Inability to work following COVID-19 vaccination-a relevant aspect for future booster vaccinations.

OBJECTIVES: COVID-19 vaccination is a key prevention strategy to reduce the spread and severity of SARS-CoV-2 infections. However, vaccine-related inability to work among healthcare workers (HCWs) could overstrain healthcare systems. STUDY DESIGN: The study presented was conducted as part of the prospective CoVacSer cohort study. METHODS: This study examined sick leave and intake of pro re nata medication after the first, second, and third COVID-19 vaccination in HCWs. Data were collected by using an electronic questionnaire. RESULTS: Among 1704 HCWs enrolled, 595 (34.9%) HCWs were on sick leave following at least one COVID-19 vaccination, leading to a total number of 1550 sick days. Both the absolute sick days and the rate of HCWs on sick leave significantly increased with each subsequent vaccination. Comparing BNT162b2mRNA and mRNA-1273, the difference in sick leave was not significant after the second dose, but mRNA-1273 induced a significantly longer and more frequent sick leave after the third. CONCLUSION: In the light of further COVID-19 infection waves and booster vaccinations, there is a risk of additional staff shortages due to postvaccination inability to work, which could negatively impact the already strained healthcare system and jeopardise patient care. These findings will aid further vaccination campaigns to minimise the impact of staff absences on the healthcare system.

Surgery in times of COVID-19-recommendations for hospital and patient management.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has escalated rapidly to a global pandemic stretching healthcare systems worldwide to their limits. Surgeons have had to immediately react to this unprecedented clinical challenge by systematically repurposing surgical wards. PURPOSE: To provide a detailed set of guidelines developed in a surgical ward at University Hospital Wuerzburg to safely accommodate the exponentially rising cases of SARS-CoV-2 infected patients without compromising the care of emergency surgery and oncological patients or jeopardizing the well-being of hospital staff. CONCLUSIONS: The dynamic prioritization of SARS-CoV-2 infected and surgical patient groups is key to preserving life while maintaining high surgical standards. Strictly segregating patient groups in emergency rooms, non-intensive care wards and operating areas prevents viral spread while adequately training and carefully selecting hospital staff allow them to confidently and successfully undertake their respective clinical duties.

Confirmation of an IRAK3 polymorphism as a genetic marker predicting response to anti-TNF treatment in rheumatoid arthritis.

Several genetic variants in Toll-like receptor (TLR) and nuclear factor (NF)-κB signalling pathways have been reported associated with responsiveness to tumour necrosis factor inhibitor (anti-TNF) treatment in rheumatoid arthritis (RA). The present study was undertaken to replicate these findings. In a retrospective case-case study including 1007 Danish anti-TNF-treated RA patients, we genotyped 7 previously reported associated single-nucleotide polymorphisms (SNPs) in these pathways. Furthermore, 5 SNPs previously reported by our group were genotyped in a subcohort (N=469). Primary analyses validated the IRAK3 rs11541076 variant as associated (odds ratio (OR)=1.33, 95% confidence interval (CI): 1.00-1.77, P-value=0.047) with a positive treatment response (EULAR (European League Against Rheumatism) good/moderate vs none response at 4±2 months), and found the NLRP3 rs461266 variant associated (OR=0.75, 95% CI: 0.60-0.94, P=0.014) with a negative treatment response. Meta-analyses combining data from previous studies suggested smaller effect sizes of associations between variant alleles of CHUK rs11591741, NFKBIB rs3136645 and rs9403 and a negative treatment response. In conclusion, this study validates rs11541076 in IRAK3, a negative regulator of TLR signalling, as a predictor of anti-TNF treatment response, and suggests true positive associations of previously reported SNPs within genes encoding activators/inhibitors of NF-κB (CHUK, MYD88, NFKBIB, and NLRP3).

Associations between functional polymorphisms and response to biological treatment in Danish patients with psoriasis.

