Ureteric injuries during hysterectomy-A Norwegian retrospective study of occurrence and claims for compensation over an 11-year period.

INTRODUCTION: Ureteric injury is a rare but serious, iatrogenic complication of hysterectomy. The risk depends on indication for surgery, predisposing risk factors, and peroperative conditions. Our aims were to evaluate and learn from compensation claims to The Norwegian System of Patient Injury Compensation (NPE) for ureteric injury occurring during hysterectomies to predict risk factors, time of identification, symptoms, and consequences, and to relate these cases to injuries registered in The Norwegian Patient Registry. MATERIAL AND METHODS: A retrospective study of ureteric injuries occurring during hysterectomies, reported to NPE and the Norwegian Patient Registry from 2009 through 2019. RESULTS: During the study period, 53 096 hysterectomies were registered in The Norwegian Patient Registry, of which ureteric injury was documented in 643 (1.2%). More ureteric injuries were registered in large hospital trusts than in small trusts (1.3% vs. 0.7%, p < 0.05). NPE received 69 claims due to ureteric injury occurring during hysterectomy, comprising 11% of all injuries in the study period. Compensation was approved for 15%. Women who claimed compensation were younger (48.1 ± 8.9 years vs. 55.1 ± 13.6 years, p < 0.01), more likely to have had a benign diagnosis (89.9% vs. 52.1%, p < 0.01), and more likely to have had the ureteric injury recognized after discharge (58.0% vs. 33.0%, p < 0.001) compared with non-complainants. Identification of the ureters during the hysterectomy was documented in 30% of the NPE patient files. Additional information for the NPE cases included the following. The most common symptoms of unidentified injury were pain (77%), fever (12%), urinary leakage (13%), and anuria (8%). Re-operation was necessary in 77% of the cases, and 10% of the women lost one kidney. Long-term consequences after repair, such as loss of a kidney or persistent pain, were seen in 17%. No women died because of the injury. CONCLUSIONS: The incidence of ureteric injury occurring during hysterectomy in Norway was 1.2%; 11% involved a claim for compensation, and 15% of these had their case approved. Most ureteric injuries were not recognized during the hysterectomy. Documentation of peroperative identification of the ureters during hysterectomy was often missing. Vigilance to pain as a postoperative symptom of peroperative unrecognized ureteric injury may result in earlier diagnosis and treatment.

Correlation between compensated patient claims and 30-day mortality.

OBJECTIVE: To test if compensation claims from patients (reported to the Norwegian System of Patient Injury Compensation) are correlated with the existing quality indicator of 30-day mortality (based on data from Norwegian Patient Registry). This correlation has not been previously evaluated. DESIGN: The association between patient claims and 30-day mortality at hospital trust level was assessed by the Pearson correlation coefficient. SETTING: The Norwegian System of Patient Injury Compensation is a governmental agency under the Ministry of Health and Care Services and deals with patient-reported complaints about incorrect treatment in the public and private healthcare services. Patient-reported claims may be an indicator of healthcare quality, as 30-day mortality. PARTICIPANTS: All 19 Norwegian hospital trusts. INTERVENTIONS: : None. MAIN OUTCOME MEASURE: Patient claims rates, 30-day mortality and Pearson correlation coefficient. RESULTS: Both number of deaths within 30 days and number of claims have declined over time. High correlation (0.77, P < 0.001) was found between number of deaths within 30 days and the total number of claims. In addition, an even stronger association was found with approved claims, with a correlation coefficient of 0.83 (P < 0.001). Moreover, adjusted 30-day mortality was significantly correlated with the patient-claim rate using number of bed-days as denominator, but not when using number of discharges. CONCLUSIONS: The results from the present study indicate an association between compensation claims from patients and 30-day mortality, suggesting that both parameters reflect the latent quality of care for the hospital trusts, but they may capture different aspects of care.

Compensation claims in pediatric orthopedics in Norway between 2012 and 2018: a nationwide study of 487 patients.

