Associations between functional polymorphisms in the NFκB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease.

Antitumor necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. Genetic markers may predict individual response to anti-TNF therapy. Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in 738 prior anti-TNF-naive Danish patients with IBD. The results were analyzed using logistic regression (crude and adjusted for age, gender and smoking status). Nineteen functional polymorphisms that alter the NFκB-mediated inflammatory response (TLR2 (rs3804099, rs11938228, rs1816702, rs4696480), TLR4 (rs5030728, rs1554973), TLR9 (rs187084, rs352139), LY96 (MD-2) (rs11465996), CD14 (rs2569190), MAP3K14 (NIK) (rs7222094)), TNF-α signaling (TNFA (TNF-α) (rs361525), TNFRSF1A (TNFR1) (rs4149570), TNFAIP3(A20) (rs6927172)) and other cytokines regulated by NFκB (IL1B (rs4848306), IL1RN (rs4251961), IL6 (rs10499563), IL17A (rs2275913), IFNG (rs2430561)) were associated with response to anti-TNF therapy among patients with CD, UC or both CD and UC (P ⩽ 0.05). In conclusion, the results suggest that polymorphisms in genes involved in activating NFκB through the Toll-like receptor (TLR) pathways, genes regulating TNF-α signaling and cytokines regulated by NFκB are important predictors for the response to anti-TNF therapy among patients with IBD. Genetically strong TNF-mediated inflammatory response was associated with beneficial response. In addition, the cytokines IL-1ß, IL-6 and IFN-γ may be potential targets for treating patients with IBD who do not respond to anti-TNF therapy. These findings should be examined in independent cohorts before these results are applied in a clinical setting.

Mycobacterium tuberculosis outbreak strain of Danish origin spreading at worrying rates among greenland-born persons in Denmark and Greenland.

Transmission of Mycobacterium tuberculosis continues at high rates among Greenland-born persons in Greenland and Denmark, with 203 and 450 notified cases per 10(5) population, respectively, in the year 2010. Here, we document that the predominant M. tuberculosis outbreak strain C2/1112-15 of Danish origin has been transmitted to Greenland-born persons in Denmark and subsequently to Greenland, where it is spreading at worrying rates and adding to the already heavy tuberculosis burden in this population group. It is now clear that the C2/1112-15 strain is able to gain new territories using a new population group as the "vehicle." Thus, it might have the ability to spread even further, considering the potential clinical consequences of strain diversity such as that seen in the widely spread Beijing genotype. The introduction of the predominant M. tuberculosis outbreak strain C2/1112-15 into the Arctic circumpolar region is a worrying tendency which deserves attention. We need to monitor whether this strain already has, or will, spread to other countries.

European union standards for tuberculosis care.

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.

Clustered tuberculosis in a low-burden country: nationwide genotyping through 15 years.

Molecular genotyping of Mycobacterium tuberculosis has proved to be a powerful tool in tuberculosis surveillance, epidemiology, and control. Based on results obtained through 15 years of nationwide IS6110 restriction fragment length polymorphism (RFLP) genotyping of M. tuberculosis cases in Denmark, a country on the way toward tuberculosis elimination, we discuss M. tuberculosis transmission dynamics and point to areas for control interventions. Cases with 100% identical genotypes (RFLP patterns) were defined as clustered, and a cluster was defined as cases with an identical genotype. Of 4,601 included cases, corresponding to 76% of reported and 97% of culture-verified tuberculosis cases in the country, 56% were clustered, of which 69% were Danes. Generally, Danes were more often in large clusters (≥ 50 persons), older (mean age, 45 years), and male (male/female ratio, 2.5). Also, Danes had a higher cluster frequency within a 2-year observation window (60.8%), and higher clustering rate of new patterns over time, compared to immigrants. A dominant genotype, cluster 2, constituted 44% of all clustered and 35% of all genotyped cases. This cluster was primarily found among Danish males, 30 to 59 years of age, often socially marginalized, and with records of alcohol abuse. In Danes, cluster 2 alone was responsible for the high cluster frequency level. Immigrants had a higher incidence of clustered tuberculosis at a younger age (0 to 39 years). To achieve tuberculosis elimination in Denmark, high-risk transmission environments, like the cluster 2 environment in Danes, and specific transmission chains in immigrants in the capital area, e.g., homeless/socially marginalized Somalis/Greenlanders, often with alcohol abuse, must be targeted, including groups with a high risk of reactivation.