Biological agents including anti-tumor necrosis factor (anti-TNF; adalimumab, infliximab, etanercept) and anti-interleukin-12/13 (IL12/23; ustekinumab) are essential for treatment of patients with severe psoriasis. However, a significant proportion of the patients do not respond to a specific treatment. Pharmacogenetics might be a way to predict treatment response. Using a candidate gene approach, 62 mainly functional single-nucleotide polymorphisms (SNPs) in 44 different genes were evaluated in 478 Danish patients with psoriasis undergoing 376 series of anti-TNF treatment and 230 series of ustekinumab treatment. Associations between genetic variants and treatment outcomes (drug survival and Psoriasis Area Severity Index reduction) were assessed using logistic regression analyses (crude and adjusted for gender, age, psoriatic arthritis and previous treatment). After correction for multiple testing controlling the false discovery rate, six SNPs (IL1B (rs1143623, rs1143627), LY96 (rs11465996), TLR2 (rs11938228, rs4696480) and TLR9 (rs352139)) were associated with response to anti-TNF treatment and 4 SNPs (IL1B (rs1143623, rs1143627), TIRAP (rs8177374) and TLR5 (rs5744174)) were associated with response to ustekinumab treatment (q<0.20). The results suggest that genetic variants related to increased IL-1ß levels may be unfavorable when treating psoriasis with either anti-TNF or ustekinumab, whereas genetic variants related to high interferon-γ levels may be favorable when treating psoriasis with ustekinumab.

Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy.

Anti-tumour 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. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1ß (IL-1ß), IL-6 and interferon gamma (IFN-γ), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF naïve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95% CI: 0.11-0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.

Self-reported influenza vaccination rates and attitudes towards vaccination among health care workers: results of a survey in a German university hospital.

OBJECTIVES: The objective of this survey was to analyse vaccination rates and attitudes towards vaccination among health care workers (HCWs). The period prevalence of self-reported acute respiratory infections in the influenza season 2014/2015 was examined. STUDY DESIGN: A cross-sectional study was conducted among HCWs of a German university hospital using an anonymised questionnaire. Recruitment was performed by providing all medical and nursing staff a paper questionnaire with an invitation to participate. METHODS: Descriptive aggregated data were generated from digitalised questionnaires for all variables. Differences in categorical variables were analysed by Chi-squared test. Textual data were analysed by an iterative process based on the grounded theory by Glaser and Strauss. RESULTS: The response rate was 31% (677/2186). Probable influenza was described by 9% (64/677) of the participants. The overall self-reported vaccination rate was 55% (366/666). Self-reported vaccination rate was higher in physicians (172/239, 72%) than in nursing staff (188/418, 45%). HCWs in paediatrics (103/148, 70%) more likely received vaccines than HCWs in surgery (31/84, 37%). Most vaccinations were provided by medical staff on the wards (164/368, 45%). Self-reported lost work-time due to adverse events after vaccination was low (6/336, 2%). Eight categories for vaccine refusal were identified, whereof doubts about effectiveness and indication of the vaccine was most frequently mentioned (72/202, 36%). CONCLUSIONS: Efforts to promote vaccination should focus on nursing staff and should provide scientific evidence on effectiveness, adverse effects, and the benefits of health care workers' vaccination for patients. Administering vaccines at the workplace proved to be a successful strategy in our setting. Studies are needed to assess the frequency of influenza causing disease in HCWs.

Systematic review and meta-analysis: pharmacogenetics of anti-TNF treatment response in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects ~1% of the Caucasian population. Over the last decades, the availability of biological drugs targeting the proinflammatory cytokine tumour necrosis factor α, anti-TNF drugs, has improved the treatment of patients with RA. However, one-third of the patients do not respond to the treatment. We wanted to evaluate the status of pharmacogenomics of anti-TNF treatment. We performed a PubMed literature search and all studies reporting original data on associations between genetic variants and anti-TNF treatment response in RA patients were included and results evaluated by meta-analysis. In total, 25 single nucleotide polymorphisms were found to be associated with anti-TNF treatment response in RA (19 from genome-wide association studies and 6 from the meta-analyses), and these map to genes involved in T cell function, NFκB and TNF signalling pathways (including CTCN5, TEC, PTPRC, FCGR2A, NFKBIB, FCGR2A, IRAK3). Explorative prediction analyses found that biomarkers for clinical treatment selection are not yet available.

Airway exposure to multi-walled carbon nanotubes disrupts the female reproductive cycle without affecting pregnancy outcomes in mice.

