Patient-centered developments in colon- and rectal cancer with a multidisciplinary international team: From translational research to national guidelines.

Rarely, scientific developments centered around the patient as a whole are published. Our multidisciplinary group, headed by gastrointestinal surgeons, applied this research philosophy considering the most important aspects of the diseases "colon- and rectal cancer" in the long-term developments. Good expert cooperation/knowledge at the Comprehensive Cancer Center Ulm (CCCU) were applied in several phase III trials for multimodal treatments of primary tumors (MMT) and metastatic diseases (involving nearly 2000 patients and 64 centers), for treatment individualization of MMT and of metastatic disease, for psycho-oncology/quality of life involving the patients' wishes, and for disease prevention. Most of the targets initially were heavily rejected/discussed in the scientific communities, but now have become standards in treatments and national guidelines or are topics in modern translational research protocols involving molecular biology for e.g., "patient centered individualized treatment". In this context we also describe the paths we had to tread in order to realize our new goals, which at the end were highly beneficial for the patients from many points of view. This description is also important for students and young researchers who, with an actual view on our recent developments, might want to know how medical progress was achieved.

[Traditional Chinese Pharmacotherapy in Patients with Chronic Rhinosinusitis - an Observational Trial Considering the Origin of Medicinal Drugs]. / Traditionelle chinesische Arzneitherapie bei Patienten mit chronischer Rhinosinusitis − eine Therapiebeobachtung mit Berücksichtigung der Arzneimittelherkunft.

BACKGROUND: The use of Chinese medicinal drugs is becoming more common in Germany. However, the import from China results in aggravated quality controls and potentially jeopardized therapeutic safety. Therefore, in 1999 the Bavarian Department for Agriculture has initiated an interdisciplinary research project to cultivate and analyze important Chinese herbal plants. Currently 16 Bavarian-produced Chinese drugs are in use and distributed to patients by pharmacies. Despite a comparable quality of Bavarian pharmaceutical products, there are concerns remaining as the Bavarian medical drugs have been used for treatment purposes on patients since 2006, without their effect having been compared to the Chinese products. Therefore we performed an observational trial using a parallel group design on patients with chronic rhinosinusitis. METHODS: The duration of the trial was 4 weeks. After a 4-week follow-up, the patients were interviewed via telephone. During the trial the patients were given 2 × 50 ml of a decoction of Chinese medicinal herbs, either (a) from Bavarian controlled cultivation (Bavaria group) or (b) from Chinese production (China group). The therapeutic success was evaluated using numerical rating scales. RESULTS: In total, 64 patients completed the observational trial (31 Bavaria group, 33 China group). Both groups showed significant improvements in the main symptom scores of chronic rhinosinusitis as well as in secondary symptoms, such as the overall state of health or the tendency to catch a cold. There were no significant differences between the groups concerning the main symptoms scores. Overall the herbal decoctions had no severe side effects. CONCLUSION: This observational trial shows that Chinese herbal drugs from Bavarian cultivation are as effective as medicinal herbs imported from China, but the effects of concomitant therapies must be considered as well. The symptom score improvements during the treatment period were obvious and should stimulate further investigation on the efficacy of this herbal formula in the treatment of chronic rhinosinusitis.

Cross matching observations on toxicological and clinical data for the assessment of tolerability and safety of Ginkgo biloba leaf extract.

Ginkgo biloba is one of the most widely used herbal remedies in Europe and the US. It may be purchased in different types of formulations, but most of the clinical studies have been performed with the controlled G. biloba extract EGb761(®). Indications include Alzheimers disease, cardiovascular disease, dementia, memory loss, and cerebral ischemia. The pharmacological modes of action cover antioxidant effects, radical scavenging, inhibition of platelet activating factor, alterations in membrane fluidity (signal transduction), and inhibition of glucocorticoid synthesis. Due to the widespread and long-term use of G. biloba - about a million doses of EGb761(®) are sold per day - tolerability and safety are a crucial issue. Based on broad and long-term clinical use of G. biloba extracts, it is regarded as well tolerated in man. Cross matching, a tool we introduced, combines different fields of knowledge and types of data to a consolidated result. In this article, we combine toxicological and clinical data and utilize other sources of information to assess tolerability and safety of G. biloba. It is well known that because of biological differences between animals and man or even between animal species, animal experiments do not necessarily mimic the effects in humans. Therefore, for adequate risk assessment, the relevance of non-clinical toxicological findings should be correlated with human data. The cross matching of toxicological data and results from clinical studies is possible because many toxicological and clinical studies are available on G. biloba. We give an in depth analysis of the modes of action in animals and describe toxicological studies with regard to metabolism, pharmacokinetics, genotoxicity, as well as carcinogenicity (e.g., the Technical Report TR 578 of the US National Toxicology Program). In addition, 75 clinical trials with high methodological quality are summarized. They included a total of 7115 patients treated with G. biloba. Based on this extensive amount of information, the broad variety of investigations, and their accordance we conclude that G. biloba extract is well tolerated and safe for humans.

