Harmful and potentially harmful constituents (HPHCs) in two novel nicotine pouch products in comparison with regular smokeless tobacco products and pharmaceutical nicotine replacement therapy products (NRTs).

BACKGROUND: Tobacco-free nicotine pouches is a novel category of oral nicotine-delivery products. Among current tobacco users such pouches may serve as a low-risk alternative to cigarettes or conventional, tobacco-based oral products e.g., snus and moist snuff. In the United States (U.S.), the market leading nicotine-pouch brand is ZYN®. However, no data on the chemical characteristics of ZYN have been published. METHODS: We screened for 43 compounds potentially present in tobacco products in seven oral nicotine-delivery products: ZYN (dry and moist), snus (General®), moist snuff (CRP2.1 and Grizzly Pouches Wintergreen), and two pharmaceutical, nicotine replacement therapy products (NRTs, Nicorette® lozenge and Nicotinell® gum). Thirty-six of the tested compounds are classified as harmful and potentially harmful constituents (HPHCs) by the Center for Tobacco Products at the U.S. Food and Drug Administration (FDA-CTP). Five additional compounds were included to cover the GOTHIATEK® product standard for Swedish snus and the last two compounds were chosen to include the four primary tobacco specific nitrosamines (TSNAs). RESULTS: The tested products contained nicotine at varying levels. The two ZYN products contained no nitrosamines or polycyclic aromatic hydrocarbons (PAHs) but low levels of ammonia, chromium, formaldehyde, and nickel. In the NRT products we quantified low levels of acetaldehyde, ammonia, cadmium, chromium, lead, nickel, uranium-235, and uranium-238. The largest number (27) and generally the highest levels of HPHCs were quantified in the moist snuff products. For example, they contained six out of seven tested PAHs, and seven out of ten nitrosamines (including NNN and NNK). A total of 19 compounds, none of which were PAHs, were quantified at low levels in the snus product. NNN and NNK levels were five to 12-fold lower in snus compared to the moist snuff products. CONCLUSIONS: No nitrosamines or PAHs were quantified in the ZYN and NRT products. Overall, the number of quantified HPHCs were similar between ZYN and NRT products and found at low levels.

Improving the Prediction of Prostate Cancer Overall Survival by Supplementing Readily Available Clinical Data with Gene Expression Levels of IGFBP3 and F3 in Formalin-Fixed Paraffin Embedded Core Needle Biopsy Material.

BACKGROUND: A previously reported expression signature of three genes (IGFBP3, F3 and VGLL3) was shown to have potential prognostic value in estimating overall and cancer-specific survivals at diagnosis of prostate cancer in a pilot cohort study using freshly frozen Fine Needle Aspiration (FNA) samples. METHODS: We carried out a new cohort study with 241 prostate cancer patients diagnosed from 2004-2007 with a follow-up exceeding 6 years in order to verify the prognostic value of gene expression signature in formalin fixed paraffin embedded (FFPE) prostate core needle biopsy tissue samples. The cohort consisted of four patient groups with different survival times and death causes. A four multiplex one-step RT-qPCR test kit, designed and optimized for measuring the expression signature in FFPE core needle biopsy samples, was used. In archive FFPE biopsy samples the expression differences of two genes (IGFBP3 and F3) were measured. The survival time predictions using the current clinical parameters only, such as age at diagnosis, Gleason score, PSA value and tumor stage, and clinical parameters supplemented with the expression levels of IGFBP3 and F3, were compared. RESULTS: When combined with currently used clinical parameters, the gene expression levels of IGFBP3 and F3 are improving the prediction of survival time as compared to using clinical parameters alone. CONCLUSION: The assessment of IGFBP3 and F3 gene expression levels in FFPE prostate cancer tissue would provide an improved survival prediction for prostate cancer patients at the time of diagnosis.

Presentation and progression of childhood-onset inflammatory bowel disease in Northern Stockholm County.

