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.

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.

High carriage rate of extended-spectrum beta-lactamase-producing Enterobacteriaceae among patients admitted for surgery in Tanzanian hospitals with a low rate of endogenous surgical site infections.

INTRODUCTION: Despite the high reported rates of surgical site infections (SSIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (EPE) in low-income countries, including Tanzania, the role of EPE carriage in subsequent occurrence of SSIs is not known. This study investigated the rates of EPE carriage among surgical patients at the time of admission and discharge, and linked EPE genotype with SSIs. METHODS: EPE were confirmed among isolates from rectal and wound/pus swabs using VITEK-2. Polymerase chain reaction and sequencing were performed to detect beta-lactamase genes. Multi-locus sequence typing was used to determine the genotypes of EPE isolates. RESULTS: Among 930 patients enrolled, EPE carriage was significantly higher on discharge than admission (36.4% vs 23.7%, P<0.001). Of 272 patients who tested negative on admission, 78 (28.7%) acquired EPE during hospitalization. History of hospital stay within the previous three months was an independent predictor of EPE acquisition [hazard ratio 2, 95% confidence interval (CI) 1.04-3.98, P=0.038]. Of the 536 patients who were successfully followed-up after surgery, 78 (14.6%, 95% CI 11.6-17.5) developed SSIs. Of 57 SSIs investigated, 33 (58%) were caused by enteric Gram-negative bacteria, of which 63.6% (21/33) were EPE. Escherichia coli sequence type (ST)131 pandemic clone and Klebsiella pneumoniae ST391 predominated among wound isolates. The blaCTX-M-15 gene was detected in 37 (97.3%) of 38 ESBL isolates. Male sex was an independent predictor of SSI (odds ratio 2.92, 95% CI 1.73-4.91, P<0.001). CONCLUSION: These findings warrant implementation of strict infection control measures, antimicrobial stewardship and exploration of the transmission dynamics of EPE in surgical wards.

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).

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.

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.

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.

Systematic review: genetic biomarkers associated with anti-TNF treatment response in inflammatory bowel diseases.

BACKGROUND: Personalised medicine, including biomarkers for treatment selection, may provide new algorithms for more effective treatment of patients. Genetic variation may impact drug response and genetic markers could help selecting the best treatment strategy for the individual patient. AIM: To identify polymorphisms and candidate genes from the literature that are associated with anti-tumour necrosis factor (TNF) treatment response in patients with inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis. METHODS: We performed a PubMed literature search and retrieved studies reporting original data on association between polymorphisms and anti-TNF treatment response and conducted a meta-analysis. RESULTS: A functional polymorphism in FCGR3A was significantly associated with anti-TNF treatment response among CD patients using biological response criterion (decrease in C-reactive protein, levels). Meta-analyses showed that polymorphisms in TLR2 (rs3804099, OR (95% CI) = 2.17 (1.35-3.47)], rs11938228 [OR = 0.64 (0.43-0.96)], TLR4 (rs5030728) [OR = 3.18 (1.63-6.21)], TLR9 (rs352139) [OR = 0.43 (0.21-0.88)], TNFRSF1A (rs4149570) [OR = 2.06 (1.02-4.17)], IFNG (rs2430561) [OR = 1.66 (1.05-2.63)], IL6 (rs10499563) [OR = 1.65 (1.04-2.63)] and IL1B (rs4848306) [OR = 1.88 (1.05-3.35)] were significantly associated with response among IBD patients using clinical response criteria. A positive predictive value of 0.96 was achieved by combining five genetic markers in an explorative analysis. CONCLUSIONS: There are no genetic markers currently available which are adequately predictive of anti-TNF response for use in the clinic. Genetic markers bear the advantage that they do not change over time. Therefore, hypothesis-free approaches, testing a large number of polymorphisms in large, well-characterised cohorts, are required in order to identify genetic profiles with larger effect sizes, which could be employed as biomarkers for treatment selection in clinical settings.

A Case of Choroidal Melanoma Metastatic to the Breast.