Safety aspects of Chinese herbal medicine in pregnancy-re-evaluation of experimental data of two animal studies and the clinical experience.

INTRODUCTION: Chinese herbal medicine is an increasingly popular worldwide medical therapy which also has an impact in pregnancy. However, the question of its drug safety during pregnancy remains unresolved. Potential problems include teratogenicity, abortion, perinatal toxicity, pre- and postnatal developmental abnormalities, and eventually an increased risk for carcinomas in the offspring. Standard Materia Medica textbooks contain unreliable information when it comes to risks during pregnancy. Wang and co-workers conducted an experimental study (WS) on mice in which they investigated the effects of 17 Chinese medicinals regarding embryotoxicity and fetotoxicity. All these drugs seemed to exhibit multiple significant toxic effects. Another study by Li and co-workers (LS) investigated the reproductive toxicity of Atractylodis macrocephalae Rhizoma in mice, rats and rabbits. They described an increased pre- and postnatal mortality and, at high doses, congenital malformations. In an attempt to identify the risks of the tested medicinals during pregnancy, we analysed these two experimental studies and compared their results with possible safety data for humans from two reviews of clinical studies on threatened miscarriage (AR and CR). METHODS: We re-evaluated WS and LS in relation to accordance with internationally accepted rules, equivalence to human dose, biometric accuracy, plausibility, and coherence. Eligible studies of the two reviews on threatened miscarriage were evaluated for specific pregnancy risks concerning the 17 medicinals tested in WS and LS. RESULTS: We found that WS does not conform to international ICH guidelines and includes many inconsistencies, implausibilities and several severe biometrical flaws. It reported a total of 364 significant events out of which 145 false significant results are expected. The data-handling pointed to irregularities. Analysis of LS exhibited also many inconsistencies. The results regarding congenital malformations were statistically insignificant and are based on small case numbers. Insofar as the safety data of the 17 medicinals were documented by eligible studies of the two reviews, there was no indication of an increased abortion rate in humans. Fetal growth retardation was not observed in the human studies. For neonatal health and postnatal development, there were sufficient safety data only for a few medicinals in the human studies. As for teratogenicity, only small case numbers (0 to 109) were available from the human data. CONCLUSION: WS and LS are not reliable data sources for deriving pregnancy risks in humans for the tested Chinese medicinals. In addition, the results appear to contradict the outcomes observed in the treatment of humans. Regarding teratogenicity, for most Chinese medicinals, neither the safety nor the risk during pregnancy can be definitively ascertained. Further studies on the risks of Chinese medicinals during pregnancy are urgently needed.

Which level of evidence does the US National Toxicology Program provide? Statistical considerations using the Technical Report 578 on Ginkgo biloba as an example.

The US National Toxicology Program (NTP) is assessed by a statistician. In the NTP-program groups of rodents are fed for a certain period of time with different doses of the substance that is being investigated. Then the animals are sacrificed and all organs are examined pathologically. Such an investigation facilitates many statistical tests. Technical Report TR 578 on Ginkgo biloba is used as an example. More than 4800 statistical tests are possible with the investigations performed. Due to a thought experiment we expect >240 false significant tests. In actuality, 209 significant pathological findings were reported. The readers of Toxicology Letters should carefully distinguish between confirmative and explorative statistics. A confirmative interpretation of a significant test rejects the null-hypothesis and delivers "statistical proof". It is only allowed if (i) a precise hypothesis was established independently from the data used for the test and (ii) the computed p-values are adjusted for multiple testing if more than one test was performed. Otherwise an explorative interpretation generates a hypothesis. We conclude that NTP-reports - including TR 578 on Ginkgo biloba - deliver explorative statistics, i.e. they generate hypotheses, but do not prove them.

Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice.

Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)-induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro- and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54-95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24-48 h). Combined treatment increased median survival to 96 h (range 24-240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24-48 h] and 48 h [24-96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis.