BACKGROUND: Some studies have suggested that childhood-onset inflammatory bowel disease (IBD) is characterized by extensive intestinal involvement and rapid progression to complications. Here, we report the presentation and progression of patients diagnosed with IBD during childhood in a population-based cohort from northern Stockholm County. METHODS: Medical records for all 280 patients diagnosed in the period 1990-2007 with childhood-onset IBD in northern Stockholm County were followed until 2011 (median follow-up time, 8.8 yr). Disease phenotypes were classified according to the Paris pediatric IBD classification. RESULTS: Among the 74 patients with ulcerative colitis, 72% presented with pancolitis. Among the 200 patients with Crohn's disease (CD), 75% presented with colitis. Complicated disease behavior was observed in 18% of patients with CD by end of follow-up. Extension of the disease territory was observed in 22% of patients with ulcerative colitis and 15% of patients with CD. The cumulative risk of intra-abdominal surgery after 10 years was 8% (95% confidence interval, 4%-20%) for ulcerative colitis and 22% (95% confidence interval, 15%-28%) for patients with CD. Nonmucosal healing at 1 year was associated with a complicated disease course in patients with CD (hazard ratio = 14.56; 95% confidence interval, 1.79-118.68; P = 0.01). CONCLUSIONS: Patients with childhood-onset IBD were characterized by extensive colitis that was relatively stable over time and associated with a relatively low risk of complications and abdominal surgery. Our findings confirm the more extensive disease location in pediatric IBD but did not identify the proposed dynamic and aggressive nature of the childhood-onset phenotype. The association of nonmucosal healing with a complicated disease course suggests that endoscopy should guide treatment intensity in childhood-onset CD.

Operator dependent choice of prostate cancer biopsy has limited impact on a gene signature analysis for the highly expressed genes IGFBP3 and F3 in prostate cancer epithelial cells.

BACKGROUND: Predicting the prognosis of prostate cancer disease through gene expression analysis is receiving increasing interest. In many cases, such analyses are based on formalin-fixed, paraffin embedded (FFPE) core needle biopsy material on which Gleason grading for diagnosis has been conducted. Since each patient typically has multiple biopsy samples, and since Gleason grading is an operator dependent procedure known to be difficult, the impact of the operator's choice of biopsy was evaluated. METHODS: Multiple biopsy samples from 43 patients were evaluated using a previously reported gene signature of IGFBP3, F3 and VGLL3 with potential prognostic value in estimating overall survival at diagnosis of prostate cancer. A four multiplex one-step qRT-PCR test kit, designed and optimized for measuring the signature in FFPE core needle biopsy samples was used. Concordance of gene expression levels between primary and secondary Gleason tumor patterns, as well as benign tissue specimens, was analyzed. RESULTS: The gene expression levels of IGFBP3 and F3 in prostate cancer epithelial cell-containing tissue representing the primary and secondary Gleason patterns were high and consistent, while the low expressed VGLL3 showed more variation in its expression levels. CONCLUSION: The assessment of IGFBP3 and F3 gene expression levels in prostate cancer tissue is independent of Gleason patterns, meaning that the impact of operator's choice of biopsy is low.

Increasing incidence of paediatric inflammatory bowel disease in northern Stockholm County, 2002-2007.

OBJECTIVES: A sharp increase in paediatric (younger than 16 years) inflammatory bowel disease (IBD) incidence was observed in northern Stockholm County, Sweden, in 1990-2001. The increasing incidence was primarily explained by a rising incidence of Crohn disease (CD). Here, we present an update on the trends in incidence of paediatric IBD, 2002-2007. METHOD: Medical records of all children diagnosed as having suspected IBD in northern Stockholm County, 2002-2007, were scrutinised using defined diagnostic criteria. Disease extension, localisation, and behaviour at diagnosis were classified within the framework of the Paris classification. RESULT: A total of 133 children were diagnosed as having IBD 2002-2007 corresponding to a sex- and age-standardised incidence (per 10 person-years) for paediatric IBD of 12.8 (95% CI 10.8-15.2). The standardised incidence was 9.2 (95% CI 7.5-11.2) for CD and 2.8 (95% CI 1.9-4.0) for ulcerative colitis (UC). A significant increasing incidence of UC (P < 0.05) was observed during the study period. No temporal trend was observed for the incidence of CD. CONCLUSIONS: The incidence rate of paediatric IBD in northern Stockholm was significantly higher in 2002-2007 than that observed in our earlier study covering 1990-2001. The former sharp increase in incidence of paediatric CD seems, however, to have levelled out, although at a higher rate than reported from most other regions in the world. Although CD was still predominant, the observed increase in incidence of UC during the study period is notable.