Background and purpose - In Norway all compensation claims based on healthcare services are handled by a government agency (NPE, Norsk Pasientskade Erstatning). We provide an epidemiological overview of claims within pediatric orthopedics in Norway, and identify the most common reasons for claims and compensations.Patients and methods - All compensation claims handled by NPE from 2012 to 2018 within pediatric orthopedics (age 0 to 17 years) were reviewed. Data were analyzed with regard to patient demographics, diagnoses, type of injury, type of treatment, reasons for granted compensation, and total payouts.Results - 487 compensation claims (259 girls, 228 boys) within orthopedic surgery in patients younger than 18 years at time of treatment were identified. Mean age was 12 years (0-17). 150 out of 487 claims (31%) resulted in compensation, including 79 compensations for inadequate treatment, 58 for inadequate diagnostics, 12 for infections, and 1 based on the exceptional rule. Total payouts were US$8.45 million. The most common primary diagnoses were: upper extremity injuries (26%), lower extremity injuries (24%), congenital malformations and deformities (12%), spine deformities (11%), disorders affecting peripheral joints (9%), chondropathies (6%), and others (12%).Interpretation - Most claims were submitted and granted for mismanagement of fractures in the upper and lower extremity, and mismanagement of congenital malformations and disorders of peripheral joints. Knowledge of the details of malpractice claims should be implemented in educational programs and assist pediatric orthopedic surgeons to develop guidelines in order to improve patient safety and quality of care.

Compensation claims after hip arthroplasty surgery in Norway 2008-2018.

Background and purpose - Orthopedic surgery is one of the specialties with most compensation claims, therefore we assessed the most common reasons for complaints following total hip arthroplasty (THA) reported to the Norwegian System of Patient Injury Compensation (NPE) and viewed these complaints in light of the data from the Norwegian Arthroplasty Register (NAR).Patients and methods - We collected data from NPE and NAR for the study period (2008-2018), including age, sex, and type of complaint, and reason for accepted claims from NPE, and the number of arthroplasty surgeries from NAR. The institutions were grouped by quartiles into quarters according to annual procedure volume, and the effect of hospital procedure volume on the risk for accepted claim was estimated.Results - 70,327 THAs were reported to NAR. NPE handled 1,350 claims, corresponding to 1.9% of all reported THAs. 595 (44%) claims were accepted, representing 0.8% of all THAs. Hospital-acquired infection was the most common reason for accepted claims (34%), followed by wrong implant position in 11% of patients. Low annual volume institutions (less than 93 THAs per year) had a statistically significant 1.6 times higher proportion of accepted claims compared with higher volume institutions.Interpretation - The 0.8% risk of accepted claims following THAs is 1.6 times higher for patients treated in low-volume institutions, which should consider increasing the volume of THAs or referring these patients to higher volume institutions.

Compensation claims after knee arthroplasty surgery in Norway 2008-2018.

Background and purpose - Orthopedic surgery is one of the specialties with most compensation claims. We assessed the claims following knee arthroplasty surgery reported to the Norwegian System of Patient Injury Compensation (NPE) in light of institutional procedure volume.Patients and methods - We collected data from NPE and the Norwegian Arthroplasty Register (NAR) for the study period (2008-2018). Age, sex, type of claim, and reason for compensation were collected from NPE, while the number of arthroplasty surgeries was collected from NAR. The treating hospitals were grouped by quartiles according to annual procedure volume. The effect of hospital volume on the likelihood of an accepted claim was estimated.Results - NAR received 64,241 reports of arthroplasty procedures, of which 572 (0.9%) patients filed a claim for treatment injury. 55% of the claims were accepted, representing 0.5% of all knee arthroplasties. The most common reason for accepted claim was a hospital-acquired infection, in 28% of the patients, followed by misplaced implant (26%) and aseptic loosening (13%). The hospitals with the lowest annual volume (57 or fewer arthroplasties per year, first quarter) had a statistically significantly larger fraction of granted claims per procedures compared with other institutions.Interpretation - The overall risk of ending up with compensation due to treatment error following knee arthroplasty was 0.5%. The risk of accepted claim was greater for patients operated in the lowest volume hospitals.

Loss of progesterone receptor is associated with distinct tyrosine kinase profiles in breast cancer.