Ongoing tuberculosis transmission to children in Greenland.

Inuit in the Arctic are experiencing an increase in tuberculosis cases, reaching levels in Greenland comparable to high-incidence countries. This prompted us to study the level of tuberculosis transmission to Greenlandic children. Specifically, we estimated the current prevalence of Mycobacterium tuberculosis infection (MTI) and the underlying annual risk of MTI. 2,231 Greenlandic school children aged 5-17 yrs (∼25% of the Greenlandic population in the relevant age group) were tested for MTI using the tuberculin skin test and the QuantiFERON®-TB Gold in-tube test. Subjects with dual-positive results were considered infected and subjects with dual-negative results uninfected. The children with discordant test results were classified as probably having MTI and analysed separately. 8.1% of the children had dual-positive test results. The annual risk of MTI was estimated as 0.80% (95% CI 0.67-0.92%) giving a cumulative risk at the 18th birthday of 13.4%. The annual risk of MTI varied substantially by ethnicity (0.87% in Inuit children, 0.02% in non-Inuit children; p<0.001) and by location (0.13% on the west coast, 1.68% on the south coast; p<0.001). M. tuberculosis transmission occurs at a very high level in Inuit children with pronounced geographic differences emphasising the need for immediate public health interventions.

Re-activation of bovine tuberculosis in a patient treated with infliximab.

Treatment with tumour necrosis factor-alpha inhibitors increases the risk of tuberculosis (TB). Screening for latent TB infection (LTBI) and prophylactic treatment has become mandatory. A 79-yr-old female with a history of severe erosive sero-positive rheumatoid arthritis was screened for LTBI before initiation of treatment with infliximab. The tuberculin skin test (TST) was negative, chest radiography was normal and she had no known risk factors for TB. After 4 months of treatment with infliximab, the patient developed ascites caused by Mycobacterium bovis. The TST was repeatedly negative. QuantiFERON-TB (QFT) testing performed during screening and immunosuppressive treatment was indeterminate, whereas the QFT test performed at the time of ascites puncture was positive. The patient history revealed previous work at a dairy, with probable exposure to unpasteurised milk from M. bovis-infected cattle. Re-activation of bovine tuberculosis is a risk in people with recent or previous exposure to unpasteurised dairy products. The QuantiFERON-TB test has the potential to detect Mycobacterium bovis infection. Indeterminate test results reflect either anergy, due to poor immunity, or technical problems and should be cautiously interpreted and as a minimum be repeated. Studies are ongoing to determine the role of QuantiFERON-TB testing in the screening for latent tuberculosis infection.

Multidrug-resistant tuberculosis: rapid detection of resistance to rifampin and high or low levels of isoniazid in clinical specimens and isolates.

The aim of the present study was to evaluate a new improved multiplex polymerase chain reaction (PCR) hybridisation assay to detect multidrug-resistant tuberculosis. The assay, developed to detect rifampin (rpoB) and isoniazid (katG) gene mutations causing Mycobacterium tuberculosis resistance, was recently extended to include inhA gene mutations that code for low-level isoniazid resistance. Interpretable results were obtained in 115 isolates and in all smear-positive clinical specimens. Rifampin resistance was correctly identified in all specimens and in 20 of 21 (95%) multidrug-resistant isolates compared to BACTEC 460TB. Isoniazid resistance correlated in 18 of 22 (82%) specimens, in 31 of 31 (100%) high-level and 24 of 28 (86%) low-level isoniazid-resistant isolates. The assay was rapid, easy to perform and directly applicable in smear-positive specimens. We predict that the assay may be a useful tool to combat and prevent new cases of multi- and extensively drug-resistant tuberculosis.