Nitric oxide pathway-related gene alterations in inflammatory bowel disease.

OBJECTIVE: To reveal specific gene activation in nitric oxide (NO)-related inflammation we studied differential gene expression in inflammatory bowel disease (IBD). METHODS: Total RNA was isolated from 20 biopsies of inflamed mucosa from Crohn's disease (CD) and ulcerative colitis (UC) patients each as well as from six controls, labeled with (32)P-dCTP and hybridized to a human NO gene array. Significant genes were analyzed for functional gene interactions and heatmaps generated by hierarchical clustering. A selection of differentially expressed genes was further evaluated with immunohistochemical staining. RESULTS: Significant gene expression differences were found for 19 genes in CD and 23 genes in UC compared to controls, both diseases with high expression of ICAM1 and IL-8. Correlation between microarray expression and corresponding protein expression was significant (r = 0.47, p = 0.002). Clustering analysis together with functional gene interaction analysis revealed clusters of coregulation and coexpression in CD and UC: transcripts involved in angiogenesis, inflammatory response mediated by the transcription factor hypoxia-inducible factor 1, and tissue fibrosis. Also, a fourth cluster with transcripts regulated by the transcription factor Sp1 was found in UC. CONCLUSIONS: Expression analysis in CD and UC revealed disease-specific regulation of NO-related genes, which might be involved in perpetuating inflammatory disease activity in IBD.

Significant communities in large sparse networks.

Researchers use community-detection algorithms to reveal large-scale organization in biological and social networks, but community detection is useful only if the communities are significant and not a result of noisy data. To assess the statistical significance of the network communities, or the robustness of the detected structure, one approach is to perturb the network structure by removing links and measure how much the communities change. However, perturbing sparse networks is challenging because they are inherently sensitive; they shatter easily if links are removed. Here we propose a simple method to perturb sparse networks and assess the significance of their communities. We generate resampled networks by adding extra links based on local information, then we aggregate the information from multiple resampled networks to find a coarse-grained description of significant clusters. In addition to testing our method on benchmark networks, we use our method on the sparse network of the European Court of Justice (ECJ) case law, to detect significant and insignificant areas of law. We use our significance analysis to draw a map of the ECJ case law network that reveals the relations between the areas of law.

Survival in patients with human papillomavirus positive tonsillar cancer in relation to treatment.

The incidence of tonsillar cancer and the proportion of human papillomavirus (HPV) positive tonsillar cancer cases have increased in the last decades. In parallel, treatment for tonsillar cancer has been intensified e.g., by accelerated radiotherapy, and chemotherapy, resulting in more side effects. Patients with HPV-positive tonsillar cancer have better prognosis than those with HPV-negative tumors, and the former group could hypothetically benefit from reduced, less-toxic treatment without compromising survival. Here, we therefore evaluated possible differences in overall and disease-specific survival after different oncological treatments in 153 patients with HPV DNA- and P16-positive tonsillar cancer who were diagnosed and treated with intent to cure between 2000 and 2007, in Stockholm, Sweden. Of these patients, 86 were treated with conventional radiotherapy, 40 were treated with accelerated radiotherapy and 27 were treated with chemoradiotherapy. There were no significant differences in overall or disease-free survival between the groups. However, there was a trend, implying a beneficial effect of the intensified treatment, with chemoradiotherapy being better than radiotherapy despite that more patients had stage IV disease in the former group; and accelerated radiotherapy being better than conventional radiotherapy. This needs to be followed further in larger more homogenous groups of patients. In conclusion, patients with HPV-positive tonsillar cancer treated with conventional- or accelerated radiotherapy or chemoradiotherapy disclosed similar survival rates. The trend for better survival and less metastasis after intensified treatment underlines the need for large prospective studies comparing less intense to more intense treatment (chemoradiotherapy).

Human papillomavirus and survival in patients with base of tongue cancer.