PURPOSE: The aim of this study was to assess protein tyrosine kinase profiles in primary breast cancer samples in correlation with the distinct hormone and growth receptor profiles ER, PR, and HER2. EXPERIMENTAL DESIGN: Pamchip® microarrays were used to measure the phosphorylation of 144 tyrosine kinase substrates in 29 ER+ breast cancer samples and cell lines MCF7, BT474 and ZR75-1. mRNA expression data from the METABRIC cohort and publicly available PR chip-sequencing data were used for validation purposes, together with RT-PCR. RESULTS: In ER+ breast tumors and cell lines, we observed that the loss of PR expression correlated to higher kinase activity in samples and cell lines that were HER2-. A number of kinases, representing mostly proteins within the PI3K/AKT pathway, were identified as responsible for the differential phosphorylation between PR- and PR+ in ER+/HER2- tumors. We used the METABRIC cohort to analyze mRNA expression from 977 ER+/HER2- breast cancers. Twenty four kinase-encoding genes were identified as differentially expressed between PR+ and PR-, dividing ER+/HER2- samples in two distinct clusters with significant differences in survival (p < 0.05). Four kinase genes, LCK, FRK, FGFR4, and MST1R, were identified as potential direct targets of PR. CONCLUSIONS: Our results suggest that the PR status has a profound effect on tyrosine kinases, especially for FGFR4 and LCK genes, in ER+/HER2- breast cancer patients. The influence of these genes on the PI3K/AKT signaling pathway may potentially lead to novel drug targets for ER+/PR- breast cancer patients.

Claims for compensation from women with cervical cancer in Norway-A retrospective, descriptive study of a 12-year period.

INTRODUCTION: In Norway, all patient-reported claims for compensation are evaluated by The Norwegian System of Patient Injury Compensation (NPE). The number of claims from women with cervical cancer is rising, and the approval rate is high. Our aim was to study claims for compensation from women with cervical cancer to identify the type of failures, when, during the time-course of treatment, the medical failures occurred, and the consequences of the failures. MATERIAL AND METHODS: A retrospective, descriptive study of claims for compensation to NPE from cervical cancer patients during a 12-year period, from 2007 through 2018. We used anonymized medical expert statements and summaries of NPE cases. RESULTS: In all, 161 women claimed compensation for alleged medical failure related to cervical cancer. Compensation was approved for 100 (62%) women. Mean age at the time of alleged failure was 37.5 years (SD ±9.9). The main reasons why women sought medical attention were routine cervical screening (56%), or vaginal bleeding or discharge (30%). In approved cases, incorrect evaluation of cytology and histology was the cause of most failures (72%). Mean delay of cervical cancer diagnosis for approved cases was 28 months (SD ±22). Treatment not in accordance with guidelines was the cause of failure in 2% of the cases, and failure during follow up was the cause of failure in 12%. Consequences of the failures were as follows: worsening of cancer prognosis (89%), treatment-induced adverse effects, such as loss of fertility (43%) and/or loss of ovarian function in premenopausal women (50%), and permanent injury after chemo-radiation (27%). Seven women (7%) died, most probably as a consequence of the failure. CONCLUSIONS: The main cause of medical failure in women with cervical cancer was incorrect pathological diagnosis. The main consequences of failures were worsening of cancer prognosis and treatment-induced adverse effects. Increased focus on the quality of pathological examinations, and better routines in all parts of the cervical examinations might improve patient safety for women in risk of cervical cancer.

A national study of the causes, consequences and amelioration of adverse events in the use of MRI, CT, and conventional radiography in Norway.

BACKGROUND: Rapid technological developments, increased complexity, and increased demand have made patient safety a challenge in radiology. PURPOSE: To uncover the causes and consequences behind patient injury compensation claims in the use of MRI, CT, and conventional X-ray examinations, and to determine the system factors that need to be focused on in order to prevent these events. MATERIAL AND METHODS: This descriptive cross-sectional study uses data acquired from The Norwegian System of Patient Injury Compensation. A total of 240 cases from 2012-2016 were included. RESULTS: According to our study, the main factors contributing to patient injury compensation claims in radiology were false-negative findings (48.7%), misinterpretation (13.1%), and "satisfaction of search" (12%). Another source of error was routines (8.7%), mainly where the patient should have been (further) examined using another modality. Other causes were related to communication (7.6%), procedures (2.9%), technical factors (2.5%), organizational and management factors (1.5%), competence (0.7%), location of the lesion (0.7%), patient factors (0.7%), false-positive findings (0.4%), and work environment (0.4%). These events led to delayed diagnosis and/or treatment in the range of 0-3650 days. CONCLUSION: Errors of perception (false negative and "satisfaction of search") and cognitive errors (misinterpretation) were the main reasons behind patient injury compensation claims in radiology. We suggest that a combination of double-reading, specialization, increased collaboration between professionals, as well as a reduction of unnecessary examinations should be considered to reduce adverse events in radiology.