BACKGROUND: The use of multiwalled carbon nanotubes (MWCNT) is increasing due to a growing use in a variety of products across several industries. Thus, occupational exposure is also of increasing concern, particularly since airway exposure to MWCNTs can induce sustained pulmonary acute phase response and inflammation in experimental animals, which may affect female reproduction. This proof-of-principle study therefore aimed to investigate if lung exposure by intratracheal instillation of the MWCNT NM-400 would affect the estrous cycle and reproductive function in female mice. RESULTS: Estrous cycle regularity was investigated by comparing vaginal smears before and after exposure to 67 µg of NM-400, whereas reproductive function was analyzed by measuring time to delivery of litters after instillation of 2, 18 or 67 µg of NM-400. Compared to normal estrous cycling determined prior to exposure, exposure to MWCNT significantly prolonged the estrous cycle during which exposure took place, but significantly shortened the estrous cycle immediately after the exposed cycle. No consistent effects were seen on time to delivery of litter or other gestational or litter parameters, such as litter size, sex ratio, implantations and implantation loss. CONCLUSION: Lung exposure to MWCNT interfered with estrous cycling. Effects caused by MWCNTs depended on the time of exposure: the estrous stage was particularly sensitive to exposure, as animals exposed during this stage showed a higher incidence of irregular cycling after exposure. Our data indicates that MWCNT exposure may interfere with events leading to ovulation.

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.

Predicted strain coverage of a new protein-based meningococcal vaccine in the Czech Republic.

BACKGROUND: Recent data indicate that Neisseria meningitidis B strains cause about 70% of invasive meningococcal disease (IMD) cases in Europe and the availability of a vaccine effective against N. meningitidis B is desirable. A new protein-based MenB vaccine was licensed for use in Europe in January 2013. Meningococcal antigen typing system (MATS) was developed to predict strain coverage of this vaccine. Reports have recently been published for a European consortium, including aggregated data for the Czech Republic. The aim of this paper is to provide a detailed breakdown of MATS results for the Czech N. meningitidis B isolates. MATERIALS AND METHODS: One hundred and eight N. meningitidis B isolates from IMD collected in the Czech Republic during 2007-2010 were selected. MATS analysis was done according to the method previously published. RESULTS: Based on MATS analysis, the overall estimate of strain coverage of the new MenB vaccine for a panel of 108 Czech N. meningitidis B strains is 74% (95% CI: 59-87%). Thirty-nine strains (36%) are predicted to be covered by a single antigen and 41 strains (38%) by more than one antigen. For 28 strains (26%), no antigen coverage was found. CONCLUSIONS: MATS analysis showed that the new protein-based MenB vaccine could protect against a substantial proportion of IMD caused by N. meningitidis B in the Czech Republic. Continued detailed surveillance of IMD will be essential if the MenB vaccine is introduced to the country.

Establishing semi-automated infection surveillance in obstetrics and gynaecology.

BACKGROUND: Surveillance is an acknowledged method to decrease nosocomial infections, such as surgical site infections (SSIs). Electronic healthcare records create the opportunity for automated surveillance. While approaches for different types of surgeries and indicators already exist, there are very few for obstetrics and gynaecology. AIM: To analyse the sensitivity and workload reduction of semi-automated surveillance in obstetrics and gynaecology. METHODS: In this retrospective, single-centre study at a 1438-bed tertiary care hospital in Germany, semi-automated SSI surveillance using the indicators 'antibiotic prescription', 'microbiological data' and 'administrative data' (diagnosis codes, readmission, post-hospitalization care) was compared with manual analysis and categorization of all patient files. Breast surgeries (BSs) conducted in 2018 and caesarean sections (CSs) that met the inclusion criteria between May 2013 and December 2019 were included. Indicators were analysed for sensitivity, number of analysed procedures needed to identify one case, and potential workload reduction in detecting SSIs in comparison with the control group. FINDINGS: The reference standard showed nine SSIs in 416 BSs (2.2%). Sensitivities for the indicators 'antibiotic prescription', 'diagnosis code', 'microbiological sample taken', and the combination 'diagnosis code or microbiological sample' were 100%, 88.9%, 66.7% and 100%, respectively. The reference standard showed 54 SSIs in 3438 CSs (1.6%). Sensitivities for the indicators 'collection of microbiological samples', 'diagnosis codes', 'readmission/post-hospitalization care', and the combination of all indicators were 38.9%, 27.8%, 85.2% and 94.4%, respectively. CONCLUSIONS: Semi-automated surveillance systems may reduce workload by maintaining high sensitivity depending on the type of surgery, local circumstances and thorough digitalization.