A 61-year-old woman developed blurred vision in her left eye in December 2006. A clinical diagnosis of choroidal melanoma was made. The patient underwent excision of the left lens, followed by vitrectomy and stereotactic radiotherapy. She remained systemically healthy until 50 months later when, during a CT scan done for staging purposes, a newly visible lump was noted in the lower quadrant of her left breast. Core needle biopsy of the lesion in the left breast was performed, and histologic examination revealed metastasis from the choroidal melanoma. The patient underwent breast-conserving surgery of the left breast. Definitive histological examination showed clear tumor margins in the resected specimen and one sentinel lymph node without evidence of metastatic cells. Twenty-nine months after surgery, a similar nodule was detected in the upper quadrant of the left breast. Core biopsy again showed metastatic melanoma, and similar breast-conserving surgery was performed. Systemic examination, including magnetic resonance imaging of the head and computed tomography of the pelvis, abdomen, and chest, was done regularly and revealed no significant findings. Solitary breast metastases from choroidal melanoma are extremely rare. Nevertheless, clinicians should be aware of this rare form of metastasis when treating patients with suspicious breast lesions and a history of choroidal melanoma. If solitary metastasis is confirmed, then breast-conserving surgery may be recommended.

In vitro screening of inhibition of PPAR-γ activity as a first step in identification of potential breast carcinogens.

Alcohol consumption and increased estrogen levels are major risk factors for breast cancer, and peroxisome proliferator-activated receptor γ (PPAR-γ) plays an important role in alcohol-induced breast cancer. PPAR-γ activity is inhibited by ethanol, leading to increased aromatase activity and estrogen biosynthesis ultimately leading to breast cancer. If other organic solvents inhibit PPAR-γ activity, they should also lead to increased oestrogen biosynthesis and thus be potential breast carcinogens. Ten commonly used hydrophilic organic solvents were first tested in a cell-based screening assay for inhibitory effects on PPAR-γ transactivation. The chemicals shown to inhibit PPAR-γ were tested with vectors encoding PPAR-γ with deleted AB domains and only the ligand-binding domain to rule out unspecific toxicity. Next, the effects on biosynthesis of estradiol, testosterone and oestrone sulphate were measured in the H295R steroidogenesis assay after incubation with the chemicals. Ethylene glycol, ethyl acetate, and dimethyl sulphoxide inhibited PPAR-γ transactivation in a dose-dependent manner. The inhibitory effect on PPAR-γ was specific for PPAR-γ since the AB domain of PPAR-γ was required for the inhibitory effect. In the second step, ethylene glycol significantly increased production of oestradiol by 19% (p < 0.05) and ethyl acetate inhibited production of testosterone (p < 0.05). We here show that screening of 10 commonly used organic solvents for the ability to inhibit PPAR-γ transactivation followed by a well-established steroidogenesis assay for production of sex hormones in exposed H295 R cells may provide a screening tool for potential breast carcinogens. This initial screening thus identified ethylene glycol and possibly ethyl acetate as potential breast carcinogens.

Systematic review: interactions between aspirin, and other nonsteroidal anti-inflammatory drugs, and polymorphisms in relation to colorectal cancer.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin (acetylsalicylic acid, ASA). Long-term use of NSAIDs has been associated with lowered risk of colorectal cancer (CRC), but the use is hampered by adverse effects. Also, the anti-carcinogenic effects of NSAIDs are incompletely understood. Understanding biological effects of NSAIDs may help developing new preventive medical strategies. AIM: To identify gene-environment interactions between genetic variation and NSAID use in relation to risk of CRC. METHODS: We performed a PubMed literature search and all studies reporting original data on interactions between NSAIDs and polymorphisms in relation to CRC were evaluated. RESULTS: We found indications that aspirin interacted with rs6983267 close to MYC (encoding a transcription factor involved in cell cycle progression, apoptosis and cellular transformation) and NSAIDs interacted with rs3024505 and rs1800872 in or close to IL10 (encoding IL-10) in preventing CRC. Homozygous carriers of the variant allele of rs6983267 (ca. 25% of the population) halved their risk for CRC by aspirin use compared to homozygous wildtype carriers who did not benefit from aspirin intake. No interaction between use of NSAIDs and PTGS-2 (encoding COX-2) in relation to CRC risk was detected. Other findings of interactions between genes in inflammatory and oncogenic pathways and NSAIDs were considered suggestive. CONCLUSIONS: Knowledge of underlying biological effects of NSAIDs in relation to CRC is scarce and the basis for stratifying the patients for preventive treatment is not yet available. Further studies assessing interactions between long-term NSAID exposure and genetic variation in relation to CRC are warranted in large well-characterised prospective cohorts.