Diagnosis of pulmonary tuberculosis. Application of gen-probe amplified Mycobacterium tuberculosis direct test.

The purpose of this investigation was to evaluate the Amplified Mycobacterium tuberculosis Direct Test (AMTDT) for the diagnosis of pulmonary tuberculosis (TB). Six hundred and forty-six sputum samples were analysed by microscopy for acid-fast bacilli, by culture for mycobacterial growth, and by AMTDT for the presence of M. tuberculosis complex rRNA. If there were discrepant results, information as to whether the patient had a history of TB was obtained. The sensitivity was 85.7% (smear positive 100% and smear negative 71.4%, respectively) and the specificity was 96.8% compared with culture. By retesting, 12 of 13 false-positive samples could be divided into two major categories. The samples in one category were retest positive, had highly positive results, and the patients had previous culture-proven TB. The samples in the other category had less positive AMTDT results, were retest negative, and the patients were not notified as having TB. This investigation shows that AMTDT is a sensitive supplementary method for rapid detection of M. tuberculosis complex in respiratory specimens, that there is a risk of contamination which has to be monitored closely, and that positive samples should be retested.

Tuberculosis in Greenland--current situation and future challenges.

OBJECTIVE: To describe the tuberculosis (TB) epidemiology in Greenland in 1998-2002 and to identify possible obstacles for reducing the TB incidence. STUDY DESIGN/METHODS: TB notification data were collected from the annual reports of the Chief Medical Officer, and culture verification data were collected from the International Reference Laboratory of Mycobacteriology at Statens Serum Institut, Denmark. RESULTS: The TB incidence in Greenland reached a peak of 185/100,000 in 2001. In 1999-2001, the majority of cases were related to an outbreak in the Southern districts. In 1998-2002, 0.5% drug-resistance was found among patients living in Greenland in contrast to 13.1% drug-resistance found previously among Inuit patients in Denmark. In 1998-2001, microscopy positive cases made up 65% of all culture confirmed cases and DNA subtyping demonstrated the emergence of Mycobacterium tuberculosis strains that were previously infrequently found. CONCLUSION: It is important to eliminate factors that fuel the epidemic and to improve general living conditions in Greenland. Treatment seems effective as limited drug-resistance is detected. TB reduction will therefore depend on early detection of active disease and thorough contact tracing. Greenland will face a pool of persons latently infected some of whom will progress to active disease. Sufficient resources need to be allocated for TB control in the years to come.

[Tuberculosis among children in Denmark, 1990-1999]. / Tuberkulose blandt børn i Danmark 1990-1999.

INTRODUCTION: During a century with a decreasing incidence of tuberculosis (TB) in Denmark, the last 15 years have seen an increase. We describe the epidemiology of TB in children in Denmark with the focus on the impact of immigration. MATERIALS AND METHODS: Data from the national TB surveillance of 1990-1999 were analysed. The variables were age, gender, nationality, TB location(s), and the results of microscopy and culture. RESULTS: Three hundred and forty-nine children below 15 years of age were found, representing 8% of all notified cases of TB. Of these, 268 children (78%) were immigrants. The number of children increased over time, as did the proportion of immigrants (p < 0.0001). The median age was four years in the native Danes and nine years in the immigrant children (p < 0.001). The mean annual incidence of TB in the children was 3.9 per 10(5); 45.8 per 10(5) in the immigrants and 0.92 per 10(5) in the native Danes. The incidence increased from 2.0 in 1990 to 5.3 per 10(5) in 1999. Forty-nine per cent of the immigrants were Somalis, 13% were Pakistanis. The mean annual TB incidence was 581 per 10(5) in Somalis and 78 per 10(5) in Pakistanis. The incidence increased with age in children from Pakistan and Somalia and decreased in native Danes. Seventy-seven per cent of native Danes and 65% of immigrants had pulmonary TB +/- other locations (p < 0.05). Sixty-seven per cent of immigrant children with extrapulmonary TB had TB in the glands, 9% had TB in the bones, and another 9% had TB in the digestive system, proportions that were 38% (p < 0.05), 8%, and 0%, respectively, in native Danes. DISCUSSION: Immigration has had an impact on the incidence of TB, as well as on the pattern of TB location in children in Denmark. The incidence was 48 times higher in immigrant than in native Danish children.