Selective replication and vertical transmission of Ebola virus in experimentally infected Angolan free-tailed bats.

The natural reservoir of Ebola virus (EBOV), agent of a zoonosis burdening several African countries, remains unidentified, albeit evidence points towards bats. In contrast, the ecology of the related Marburg virus is much better understood; with experimental infections of bats being instrumental for understanding reservoir-pathogen interactions. Experiments have focused on elucidating reservoir competence, infection kinetics and specifically horizontal transmission, although, vertical transmission plays a key role in many viral enzootic cycles. Herein, we investigate the permissiveness of Angolan free-tailed bats (AFBs), known to harbour Bombali virus, to other filoviruses: Ebola, Marburg, Taï Forest and Reston viruses. We demonstrate that only the bats inoculated with EBOV show high and disseminated viral replication and infectious virus shedding, without clinical disease, while the other filoviruses fail to establish productive infections. Notably, we evidence placental-specific tissue tropism and a unique ability of EBOV to traverse the placenta, infect and persist in foetal tissues of AFBs, which results in distinct genetic signatures of adaptive evolution. These findings not only demonstrate plausible routes of horizontal and vertical transmission in these bats, which are expectant of reservoir hosts, but may also reveal an ancillary transmission mechanism, potentially required for the maintenance of EBOV in small reservoir populations.

A cluster of invasive meningococcal disease in young men who have sex with men in Berlin, October 2012 to May 2013.

Between October 2012 and May 2013, five cases of invasive meningococcal disease in young men who have sex with men (MSM) living in Berlin were notified to local health authorities in Germany. Three of the five cases died. All were caused by serogroup C variants with the finetype P1.5-1,10-8:F3-6. Awareness was increased through the use of community networks; an extension of the existing vaccination recommendation to all MSM is currently being considered.

Effects of a 17q21 chromosome gene variant, tobacco smoke and furred pets on infant wheeze.

The first common genetic factor identified for pediatric asthma by genome-wide association is the chromosome 17q21 locus, harbouring the ORMDL3 gene. ORMDL3 is involved in facilitation of endoplasmic reticulum-mediated inflammatory responses, believed to underlie its asthma association. We investigated associations between the rs7216389 polymorphism in the 17q21 locus affecting ORMDL3 expression and the risk for recurrent wheeze and interactions with exposure to tobacco smoke and furred pets during pregnancy and infancy using a birth cohort of 101,042 infants. Rs7216389 was significantly associated with recurrent wheeze risk among 18-month-old infants. There was a 1.35-fold higher risk of recurrent wheeze among homozygous variant allele carriers compared with homozygous wild-type allele carriers. There was significant interaction between rs7216389 and domestic furred pets, with a positive association between pets and wheeze among homozygous wild-type carriers and a negative association among homozygous variant allele carriers. There was no interaction between rs7216389 and tobacco smoke exposure.

Kidney-specific cadherin correlates with the ontogenetic origin of renal cell carcinoma subtypes: an indicator of a malignant potential?

INTRODUCTION AND OBJECTIVES: To evaluate retrospectively kidney-specific cadherin (Ksp-cad) expression in renal cell carcinoma (RCC) subtypes and oncocytoma in correlation with its ontogenetic origin of distal and proximal tubules and to correlate Ksp-cad expression with tumour characteristics. MATERIALS AND METHODS: Membranous and cytoplasmic expression of Ksp-cad was determined in 40 clear cell (ccRCC), 25 papillary (pRCC), 19 chromophobe carcinomas (chRCC), 27 oncocytomas (oncocytomas) (n = 111) and 32 benign kidney parenchyma specimens separated in distal tubules (DT) and proximal tubules (PT) by immunohistochemistry using tissue microarray technique. Staining intensity was quantified as a score ranging from 0 to 12. Comparison of data and correlation with tumour characteristics were done by Wilcoxon/Kruskal-Wallis tests (post hoc Tukey-Kramer analysis). RESULTS: In benign renal tissue, membranous and cytoplasmic expression of Ksp-cad in the DT was significantly higher than that in the PT (12.0 ± 0 vs. 5.2 ± 0.3 and 6.3 ± 0.5 vs. 0.0 ± 0.0, respectively; (P < 0.05)). Membranous KSP-cad expression was significantly higher in chRCC (5.2 ± 0.8) and oncocytomas (3.7 ± 0.4) than that in ccRCC (0.8 ± 0.2) and pRCC (1.4 ± 0.4; P < 0.05), while expression between oncocytomas and chRCC did not differ significantly. In RCC, Ksp-cad expression was significantly associated with higher T stage and the occurrence of synchronous metastasis (P < 0.05). Higher N stages and grading tended to correlate with a lower Ksp-cad expression. CONCLUSIONS: In this cohort, the origin of tumour subtypes-chRCC and oncocytomas develop from DT and ccRCC and pRCC from PT cells-is mirrored by the respective Ksp-cad expression. This raises the question whether DT-derived tumours have a less malignant potential than PT-derived tumours.