Is a controlled randomised trial the non-plus-ultra design? A contribution to discussion on comparative, controlled, non-randomised trials.

BACKGROUND: Clinical studies provide formalised experience for evidence-based medicine (EBM). Many people consider a controlled randomised trial (CRT, identical to a randomised controlled trial RCT) to be the non-plus-ultra design. However, CRTs also have limitations. The problem is not randomisation itself but informed consent for randomisation and masking of therapies according to today's legal and ethical standards. We do not want to de-rate CRTs, but we would like to contribute to the discussion on clinical research methodology. SITUATION: Informed consent to a CRT and masking of therapies plainly select patients. The excellent internal validity of CRTs can be counterbalanced by poor external validity, because internal and external validity act as antagonists. In a CRT, patients may feel like guinea pigs, this can decrease compliance, cause protocol violations, reduce self-healing properties, suppress unspecific therapeutic effects and possibly even modify specific efficacy. DISCUSSION: A control group (comparative study) is most important for the degree of evidence achieved by a trial. Study control by detailed protocol and good clinical practice (controlled study) is second in importance and randomisation and masking is third (thus the sequence CRT instead of RCT). Controlled non-randomised trials are just as ambitious and detailed as CRTs. RECOMMENDATION: We recommend clinicians and biometricians to take high quality controlled non-randomised trials into consideration more often. They combine good internal and external validity, better suit daily medical practice, show better patient compliance and fewer protocol violations, deliver estimators unbiased by alienated patients, and perhaps provide a clearer explanation of the achieved success.

[Evaluation of methods of traditional chinese medicine at the clinic at Steigerwald Part 2: therapy success and sustainability]. / Evaluation von verfahren der traditionellen chinesischen medizin in der klinik am steigerwald. teil 2: therapieerfolg und dessen nachhaltigkeit.

INTRODUCTION: in 2008, we described the documentation system of the 'Klinik am Steigerwald'. Now, we report on the results gained with this system, especially on the therapeutic success and its sustainability. PATIENTS AND METHODS: we evaluated 1,972 in-patients treated between 1999 and 2007. 74% of these patients were followed for up to 24 months. The therapeutic success achieved at the time of discharge from hospital was comparable in patients with follow-up and in patients lost to follow-up. Therefore, no relevant bias has to be assumed. RESULTS: at discharge from hospital complaints had improved markedly or somewhat in 62­77% of the patients. 2 years after discharge from hospital between 62 and 85% of the patients said that their complaints had improved as compared to the time before admission. This is also true for progressive diseases and if medication had been reduced. The proportion of days with inability to work decreased from 21.6% before admission to 16.0% at 0­6 months after discharge to 14.0% at 6­12 months after discharge to 11.9% at 18­24 months after discharge from hospital. Special focus is laid on Morbus Crohn /colitis ulcerosa and polyneuropathy which are core areas of the 'Klinik am Steigerwald'. CONCLUSION: documentation of the therapeutic success and its sustainability is essential for an evidence based medicine. Assessment of therapeutic success by complaints of patients is according to the idea of quality of life. This holds for modern as well as for traditional medical procedures like e.g., traditional Chinese medicine.

The efficacy and safety of Crataegus extract WS 1442 in patients with heart failure: the SPICE trial.

BACKGROUND: Crataegus preparations have been used for centuries especially in Europe. To date, no proper data on their efficacy and safety as an add-on-treatment are available. Therefore a large morbidity/mortality trial was performed. AIM: To investigate the efficacy and safety of an add-on treatment with Crataegus extract WS 1442 in patients with congestive heart failure. METHODS: In this randomised, double-blind, placebo-controlled multicenter study, adults with NYHA class II or III CHF and reduced left ventricular ejection fraction (LVEF< or =35%) were included and received 900 mg/day WS 1442 or placebo for 24 months. Primary endpoint was time until first cardiac event. RESULTS: 2681 patients (WS 1442: 1338; placebo: 1343) were randomised. Average time to first cardiac event was 620 days for WS 1442 and 606 days for placebo (event rates: 27.9% and 28.9%, hazard ratio (HR): 0.95, 95% CI [0.82;1.10]; p=0.476). The trend for cardiac mortality reduction with WS 1442 (9.7% at month 24; HR: 0.89 [0.73;1.09]) was not statistically significant (p=0.269). In the subgroup with LVEF> or =25%, WS 1442 reduced sudden cardiac death by 39.7% (HR 0.59 [0.37;0.94] at month 24; p=0.025). Adverse events were comparable in both groups. CONCLUSIONS: In this study, WS 1442 had no significant effect on the primary endpoint. WS 1442 was safe to use in patients receiving optimal medication for heart failure. In addition, the data may indicate that WS 1442 can potentially reduce the incidence of sudden cardiac death, at least in patients with less compromised left ventricular function.