[Resistant tuberculosis in Denmark]. / Resistent tuberkulose i Danmark.

INTRODUCTION: Increased rates of multidrug-resistant (MDR) tuberculosis (TB) has been reported from countries close to Denmark. We evaluated the incidence of drug resistance in Denmark in order to determine the magnitude of the problem. MATERIALS AND METHODS: Susceptibility testing was performed in isolates from 85.4% of all notified patients during 1991-1998. Epidemiological information was retrieved from the mandatory notification forms. RESULTS: Total drug resistance remained largely constant, although a minor increase was observed in 1997-1998. Monoresistance was observed in 7.3% of the isolates. Among 3.6% polyresistant isolates, resistance to isoniazid and streptomycin accounted for 2.8%, whereas MDR accounted for 0.5%. The MDR strains displayed different restriction fragment length polymorphism (RFLP) patterns, and no matches were identified in the international MDR database. Drug resistance in untreated Danes and foreigners were 5.9% and 14.6%, respectively. Among Danes and foreigners with previous TB, 6.2% and 22.7% had drug resistance, respectively. Increased drug resistance was found among untreated Danes aged 25-54 years mainly due to a single isoniazid- and streptomycin-resistant RFLP-cluster. Among all patients with isoniazid- and streptomycin-resistance, 77.0% had clustered strains. DISCUSSION: In conclusion, although drug resistance among untreated Danes was close to the rate estimated in good national programmes, close monitoring is needed in future years, as active transmission of isoniazid- and streptomycin-resistant Mycobacterium tuberculosis was demonstrated.

Nontuberculous mycobacterial disease is not a contraindication to lung transplantation in patients with cystic fibrosis: a retrospective analysis in a Danish patient population.

Whether nontuberculous mycobacterial (NTM) disease is a contraindication to lung transplantation remains controversial. We conducted a nationwide study to evaluate the clinical importance of NTM infection among lung transplant patients with cystic fibrosis (CF) in Denmark and to determine if NTM infection poses a contraindication to lung transplantation. All CF patients with current or prior NTM who had undergone lung transplantation were identified. Out of 52 lung transplant patients with CF 9 (17%) had NTM disease. Five patients had known infection at the time of transplantation. Two of these died of non-NTM-related causes whereas two developed deep Mycobacterium abscessus wound infections and one was transiently culture negative until M abscessus was reactivated. One patient was subsequently cured; the other two remained on therapy with good performance status. The study supports the contention that CF patients with prior or active NTM can undergo lung transplantation although postoperative complications can be expected.

Recurrent tuberculosis in Denmark: relapse vs. re-infection.

SETTING: Denmark, a country with a low-incidence of tuberculosis (TB). OBJECTIVE: To analyse the proportion of relapse vs. re-infection and to compare selected characteristics between the two subgroups. DESIGN: A population-based cohort study. All 4154 Mycobacterium tuberculosis isolates from patients in Denmark genotyped by insertion sequence 6110 restriction fragment length polymorphism were followed for recurrent TB over 13.5 years. Recurrent cases were classified as relapse or re-infection by genotype patterns in initial and serial disease episodes. RESULTS: Recurrent TB was found in 73 (1.8%) cases. Identical M. tuberculosis genotypes in initial and serial episodes were found in 54 (1.3%), indicating relapse, whereas different genotypes, representing re-infection, were found in 19 (0.5%) cases. Cavitary TB in the initial episode was significantly associated with relapse (OR 4.6, 95%CI 1.1-26.9) compared to re-infection. CONCLUSION: The rate of recurrent TB is low in Denmark. Comparing selected characteristics between the relapse and re-infection subgroups revealed that only the presence of cavitary disease was associated with relapse. Although recurrent TB was rarely due to re-infection, the risk of re-infection increased with time.

A patient with suspected sarcoidosis died from miliary tuberculosis.