The incidence of base of tongue cancer is increasing in Sweden and the proportion of human papillomavirus (HPV) positive cancer has increased in Stockholm, Sweden. Between 2006 and 2007, 84% of base of tongue cancer cases in Stockholm were HPV-positive. The objective of this study was to assess the impact of HPV status on prognosis for base of tongue cancer patients. One-hundred and nine patients were diagnosed with base of tongue cancer between 1998 and 2007 in Stockholm County and 95 paraffin-embedded diagnostic tumor biopsies were obtained and tested for HPV by PCR. Eighty-seven patients had available biopsies, were treated with intention to cure and could be included in the survival analysis. Age, sex, TNM-stage, stage, treatment and survival were recorded from patient charts. Kaplan-Meier curves were used to present survival data. In multivariable analyses, a Cox proportional hazards model was used to adjust for covariates. In total 68 (78%) tumor biopsies from the 87 included patients were HPV DNA positive. Kaplan-Meier estimates showed that the overall survival for patients with HPV-positive cancer was significantly better (p = 0.0004), (log-rank test) than that of patients with HPV-negative cancer. Patients with HPV-positive tumors also had significantly better disease-free survival (p = 0.0008), (log-rank test) than those with HPV-negative tumors. These results further strengthen the option to consider HPV-status when planning prospective studies on treatment for base of tongue cancer.

The role of human papillomavirus in the increased incidence of base of tongue cancer.

Numerous reports have shown that the incidence for oropharyngeal cancer is increasing and that human papillomavirus (HPV) is a risk factor. However, few studies have investigated the specific subsites of the oropharynx. Following our previous research on tonsillar cancer, we assessed the increase in the incidence of base of tongue cancer and the prevalence of HPV in this disease. Between 1998 and 2007, 109 patients were diagnosed for base of tongue cancer in Stockholm county. Ninety-five paraffin-embedded diagnostic tumor biopsies from patients were obtained and tested for HPV, both by general HPV PCR and HPV-16/HPV-33 type-specific PCR. Expression of HPV-16 RNA was analyzed to confirm E6 and/or E7 expression. Incidence data were obtained from the Swedish Cancer Registry. An overall increase in the incidence of base of tongue cancer from 0.15/100,000 person-years during 1970-1974 to 0.47/100,000 person-years during 2005-2007 was found in Sweden. The prevalence of HPV in base of tongue cancer in Stockholm county increased from 58% during 1998-2001 to 84% during 2004-2007 (p < 0.05). In the HPV-positive tumors, HPV-16 dominated (86%) but interestingly, HPV33 was detected in as many as 10%. E6 and/or E7 RNA were found in 85% of the samples tested. The incidence of base of tongue cancer, as well as the proportion of HPV-positive tumors, has increased in Sweden during the study period, suggesting that HPV may contribute to this increase.

EGFR protein overexpression and gene copy number increases in oral tongue squamous cell carcinoma.

New promising therapeutic agents targeting epidermal growth factor receptor (EGFR) have been developed although clinical information concerning EGFR status in oral tongue squamous cell carcinoma (OTSCC) is limited. We investigated EGFR protein expression and gene copy numbers in 78 pretreatment OTSCC paraffin samples. EGFR protein expression was found in all 78 tumours, of which 72% showed an intense staining. Fifty-four percent of the tumours had high (> or =four gene copies) EGFR gene copy numbers. EGFR gene copy number was significantly associated with EGFR protein expression (P=0.002). Pretreatment EGFR staining intensity tended to be associated with non-pathological complete remission after preoperative radiotherapy for Stage II OTSCC. No correlation was found between EGFR status and survival. EGFR FISH results were significantly (P=0.003) higher in more advanced tumours (Stages II, III and IV) than in the tumours in Stage I. Non-smokers exhibited a significantly higher EGFR gene copy number and protein overexpression in Stages I and II OTSCC than smokers (P=0.001, P=0.009). In conclusion, EGFR was found to be overexpressed in all OTSCCs making this cancer type interesting for exploring new therapeutic agents targeting the EGFR receptor.

Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?