[Infections with pneumococci, menigococci, H. influenzae and diphtheria in Germany: the RKI Reference Network for Invasive Bacterial Infections (IBI) at the 5th Würzburg Workshop on Epidemiology, Prevention and Therapy for Invasive Meningococcal Diseases 2010 (meeting report)]. / Infektionen mit Pneumokokken, Meningokokken, H. influenzae und Diphtherie in Deutschland: das RKI Referenznetzwerk für Invasive Bakterielle Infektionen (IBI) beim 5. Würzburger Workshop zur Epidemiologie, Prävention und Therapie von invasiven Meningokokkenerkrankung 2010 (Tagungsbericht).

The surveillance and prevention of invasive bacterial infections requires flexible strategic coordination of all involved health-care professionals. For this purpose, the German National Reference Centres for Meningococci, Streptococci and the Consultant Laboratories for Haemophilus influenzae and diphtheria have formed the Reference Network for Invasive bacterial infections (IBI). The 5th Würzburg Workshop on Meningococcal Diseases 2010 provided the network with a forum for the interdisciplinary exchange between scientists, public health professionals, medical microbiologists and clinicians. The topics covered the analysis of surveillance data for meningococcal disease in the last decade, as well as methods to control for antibody response following vaccination, including a serum bactericidal antibody (SBA) assay, and the development of new vaccines that also include the most common serogroup B. The presentation on diphtheria showed that this rare disease in Germany has become a diagnostic challenge, and that apart from the classical pathogen also toxigenic C. ulcerans strains must be considered. Due to the successful vaccination against Hib, H. influenzae disease has changed from a classical childhood disease to an infection of elderly people mainly caused by unencapsulated strains. Following the introduction of vaccines, changes in the serotype distribution and antibiotic resistance profiles have become apparent for S. pneumoniae infections. The epidemiological data were complemented by clinical aspects concerning the vaccination of immunocompromised children.

[MusiQol: international questionnaire investigating quality of life in multiple sclerosis: validation results for the German subpopulation in an international comparison]. / MusiQol: Internationaler Fragebogen zur Erfassung der Lebensqualität bei Multipler Sklerose : Validierungsergebnisse der deutschen Subpopulation im internationalen Vergleich.

BACKGROUND: The existing health-related quality of life questionnaires on multiple sclerosis (MS) only partially reflect the patient's point of view on the reduction of activities of daily living. Their development and validation was not performed in different languages. That is what prompted the development of the Multiple Sclerosis International Quality of Life (MusiQoL) Questionnaire as an international multidimensional measurement instrument. This paper presents this new development and the results of the German subgroup versus the total international sample. PATIENTS AND METHODS: A total of 1,992 MS patients from 15 countries, including 209 German patients, took part in the study between January 2004 and February 2005. The patients took the MusiQoL survey at baseline and at 21±7 days as well as completing a symptom-related checklist and the SF-36 short form survey. Demographics, history and MS classification data were also generated. Reproducibility, sensitivity, convergent and discriminant validity were analysed. RESULTS: Convergent and discriminant validity and reproducibility were satisfactory for all dimensions of the MusiQoL. The dimensional scores correlated moderately but significantly with the SF-36 scores, but showed a discriminant validity in terms of gender, socioeconomic status and health status that was more pronounced in the overall population than in the German subpopulation. The highest correlations were observed between the MusiQoL dimension of activities of daily living and the Expanded Disability Status Scale (EDSS). CONCLUSION: The results of this study confirm the validity and reliability of MusiQoL as an instrument for measuring the quality of life of German and international MS patients.

MTHFR polymorphisms and 5-FU-based adjuvant chemotherapy in colorectal cancer.