In Western Europe, awareness of tuberculous lymphadenitis (TLA) has declined. This report describes a patient who had suspected sarcoidosis for 3.5 y, who eventually died from miliary tuberculosis due to delay in diagnosis. The report includes a discussion of the differential diagnosis of TLA and sarcoidosis.

Results from 8 yrs of susceptibility testing of clinical Mycobacterium tuberculosis isolates in Denmark.

Increased rates of multidrug-resistant (MDR) tuberculosis (TB) has been reported from countries close to Denmark. This study evaluated the incidence of drug resistance in Denmark in order to determine the magnitude of the problem. Susceptibility testing was performed in isolates from 85.4% of all notified patients during 1991-1998. Epidemiological information was retrieved from the mandatory notification forms. Total drug resistance remained largely constant, although a minor increase was observed in 1997-1998. Monoresistance was observed in 7.3%, of the isolates. Among 3.6% polyresistant isolates, resistance to isoniazid and streptomycin accounted for 2.8%, whereas MDR accounted for 0.5%. The MDR strains displayed different restriction fragment length polymorphism (RFLP) patterns, and no matches were identified in the international MDR database. Drug resistance in untreated Danes and foreigners were 5.9% and 14.6%, respectively. Among Danes and foreigners with previous TB, 6.2% and 22.7% had drug resistance, respectively. Increased drug-resistance was found among untreated Danes aged 25-54 yrs mainly due to a single isoniazid and streptomycin-resistant RFLP-cluster. Among all patients with isoniazid and streptomycin-resistance, 77.0% had clustered strains. In conclusion, although drug resistance among untreated Danes was close to the rate estimated in good national programmes, close monitoring is needed in future years, as active transmission of isoniazid- and streptomycin-resistant Mycobacterium tuberculosis was demonstrated.

Characterization of isoniazid-resistant strains of Mycobacterium tuberculosis on the basis of phenotypic properties and mutations in katG.

Forty isoniazid-resistant Mycobacterium tuberculosis isolates were characterized on the basis of phenotypic properties (i.e., catalase activity, MIC of isoniazid, and growth pattern in the presence of 7 different concentrations of isoniazid) and alterations in the katG gene (codons 315 and 463). Three different growth patterns could be distinguished: concentration-dependent inhibition of growth was observed in 29 strains, similar growth at all concentrations was seen in 7 strains, and enhanced growth at low concentrations of isoniazid was evident in 4 strains. The MIC of isoniazid was < or = microg/ml for 29 of 40 strains. Mutation at codon 315 of the katG was detected in 28 of 40 strains. However, only one of the seven strains for which the MIC of isoniazid was > or = 16 microg/ml had mutation at this codon. Five of these seven strains for which the MIC was > or = 16 microg/ml had no catalase activity. The results indicate that the MIC of isoniazid for a majority of strains is below the level achievable in serum. Therefore, isoniazid may be beneficial for the treatment of some cases of multidrug-resistant tuberculosis. Determination of catalase activity aids in the detection of isolates for which MICs are high and could, in conjunction with molecular methods, provide rapid detection of most isoniazid-resistant strains.

Tuberculosis not verified by culture in a low incidence country.

The objective was to evaluate the magnitude, diagnostic basis and characteristics of patients notified with tuberculosis (TB) not verified by culture. All patients in Denmark notified with TB between 1995 and 1999 were identified through the national TB register. Nationwide culture results were obtained from the International Reference Laboratory of Mycobacteriology. The proportion of culture verification decreased from 91% in 1995 to 80% in 1999. A total of 2518 patients were notified, of which 374 (14.9%) were not verified by culture. For 80 (3.2%) patients no specimens were submitted. Instead the diagnosis was mainly based on X-ray (72.6%) for patients with pulmonary TB and histology (38.3%) for patients with extrapulmonary TB. For 216 patients aged 0-14 y, 74 (34.3%) were not verified by culture. The proportion of TB not verified by culture in Denmark is low compared to other European countries. Some cases may be well explained, e.g. children with a close contact suffering from TB or patients with extrapulmonary TB with limited number of specimens. However, for a minority group of patients with pulmonary TB there were no obvious reasons why specimens were not submitted for culture. Culture verification should remain a priority when possible.