[Evaluating traditional Chinese medicine as applied in the Clinic at Steigerwald. Part 1: Methods of assessment]. / Evaluation von Verfahren der traditionellen chinesischen Medizin in der Klinik am Steigerwald. Teil 1: Erhebungsmethodik.

BACKGROUND: In the 'Klinik am Steigerwald' (Gerolzhofen, Germany), founded in 1996 and providing accommodation for 44 patients, European physicians apply methods of traditional Chinese medicine (TCM). OBJECTIVE: To develop an assessment system which is suitable for the evaluation of therapies, can be integrated into daily routine, takes into account the particular therapeutic approach of the hospital, and promotes quality management. PATIENTS AND METHODS: The hospital admits all kinds of patients with chronic and often therapy-resistant diseases. Patients are primarily treated with Chinese phytotherapy and acupuncture. Methods of classical naturopathy and Western medicine complete the therapeutic range. All admitted patients are to be assessed. Exclusions are made according to a previously determined set of criteria. A written consent is mandatory. RESULTS: The assessment system comprises 3 questionnaires; 2 to be filled in by the patients, and 1 to document the physician's evaluation of the therapeutic success, based on his final consultation of the patient. Between January 2000 and December 2004, 2,021 patients were admitted to the hospital and followed-up until 2006. Of these, 1,609 patients met the inclusion criteria; 1,282 of these, again, agreed to participate in the interviewing process. The questionnaires of 1,110 patients were eligible for analysis. The present paper describes the methods of assessment. Its results are to be published in a future paper. CONCLUSION: Over the past 7 years, the assessment system has shown to be effective and appropriate to evaluate the type of therapy in question. It is intended to shorten the questionnaires.

Riluzole in Huntington's disease: a 3-year, randomized controlled study.

OBJECTIVE: We conducted a randomized double-blind trial of riluzole in Huntington's disease to investigate the efficacy of this antiexcitotoxic drug in slowing disease progression. METHODS: The study included 537 adult patients with a clinical diagnosis of Huntington's disease confirmed by genotyping. Patients were randomized (2:1) to treatment with riluzole (50mg twice daily) or placebo for 3 years. Concomitant use of antichoreic medication was forbidden, and introduction of such medication was a predefined end point. The primary outcome measure was change in a combined score derived from the motor and total functional capacity subscores of the Unified Huntington's Disease Rating Scale. Safety was also evaluated. RESULTS: A total of 379 patients completed the study (mean age, 47 [standard deviation, 9.5] years; 50% female patients). The principal reason for discontinuation was introduction of antichoreic medication. The median change from baseline in the combined score (primary outcome) for the "per protocol" population was 13.7 (95% confidence interval, 11.1-17.2) in the placebo group and 14.3 (95% confidence interval, 11.7-16.6) in the riluzole group. No intergroup difference in outcome could thus be demonstrated (p = 0.93, Mann-Whitney U test). No differences in secondary efficacy outcome variables were observed except for more frequent recourse to antichoreic medication in the placebo group. No unexpected adverse events were reported, and tolerability was acceptable. INTERPRETATION: No neuroprotective or beneficial symptomatic effects of riluzole in Huntington's disease were demonstrated.

[Evaluation of a modular out-patient education program for adult asthmatics with office-based specialists--results of a controlled, randomized multicenter trial]. / Evaluation eines modularen, ambulanten Schulungsprogrammes für erwachsene Asthmatiker bei niedergelassenen Fachärzten--Ergebnisse einer kontrollierten, randomisierten, multizentrischen Studie.