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.

Systematic review: diet-gene interactions and the risk of colorectal cancer.

BACKGROUND: Diet contributes significantly to colorectal cancer (CRC) aetiology and may be potentially modifiable. AIM: To review diet-gene interactions, aiming to further the understanding of the underlying biological pathways in CRC development. METHODS: The PubMed and Medline were systematically searched for prospective studies in relation to diet, colorectal cancer and genetics. RESULTS: In a meta-analysis, no interaction between NAT1 phenotypes and meat intake in relation to risk of CRC was found (P-value for interaction 0.95). We found a trend towards interaction between NAT2 phenotypes and meat intake in relation to risk of CRC. High meat intake was not associated with risk of CRC among carriers of the slow NAT2 phenotype, whereas NAT2 fast acetylators with high meat intake were at increased risk of CRC (OR = 1.25; 95% confidence interval (CI): 0.92-2.01) compared with slow acetylators with low meat intake (reference), P-value for interaction = 0.07. Low meat intake in the studied populations may influence the result. Interactions between meat, cruciferous vegetables, fibres, calcium, vitamins, and alcohol and ABCB1, NFKB1, GSTM1, GSTT1, CCND1, VDR, MGTM, IL10 and PPARG are suggested. CONCLUSIONS: A number of interactions between genetic variation and diet are suggested, but the findings need replication in independent, prospective, and well-characterised cohorts before conclusions regarding the underlying biological mechanisms can be reached. When the above criteria are met, studies on diet-gene interactions may contribute valuable insight into the biological mechanisms underlying the role of various dietary items in colorectal carcinogenesis.

Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphisms, alcohol intake and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study.

BACKGROUND/OBJECTIVES: Heavy alcohol drinking is a risk factor of colorectal cancer (CRC), but little is known on the effect of polymorphisms in the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) on the alcohol-related risk of CRC in Caucasian populations. SUBJECTS/METHODS: A nested case-control study (1269 cases matched to 2107 controls by sex, age, study centre and date of blood collection) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the impact of rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms on CRC risk. Using the wild-type variant of each polymorphism as reference category, CRC risk estimates were calculated using conditional logistic regression, with adjustment for matching factors. RESULTS: Individuals carrying one copy of the rs1229984(A) (ADH1B) allele (fast metabolizers) showed an average daily alcohol intake of 4.3 g per day lower than subjects with two copies of the rs1229984(G) allele (slow metabolizers) (P(diff)<0.01). None of the polymorphisms was associated with risk of CRC or cancers of the colon or rectum. Heavy alcohol intake was more strongly associated with CRC risk among carriers of the rs1573496(C) allele, with odds ratio equal to 2.13 (95% confidence interval: 1.26-3.59) compared with wild-type subjects with low alcohol consumption (P(interaction)=0.07). CONCLUSIONS: The rs1229984(A) (ADH1B) allele was associated with a reduction in alcohol consumption. The rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms were not associated with CRC risk overall in Western-European populations. However, the relationship between alcohol and CRC risk might be modulated by the rs1573496 (ADH7) polymorphism.

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.

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.

Comprehensive analysis of hormone and genetic variation in 36 genes related to steroid hormone metabolism in pre- and postmenopausal women from the breast and prostate cancer cohort consortium (BPC3).

