investigated by variance component estimation. It was found that intraindividual variance is by far the most important factor influencing the overall variance of the measured values. Therefore, caution is called for when judging the stability of the precorneal tear film by the tear film break-up time in healthy individuals.

The preparation of homeopathic drugs is based on potentiation. In this potentiation the primary substance is specially mixed with a carrier (typically 90% ethanol) in the ratio 1:10. Usually this potentiation is done repeatedly and the final drug is labeled, e.g., "D6" which means a 6 times decimal potentiation. In a controlled randomized strictly double-blind trial with 164 patients the effectiveness of homeopathically prepared Galphimia D6, a conventional Galphimia dilution 10(-6) and a placebo was investigated for the therapy of pollinosis. The average duration of treatment was about 5 weeks. Although no statistical significance was achieved, it is remarkable that there was a clear trend for the superiority of Galphimia D6 while the Galphimia dilution 10(-6) was about equally effective compared with placebo. The study itself demonstrates that it is possible to do strictly controlled trials for homeopathic drugs and with medical practitioners.

The organizational and statistical concept of the cooperative randomized controlled clinical trial on gnotobiotic care and its effect in acute leukamia patients is described. The purpose is the clarification of the concept of the study and the comparison with other studies on the same subject. It is concluded that the value of the results and of the decisions based on them depend mainly on the statistical design, the protocol, and the performance of a study. The performance of a controlled study depends on its organizational details, its monitoring, documentation, and appropriate biometric evaluation. In this particular study it proved fruitful that a statistician was engaded in the evaluation and also in developing the protocol and in carrying out the study.

Between 1971 and 1978 the diagnosis of isolated ventricular septal defect was made in 149 patients. Most of these defects were small. In the majority of cases the diagnosis was made clinically. Spontaneous closure was assumed when, all other cardiac findings being normal, the heart murmur had disappeared. This took place in 50 of the 149 cases (34%) during the period of observation. Closure rate was independent of sex and birth rate, but related to size of defect and age of patient at time of diagnosis. Closure rate was 53% for small defects, 15% for larger ones. Because of the limited period of observation the reported spontaneous closure rate is less than the true one, estimated at 70-75% up to the age of nine years.