The efficacy of a modular education program for adult asthmatics was evaluated in a controlled, randomized multicenter trial under outpatient conditions for six months. The education was performed with material (patient handout and PowerPoint slides) of the MASA Program (i.e. a modular outpatient education program for adult asthmatics) according to the contents list of the NASA Program (i.e. a national education program for adult asthmatics). In total, 75 patients of seven asthma specialists were included. The complete data of 53 patients were obtained and evaluated. All patients had been diagnosed with asthma in the year before, most of them (54%) with moderately severe asthma. The patients in the intervention group attended a two-hour teaching program for three times; the control group once received a short introduction to the use of a peak-flow meter, an asthma diary and asthma emergency instructions. Compared to the control group, the intervention group patients showed significantly less mild asthma attacks. The mean requirement for inhalation of short-acting beta-agonists was 0.18 times vs. 1.5 times per week for the intervention and the control group, respectively (p = 0.0062). Another primary outcome was the number of unscheduled asthma-related visits to the doctor within six months. There was a trend to lower numbers in the intervention group, but due to the small number of patients the results did not reach significance. The same applies to the patients' estimation of their quality of life, measured by the SF-36 questionnaire. Patients in the intervention group had a significantly better knowledge about their disease (improvement in the number of correctly answered questions: 6.7 times in the intervention and 5.5 times in the control group; p = 0.0062) and showed a better adherence to their regular medication. In conclusion, this trial proves the quality of the MASA education program and its feasibility in the outpatient setting of a chest physician's practice, and it demonstrates the efficacy of outpatient education programs for asthmatics.

Meta-analysis of the efficacy of the acetonic kava-kava extract WS1490 in patients with non-psychotic anxiety disorders.

INTRODUCTION: The herbal medicinal product kava-kava, used for treating anxiety disorders, was assessed positively by the Cochrane Review. However, it was withdrawn from the market in Switzerland and Germany due to cases of liver failure and 'unproven' efficacy. METHODS: A protocol for the meta-analysis based on patient source data was written, a literature search was done, and six placebo-controlled, randomized trials with the kava extract WS1490 were identified. The endpoints were the change in HAMA during treatment (continuous and binary). RESULTS: WS1490 has an effective success rate of OR=3.3 (95% confidence interval of 2.09-5.22) in patients with non-psychotic anxiety disorders. The continuous outcome supports this result: mean improvement with WS1490 by 5.94 (95% confidence interval -0.86 to 12.8) points on the HAMA scale better than placebo. Kava seems to be more effective in females and in younger patients. DISCUSSION: This meta-analysis has no publication bias, no remarkable heterogeneity and is based on trials with high methodological standards. It is concluded that WS1490, and possibly other kava extracts, are effective. Therefore they remain alternatives to benzodiazepines, selective serotonin re-uptake inhibitors (SSRIs) and other antidepressants in the treatment of non-psychotic anxiety disorders.

Pharmacokinetic herb-drug interactions: are preventive screenings necessary and appropriate?

Pharmacokinetic interactions often occur as a result of activity changes of drug-metabolizing and transporting proteins, especially cytochrome P450 (CYP) isoenzymes and P-glycoprotein (P-gp). The activity of these enzymes and drug transporters can be enhanced or inhibited by synthetic drugs as well as by natural products. Since the number of herb-drug interactions has increased in recent years, systematic in vitro screenings and more clinical studies to identify such interactions were proposed for herbal medicinal products. However, previous results regarding this issue are not only contradictory but also of less predictability. One reason for the discrepancies could be the lack of validation of the recommended in vitro tests. Furthermore, it has to be considered that pharmacokinetic drug interactions are not only mediated by herbal medicines but also by several foods, beverages and life-style products. Since herbal medicines are considered to have a broad therapeutic range, a preventive risk assessment for pharmacokinetic drug interactions should first be realized for synthetic drugs with a narrow therapeutic index. Efforts to identify all possible interactions will lead to limitless investigations and to inconsistent decisions.

Applying evidence to support ethical decisions: is the placebo really powerless?.

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.

Risk factors for alveolar echinococcosis in humans.

We conducted a case-control study to investigate risk factors for acquiring autochthonous alveolar echinococcosis in Germany. Forty cases and 120 controls matched by age and residence were interviewed. Patients were more likely than controls to have owned dogs that killed game (odds ratio [OR] = 18.0), lived in a farmhouse (OR = 6.4), owned dogs that roamed outdoors unattended (OR = 6.1), collected wood (OR = 4.7), been farmers (OR = 4.7), chewed grass (OR = 4.4), lived in a dwelling close to fields (OR = 3.0), gone into forests for vocational reasons (OR = 2.8), grown leaf or root vegetables (OR = 2.5), owned cats that roamed outdoors unattended (OR = 2.3), and eaten unwashed strawberries (OR = 2.2). Sixty-five percent of cases were attributable to farming. Measures that prevent accidental swallowing of possibly contaminated material during farming or adequate deworming of pet animals might reduce the risk for alveolar echinococcosis.

Intralesional recombinant interferon beta-1a in the treatment of basal cell carcinoma: results of an open-label multicentre study.

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.