In the county of Stockholm, between 1970 and 2002, we have previously reported a 3-fold parallel increase in the incidence of tonsillar squamous cell carcinoma (SCC) and the proportion of human papillomavirus (HPV) positive tonsillar SCC. Here, we have followed the above parameters in all patients (n = 120) diagnosed with tonsillar SCC during 2003-2007 in the same area, and also in correlation to our previous data. Ninety-eight pretreatment biopsies were available and presence of HPV DNA and HPV-16 E6 and E7 RNA were tested by polymerase chain reaction (PCR) and RT-PCR. Incidence data were obtained from the Swedish Cancer Registry. Data reported from 1970 to 2002 were also obtained for comparison. HPV DNA was present in 83 of 98 (85%) of the tonsillar SCC biopsies from 2003 to 2007 and 77 of these were HPV-16 positive. HPV-16 E6 and E7 RNA were found in 98% of 52 analyzed HPV-16 positive cases. The proportion of HPV-positive cancers had significantly increased both from 1970 to 2007 (p < 0.0001) as well from 2000 to 2007 (p < 0.01), with 68% (95% confidence interval (CI), 53-81) 2000-2002; 77% (95% CI, 63-87) 2003-2005; and 93% (95% CI, 82-99) 2006-2007. The incidence rate of HPV-positive tumors almost doubled each decade between 1970 and 2007, in parallel with a decline of HPV-negative tumors. In conclusion, the incidence of HPV-positive cancers is still increasing in the County of Stockholm, suggesting an epidemic of a virus-induced carcinoma, with soon practically all tonsillar SCC being HPV positive, as in cervical cancer.

The importance of rectal cancer MRI protocols on interpretation accuracy.

BACKGROUND: Magnetic resonance imaging (MRI) is used for preoperative local staging in patients with rectal cancer. Our aim was to retrospectively study the effects of the imaging protocol on the staging accuracy. PATIENTS AND METHODS: MR-examinations of 37 patients with locally advanced disease were divided into two groups; compliant and noncompliant, based on the imaging protocol, without knowledge of the histopathological results. A compliant rectal cancer imaging protocol was defined as including T2-weighted imaging in the sagittal and axial planes with supplementary coronal in low rectal tumors, alongside a high-resolution plane perpendicular to the rectum at the level of the primary tumor. Protocols not complying with these criteria were defined as noncompliant. Histopathological results were used as gold standard. RESULTS: Compliant rectal imaging protocols showed significantly better correlation with histopathological results regarding assessment of anterior organ involvement (sensitivity and specificity rates in compliant group were 86% and 94%, respectively vs. 50% and 33% in the noncompliant group). Compliant imaging protocols also used statistically significantly smaller voxel sizes and fewer number of MR sequences than the noncompliant protocols CONCLUSION: Appropriate MR imaging protocols enable more accurate local staging of locally advanced rectal tumors with less number of sequences and without intravenous gadolinium contrast agents.

Evidence of the oncologic superiority of cylindrical abdominoperineal excision for low rectal cancer.

PURPOSE: Abdominoperineal excision (APE) of the rectum and anus for rectal cancer continues to have greater local recurrence and poorer survival than that seen following anterior resection. Changing to an extended prone perineal dissection results in a more cylindrical specimen and should improve outcomes. PATIENTS AND METHODS: One hundred twenty-eight specimens from patients who underwent APE that was performed for potentially curable primary rectal adenocarcinoma were dissected according to standard protocol in Leeds and Stockholm between 1997 and 2007 and were studied. Tissue morphometry was performed on the cross sectional photographs of 93 patient cases. RESULTS: The cylindrical technique removed more tissue in the distal rectum and in all slices that contained tumor compared with the standard operation (both P < .0001). Greater distance was observed from the muscularis propria or internal sphincter to the anterior, posterior, and lateral resection margins (all P < .0001). This was associated with lower circumferential resection margin (CRM) involvement (14.8% v 40.6%; P = .013) and intraoperative perforations (3.7% v 22.8%; P = .0255). An increase in the amount of tissue removed in the distal rectum (P < .0001) was demonstrated by a single surgeon who changed from the standard to the cylindrical technique during the study period; the change was associated with a reduction in CRM positivity (from 36.2% to 12.5%) and in perforations (from 12.8% to 0.0%). CONCLUSION: Cylindrical APE performed in the prone position for low rectal cancer removes more tissue around the tumor that leads to a reduction in CRM involvement and intraoperative perforations, which should reduce local disease recurrence. The cylindrical technique has the potential to improve patient outcomes substantially if appropriate surgical education programs are developed.