Evaluation of a new commercial assay for diagnosis of pulmonary and nonpulmonary tuberculosis.

A new commercial assay for the diagnosis of tuberculosis, the BDProbeTec ET Direct Detection assay (Becton Dickinson, USA), was evaluated using 351 respiratory and 372 nonrespiratory specimens. The results were compared to detection of Mycobacterium tuberculosis complex (MTC) by conventional culture. Among the 351 respiratory specimens, MTC bacteria were identified in 150, of which 85 were positive by both microscopy and the assay. Sixty-five specimens culture positive for MTC were microscopy negative; of these, 39 were positive in the assay. All 26 specimens culture positive for nontuberculous mycobacteria (NTM) were negative by the assay. Of 175 specimens culture negative for MTC, 3 were falsely positive by the assay and 1 yielded inhibition. The overall sensitivity and specificity values were 82.7% and 98.5%, respectively. The sensitivity for microscopy-positive and -negative respiratory specimens was 100% and 60%, respectively. After correction for discrepancies, the specificity was 99% compared with notification data. The BDProbeTec ET assay detected 66 of 67 microscopy-positive and 50 of 125 microscopy-negative nonrespiratory specimens. The result for one specimen was inconclusive. All nine specimens containing NTM were negative by the assay. Of 171 specimens culture negative for MTC, 6 were falsely positive by the assay. The overall sensitivity and specificity values obtained with nonrespiratory specimens were 60.7% and 96.7%, respectively. After examining discrepancies by reviewing the patients' histories, the specificity was 98.9%. The sensitivity was 98.5% in microscopy-positive specimens and 40.3% in microscopy-negative specimens. The overall inhibition rate was 0.3%. The BDProbeTec ET assay is a fast, effective, and user-friendly system that can be used for rapid detection of MTC bacteria in respiratory and microscopy-positive nonrespiratory specimens as an important supplement to smear and culture.

False-positive results from cultures of Mycobacterium tuberculosis due to laboratory cross-contamination confirmed by restriction fragment length polymorphism.

During 1994, a cross-contamination problem leading to false-positive cultures of Mycobacterium tuberculosis was revealed in a mycobacteriology laboratory processing 30,000 to 35,000 samples per year. Molecular strain typing based on restriction fragment length polymorphism confirmed the contaminations. Out of 1,439 positive cultures of Mycobacterium tuberculosis, 49 samples from 48 patients were suspected to be cross-contaminated. In 37 cases, growth was observed both in BACTEC vials and on solid media, indicating that the contamination took place during the processing of the samples. The majority of the contaminated samples had been handled by the same technician.

Disseminated infection with Mycobacterium genavense: a challenge to physicians and mycobacteriologists.

In the present study we compared the clinical presentations of patients with a clinical diagnosis of AIDS and disseminated Mycobacterium genavense infection (n = 12) with those of patients with AIDS and disseminated M. avium complex (MAC) infection (n = 24). Abdominal pain was seen more frequently in the group of patients infected with M. genavense than in patients infected with MAC (P = 0. 003). Analysis of microbiological data revealed that stool specimens from patients infected with M. genavense were more often smear positive than stool specimens from patients infected with MAC (P = 0. 00002). However, M. genavense could be cultured on solid media from only 15.4% of the stool specimens, whereas MAC could be cultured from 71.4% of the specimens. Bone marrow and liver biopsy specimens yielded growth of M. genavense within a reasonably short time, allowing species identification by DNA technology. Microbiological data clearly demonstrated the importance of acidic liquid medium for primary culture, the avoidance of pretreatment and the use of additives in culture, and the necessity for prolonged incubation if M. genavense is suspected. Susceptibility testing showed that M. genavense is sensitive to rifamycins, fluoroquinolones, and macrolides, whereas it is resistant to isoniazid. Susceptibility to ethambutol and clofazimine could not be evaluated. The mean survival times of patients in the two groups were similar.