BACKGROUND: Methylenetetrahydrofolate reductase is a pivotal enzyme in folate metabolism and 5-fluorouracil (5-FU) cytotoxicity. Two common single-nucleotide polymorphisms (SNPs), MTHFR 677C>T (rs1801133) and 1298A>C (rs1801131), reduce enzyme activity. Initially, these SNPs were claimed to predict clinical efficacy, but further studies have yielded contradictory results. We tested whether these two polymorphisms are determinants of clinical outcome in a large patient group with a long follow-up time. PATIENTS AND METHODS: We included 331 patients who had been treated with adjuvant 5-FU/leucovorin chemotherapy after intended curative resection between 1997 and 2003. Clinical data, including relapse rates, overall survival, and tumor stage, were collected. DNA was extracted from formalin-fixed tumor tissue and analyzed for the MTHFR 677C>T and 1298A>C SNPs with real-time PCR. RESULTS: The MTHFR 677C>T and 1298A>C polymorphisms were not associated with survival or relapse-free survival (P > 0.2). The 677 CC genotype was associated to toxicity (odds ratio = 1.83, P = 0.01). CONCLUSIONS: The MTHFR 677C>T and 1298A>C polymorphisms probably do not predict efficacy of adjuvant 5-FU treatment in colorectal cancer after complete resection; however, the 677C>T polymorphism may be associated with lower toxicity in 5-FU treatment. Implementation of SNP analysis for these polymorphisms for individualized treatment is premature.

Risk-benefit analysis of preoperative breast MRI in patients with primary breast cancer.

AIM: To analyse and compare the risks and benefits of preoperative breast MRI (BMRI) in patients with primary breast cancer (PBC), and to determine the influence of mammographic breast density (BD) and histological tumour type (TT). MATERIALS AND METHODS: One hundred and nineteen patients who underwent preoperative bilateral breast MRI for staging of PBC during a 1-year period from July 2005 to August 2006 were prospectively evaluated. Changes in clinical management due to BMRI findings were recorded. MRI-detected lesions were correlated with histology. Additional MRI-detected malignant lesions and spared additional biopsies because of negative MRI in case of unclear ultrasound findings were determined as beneficial for the patient. Biopsies of benign MRI detected lesions were defined as disadvantageous. The influence of BD (ACR 1-4) and TT on the change in clinical management and patient benefit was evaluated. RESULTS: The findings of the BMRI examinations changed the clinical management in 48 patients (40.3%). Seventeen women underwent mastectomy instead of breast conservation, eight patients underwent extended excision, 21 additional lesions were clarified by MRI intervention, and two ultrasound-detected lesions were not biopsied because of negative MRI. Histologically malignant additional or extended biopsies (n=34) and two cases of spared biopsies resulted in 36 (30.3%) women who benefited from preoperative BMRI. Twelve patients (10.1%) had additional biopsies of MRI-detected benign lesions, and therefore, had an unfavourable outcome due to BMRI. The change in clinical management and patient benefit were independent of BD and TT (p>0.05). CONCLUSION: Preoperative BMRI was beneficial for 30.3% of 119 patients with PBC. The percentage of additional biopsies of benign lesions (10.1%) seems acceptable.

Toxicity of pristine and paint-embedded TiO2 nanomaterials.

Little is known on the toxicity of nanomaterials in the user phase. Inclusion of nanomaterials in paints is a common nanotechnology application. This study focuses on the toxicity of dusts from sanding of paints containing nanomaterials. We compared the toxicity of titanium dioxide nanomaterials (TiO2NMs) and dusts generated by sanding boards coated with paints with different amounts of two different types of uncoated TiO2NMs (diameters:10.5 nm and 38 nm). Mice were intratracheally instilled with a single dose of 18, 54 and 162 µg of TiO2NMs or 54, 162 and 486 µg of sanding dusts. At 1, 3 and 28 days post-instillation, we evaluated pulmonary inflammation, liver histology and DNA damage in lung and liver. Pulmonary exposure to both pristine TiO2NMs and sanding dusts with different types of TiO2NMs resulted in dose-dependently increased influx of neutrophils into the lung lumen. There was no difference between the sanding dusts from the two paints. For all exposures but not in vehicle controls, mild histological lesions were observed in the liver. Pulmonary exposure to pristine TiO2NMs and paint dusts with TiO2NMs caused similar type of histological lesions in the liver.