Fecal calprotectin: a quantitative marker of colonic inflammation in children with inflammatory bowel disease.

OBJECTIVES: The protein calprotectin (S100 A8/A9) is present in neutrophils, monocytes, and macrophages. Colorectal inflammation can be detected by increased excretion of fecal calprotectin (FC). The aim of this study was to evaluate FC as a quantitative marker of inflammatory activity in children with inflammatory bowel disease (IBD). PATIENTS AND METHODS: Thirty-nine children with IBD delivered a fecal spot sample and underwent colonoscopy. The samples were examined with an enzyme-linked immunosorbent assay for FC (Calprest, Eurospital, Trieste, Italy). The concentrations were correlated to macroscopic and microscopic assessments of extent and severity of inflammation in 8 colonic segments for each patient. RESULTS: FC correlated significantly to the macroscopic extent (Spearman rho = 0.61) and the severity (Spearman rho = 0.52) of colonic inflammation and to a macroscopic, combined extent and severity score (Spearman rho = 0.65). Significant correlations also were found to the microscopic extent (Spearman rho = 0.71) and severity (Spearman rho = 0.72) of colonic inflammation and to a microscopic, combined extent and severity score (Spearman rho = 0.75). The median FC was 392 mug/g (95% confidence interval [CI], 278-440) in children with clinical IBD symptoms (n = 23) and 32.9 mug/g (95% CI, 9.4-237) in asymptomatic IBD patients (n = 16). Of the asymptomatic children, 56% had a complete microscopic mucosal healing, and their median FC was 9.9 mug/g (95% CI, 5.9-41.9). CONCLUSIONS: FC can be used as a surrogate marker for estimation of colonic inflammation in pediatric IBD. Normalized FC concentration seems to indicate complete mucosal healing. FC is simple to obtain and analyze; this should facilitate objective assessment and monitoring of IBD activity.

Biotechnological approach to the synthesis of 9alpha-hydroxylated steroids.

The steroid 9alpha-hydroxylase gene has been cloned from Mycobacterium smegmatis into Escherichia coli BL21. Progesterone added to bioreactors was subjected to in vivo transformation into 9alpha-hydroxyprogesterone. In 7 days, 43.6 mg 9alpha-hydroxyprogesterone was formed from 53.8 mg/L progesterone. The enzyme also has shown evidence of processing 4-androstene-3,17-dione in vivo. An extensive analytical method development, including LLE, HPLC-DAD, MS, and NMR was performed to verify the product and to enable a quantitative analysis. Protocols for analytical and preparative separation have been developed, using binaphtol as internal standard. Both the growth pattern and the bioconversion rate were unaffected by the presence of binaphtol in the bioreactor. The enzyme was purified by immobilised metal affinity and ion exchange chromatography, resulting in low in vitro activity.

Brush cytology is superior to biopsies obtained by a new device in bile duct strictures.

BACKGROUND/AIMS: Brush cytology during ERCP has been reported to have a low sensitivity. A new device, Howell biliary system (Wilson-Cook), enables targeted biopsies for histopathologic assessment. The aim was to compare histopathology with brush cytology. METHODOLOGY: Brush cytology followed by biopsies obtained by the Howell device was taken consecutively from bile duct strictures. Coded slides were scored by 3 pathologists and 2 cytologists in a 3-graded scale; 2: benign; 3: suspicious of malignancy; 4: malignant. The clinical outcome including autopsy served as the gold standard for the definite diagnoses. RESULTS: Twenty-one malignant and 6 benign strictures were evaluated. The histopathology revealed 11 out of the 21 malignant as certain or suspected malignant (score > or = 3) (sensitivity: 0.52). The cytology scored 17 out of 21 > or = 3 (sensitivity: 0.80). The in pair kappa values for the 3 pathologists were: (0.37; 0.26; 0.41) vs. 0.56 for the 2 cytologists. Among the evaluable strictures the pathologists scorings were; (median: 3.0, SD: 0.72) for the malignant and (median: 2.3, SD: 0.98) for the benign (p = 0.27) and the cytology scorings were; (median: 3.5, SD: 0.73) for the malignant and (median: 2.7, SD: 0.65) for the benign (p = 0.09). CONCLUSIONS: Brush cytology has a higher accuracy than the targeted biopsies and should be used in combination with other methods to reach the correct diagnosis.

Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment.

BACKGROUND/AIMS: We investigated the impact of diabetes mellitus type 2, overweight, alcohol over-consumption, and chronic hepatitis B or C as risk factors, for liver fibrosis in psoriasis patients treated with methotrexate. METHODS: One hundred and sixty-nine liver biopsies from 71 patients who underwent liver biopsies as part of the monitoring of methotrexate treatment for psoriasis were reviewed. Fibrosis, steatosis and inflammation were staged according to the NAFLD activity score. RESULTS: Twenty-six patients had one or more of the risk factors and 25 (96%) of these (median cumulative dose methotrexate 1500 mg) developed liver fibrosis. Of those without risk factor, 26 (58%) (p=0.012) developed fibrosis (median cumulative dose methotrexate 2100 mg). Ten (38%) of the patients with risk factor(s) had severe fibrosis (stage 3-4) (mean cumulative dose methotrexate 1600 mg), while four (9%) (p=0.0012) of those without risk factors had severe fibrosis (median cumulative dose methotrexate 1900 mg). CONCLUSIONS: Patients with methotrexate treated psoriasis and risk factors for liver disease, especially diabetes type 2 or overweight, are at higher risk of developing severe liver fibrosis compared to those without such risk factors, even when lower cumulative methotrexate doses are given.

MRI after preoperative radiotherapy for rectal cancer; correlation with histopathology and the role of volumetry.

The objective is to assess if tumor size after radiotherapy in patients with rectal cancer can be assessed by a second magnetic resonance imaging (MRI), after radiotherapy prior to surgery and to correlate changes observed on MRI with findings at histopathology at surgery. Twenty-five patients with MRI before and after radiotherapy were included. Variables studied were changes in tumor size, T-staging and distance to the circumferential resection margin (CRM). RVs was measured as tumor volume at surgery (Vs) divided by tumor volume at the initial MRI (Vi) in percent. RVm was defined as the tumor volume at the second MRI (Vm) divided by Vi in percent. The ypT-stage was the same or more favorable than the initial MRI T-stage in 24 of 25 patients. The second MRI was not more accurately predictive than the initial MRI for ypT-staging or distance to CRM (p > 0.05). Vm correlated significantly to Vs, as did RVs to RVm, although the former was always smaller than the latter. Vm and RVm correlated well with ypT-stage (p < 0.001). Volumetry seems to correlate with ypT-stage after preoperative radiotherapy for resectable rectal cancer. The value of a second MRI after radiotherapy for assessment of distance to CRM and ypT-staging is, however, not apparent.

Significance of mesorectal volume in staging of rectal cancer with magnetic resonance imaging and the assessment of involvement of the mesorectal fascia.

The aim was to study the influence of mesorectal volume, as estimated by magnetic resonance imaging (MRI), that is to be removed during total mesorectal excision (TME), on the accuracy of the first preoperative MRI of rectal cancer compared to histopathology, and its correlation to locoregional prognostic factors. A total of 267 rectal cancer patients from a multinational study (MERCURY or MRI equivalence study) had their mesorectal volume retrospectively estimated by researchers without knowledge of the assessments made by the radiologist or the pathologist. The evaluations made by the pathologist and the radiologist were then compared, including T- and N-staging, assessment of extent of extramural tumor invasion (the largest portion of the tumor beyond the muscularis propria or EMI) and distance to mesorectal fascia; the discrepancies in the results were correlated to the mesorectal volume. T- or N-staging accuracy by MRI and the difference between the EMI as measured by the pathologist and the radiologist were not dependent on individual mesorectal volume. There was no correlation between assessment of involvement of mesorectal fascia or local neighboring organs by MRI and histopathology with mesorectal volume. Mesorectal volume does not affect locoregional prognostic factors or the accuracy of local staging of rectal cancer.