CONTEXT: Sex steroids play a central role in breast cancer development. OBJECTIVE: This study aimed to relate polymorphic variants in 36 candidate genes in the sex steroid pathway to serum concentrations of sex steroid hormones and SHBG. DESIGN: Data on 700 genetic polymorphisms were combined with existing hormone assays and data on breast cancer incidence, within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nurses' Health Study (NHS) cohorts; significant findings were reanalyzed in the Multiethnic Cohort (MEC). SETTING AND PARTICIPANTS: We analyzed data from a pooled sample of 3852 pre- and postmenopausal Caucasian women from EPIC and NHS and 454 postmenopausal women from MEC. MAIN OUTCOME MEASURES: Outcome measures were SHBG, testosterone, dehydroepiandrosterone (DHEAS), androstenedione, estrone (E1), and estradiol (E2) as well as breast cancer risk. RESULTS: Globally significant associations were found among pre- and postmenopausal women combined between levels of SHBG and the SHBG gene and between DHEAS and the FSHR and AKR1C3 genes. Among postmenopausal women, serum E1 and E2 were significantly associated with the genes CYP19 and FSHR, and E1 was associated with ESR1. None of the variants related to serum hormone levels showed any significant association with breast cancer risk. CONCLUSIONS: We confirmed associations between serum levels of SHBG and the SHBG gene and of E1 and E2 and the CYP19 and ESR1 genes. Novel associations were observed between FSHR and DHEAS, E1, and E2 and between AKR1C3 and DHEAS.

Molecular and clinicopathological findings in a tonsillar synovial sarcoma. A case study and review of the literature.

Synovial sarcoma (SS), 3-5% of which occurs in the head and neck region, has generally been regarded as high grade sarcoma. Recent analysis of clinical, morphological, and molecular characteristics of SS, however, identified low and high risk group of patients, resulting in important implications for the treatment of patients diagnosed with SS. We describe the case of a 31-year-old male who presented with biphasic SS with poorly differentiated areas (clinical stage IIA) in a palatine tonsil, an extremely rare site of SS. Molecular analyses revealed typical t(X;18) translocation of the SYT gene and a SYT/SSX1 fusion type. The tumor was surgically resected with free margins. Adjuvant radiotherapy or chemotherapy was not considered indicated. To date, the patient has remained free of tumor for 4 years after surgery. Literature review reveals that primary tonsillar HNSS has previously been documented only in three patients. In all of these patients the tumor was histologically biphasic; however only one published case and the case presented here showed areas of poor differentiation. We discuss the relevance of the presented findings with regard to prognostic and therapeutic considerations in SS in the head and neck region.

[MR imaging of the breast before and after neoadjuvant treatment - enhancement characteristics and T 2 signal intensity of breast cancers and breast parenchyma]. / MR-Mammografie vor und nach neoadjuvanter Systemtherapie - Enhancementcharakteristika und T 2-Signalinintensität von Mammakarzinomen und Drüsenparenchym.

PURPOSE: Analysis of enhancement characteristics and T 2 signal intensity (SI) of breast cancers and normal breast parenchyma on MR imaging (MRI) before and after neoadjuvant treatment (NT) to improve the assessment of therapy response. MATERIALS AND METHODS: Retrospective data analysis of 43 consecutive patients (mean age 49.9 years) with invasive breast cancers (T2 /T3) who received NT. Evaluation of breast MRI before and after NT with assessment of therapy response according to RECIST criteria as well as calculation of the maximum initial enhancement (Enh (max)), delayed enhancement (Enh (post)) and T 2 SI by ROI analyses of breast cancers and breast parenchyma. Comparison of therapy response and enhancement characteristics. RESULTS: Therapy response on MRI: 16.3 % (n = 7) complete remission (CR (MRT)), 53.5 % (n = 23) partial remission (PR (MRT)), 27.9 % (n = 12) stable disease (SD (MRT)) und 2.3 % (n = 1) progressive disease (PD (MRT)). Breast cancers showed a significant decrease in Enh (max) and T 2 SI as well as a significant increase in Enh (post) after NT (p < 0.01). Not any SI parameter of normal breast parenchyma showed a significant change after NT (p > 0.05). All cases with CR (MRT) had wash out or plateau shape of the SI time curve before NT and showed continuous enhancement thereafter. CONCLUSION: Breast MRI shows significant changes in enhancement characteristics and T 2 SI of breast cancers after NT, whereas normal breast parenchyma remains unchanged. SI data could possibly help to improve the assessment of therapy response by MRI. Prospective trials with larger study cohorts and MRI monitoring during NT are necessary to validate these results.