Patient injuries reported to the Norwegian System of Patient Injury Compensation 2011­17. / Pasientskader hos fastleger meldt til Norsk pasientskadeerstatning 2011­17.

BACKGROUND: The Norwegian System of Patient Injury Compensation (NPE) processes compensation claims from patients who believe that they have sustained injuries during treatment in the health services. The number of cases reported to NPE has tended to increase in recent years. The purpose of this study was to obtain an overview of patient-reported injuries within the regular GP scheme. MATERIAL AND METHOD: We studied all injuries to patients within the regular GP scheme in NPE in the years 2011-17. The cases of injury contained information on age, sex, diagnosis, location of the injury and compensation paid, as well as texts describing the treatment and injury. RESULTS: Out of a total of 33 748 compensation claims submitted to NPE, 3 135 cases originated from the regular GP scheme. Of the group of claimants 53 % were women, and the average age was 44.7 years (standard deviation 17.7 years). Altogether 760 (24 %) of the cases were upheld. Diagnostic error was the reason for 553 (73 %) of the cases being upheld. The groups most frequently represented were 'tumours and cancers' (847 (27 %) of the claims) and 'orthopaedics' (592 (19 %) of the claims). INTERPRETATION: The regular GP scheme accounts for many patient contacts, and a review of patient injuries may make it possible to prevent future failures.

Performance measures among non-immigrants and immigrants attending BreastScreen Norway: a population-based screening programme.

OBJECTIVES: To explore performance measures among non-immigrants and immigrants attending BreastScreen Norway. METHODS: We analysed data from 2,951,375 screening examinations among non-immigrants and 153,026 among immigrants from 1996 to 2015. Immigrants were categorised into high- and low-incidence countries according to the incidence of breast cancer in their birth country. Performance measures, including attendance and recall rates, rates of screen-detected cancer (SDC) and interval breast cancer (IBC), positive predictive value (PPV) and histopathological tumour characteristics, were analysed. We used Fisher's exact model and t tests for descriptive statistics, and Poisson regression, adjusting for age and screening history, comparing results for non-immigrants versus immigrants. RESULTS: Attendance rates were 78% for non-immigrants and 56% for immigrants (p < 0.001). Rates of prevalent screens were 24% for non-immigrants and 32% for immigrants (p < 0.001). Immigrants from low-incidence countries were younger at diagnosis than non-immigrants (57 years versus 60 years, p < 0.001). Recall rates were 3.1% for non-immigrants and 3.8% for immigrants (p < 0.001), while PPVs were 17% and 14% (p < 0.001), respectively. IBCs in immigrants from low-incidence countries were more often triple negative (RRadj 1.81, 95% CI 1.11-2.94) than those in non-immigrants. Both SDC and IBC in immigrants from low-incidence countries tended more often to be histological grade 3 than those in non-immigrants. CONCLUSION: Immigrants had lower attendance rates, higher recall rates and lower PPV than non-immigrants. The optimal age range and screening interval for immigrant women from low-incidence countries need to be further investigated. KEY POINTS: • Immigrants from countries with a low incidence of breast cancer had their breast cancer diagnosed at a younger age than non-immigrants. • Interval breast cancers detected in immigrants from countries with a low incidence of breast cancers were more often triple negative than those in non-immigrants. • The optimal age range and screening interval for immigrant women from low-incidence countries and non-immigrants might differ.

Approved claims for compensation from gynecological patients in Norway-What characterizes the cases? A 14-year nationwide study.

INTRODUCTION: The Norwegian System of Patient Injury Compensation (NPE) evaluates all patient-reported claims in Norway. Our aim was to study the cases from gynecological patients approved by NPE in order to identify the main reasons for the injuries, the consequences of the treatment failure for the women, and the time course when the treatment failure occurred. MATERIAL AND METHODS: A retrospective, descriptive study of approved gynecological compensation claims during a 14-year period, based on patient files from NPE. RESULTS: In all, 1454 women claimed compensation for injury related to gynecological treatment in Norway from 2000 to 2013. Compensation was approved for 438 (30.1%) women. Eleven women declined participation in the study and 16 cases were excluded, leaving 411 cases for further analyses. Consent to participate was given by 211 (51.3%) women, who gave full access to all their NPE files. Anonymized resumes and expert statements were used for the 138 (33.6%) women who did not respond and the 62 (15.1%) women who were deceased. Guidelines or good clinical practice were not followed in 40.5% of the cases. The most common reasons for injury were surgical complications (67.6%), delayed (22.4%) and incorrect (17.0%) diagnoses, and failure of communication (11.7%). The main consequences of injuries were need for extensive treatment (64.2%), permanent injury (55.2%) and impaired physical ability (41.9%). Worsening of cancer prognosis occurred in 58 women (14.1%) and death due to treatment failure in 29 (7.1%) women. Most failures occurred during the treatment period (75.2%). CONCLUSIONS: We found that the main reason for injuries in gynecological patients was non-adherence to guidelines or good clinical practice. Surgery-related injuries were most common. Increased focus on adherence to guidelines and surgical skills might improve patient safety for gynecological patients in Norway.

In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics.

BACKGROUND: The majority of breast cancer cases are steroid dependent neoplasms, with hormonal manipulation of either CYP19/aromatase or oestrogen receptor alpha axis being the most common therapy. Alternate pathways of steroid actions are documented, but their interconnections and correlations to BC subtypes and clinical outcome could be further explored. METHODS: We evaluated selected steroid receptors (Androgen Receptor, Oestrogen Receptor alpha and Beta, Glucocorticoid Receptor) and oestrogen pathways (steroid sulfatase (STS), 17ß-hydroxysteroid dehydrogenase 2 (17ßHSD2) and aromatase) in a cohort of 139 BC cases from Norway. Using logistic and cox regression analysis, we examined interactions between these and clinical outcomes such as distant metastasis, local relapse and survival. RESULTS: Our principal finding is an impact of STS expression on the risk for distant metastasis (p<0.001) and local relapses (p <0.001), HER2 subtype (p<0.015), and survival (p<0.001). The suggestion of a beneficial effect of alternative oestrogen synthesis pathways was strengthened by inverted, but non-significant findings for 17ßHSD2. CONCLUSIONS: Increased intratumoural metabolism of oestrogens through STS is associated with significantly lower incidence of relapse and/or distant metastasis and correspondingly improved prognosis. The enrichment of STS in the HER2 overexpressing subtype is intriguing, especially given the possible role of HER-2 over-expression in endocrine resistance.

Somatic EP300-G211S mutations are associated with overall somatic mutational patterns and breast cancer specific survival in triple-negative breast cancer.

PURPOSE: We have compared the mutational profiles of human breast cancer tumor samples belonging to all major subgroups with special emphasis on triple-negative breast cancer (TNBC). Our major goal was to identify specific mutations that could be potentially used for clinical decision making in TNBC patients. PATIENTS AND METHODS: Primary tumor specimens from 149 Norwegian breast cancer patients were available. We analyzed the tissue samples for somatic mutations in 44 relevant breast cancer genes by targeted next-generation sequencing. As a second confirmatory technique, we performed pyrosequencing on selected samples. RESULTS: We observed a distinct subgroup of TNBC patients, characterized by an almost completely lack of pathogenic somatic mutations. A point mutation in the adenoviral E1A binding protein p300 (EP300-G211S) was significantly correlated to this TNBC subgroup. The EP300-G211S mutation was exclusively found in the TNBC patients and its presence reduced the chance for other pathological somatic mutations in typical breast cancer genes investigated in our gene panel by 94.9% (P < 0.005). Interestingly, the EP300-G211S mutation also predicted a lower risk for relapses and decreased breast cancer-specific mortality during long-term follow-up of the patients. CONCLUSION: Next-generation sequencing revealed specific mutations in EP300 to be associated with the mutational patterns in typical breast cancer genes and long-term outcome of triple-negative breast cancer patients.

Compensation after treatment for anterior cruciate ligament injuries: a review of compensation claims in Norway from 2005 to 2015.

PURPOSE: To assess the most common reasons for complaints following anterior cruciate ligament (ACL) injuries reported to the Norwegian System of Patient Injury Compensation (NPE), and to view these complaints in light of the ACL reconstructions (ACL-Rs) reported to the Norwegian Knee Ligament Registry (NKLR). METHOD: Data from the NPE and the NKLR were collected for the study period (2005-2015). The age and gender and type of complaint and reason for granted compensation were collected from the NPE, while the graft choice and total number of ACL-R were collected from the NKLR. Risk for successful grant was estimated for graft type. RESULTS: 18,810 primary ACL-Rs were reported to the NKLR during the study period. A hamstring graft was used in 12,437 (66.1%) but the bone-patellar tendon-bone (BPTB) became the graft of choice at the end of the study period. 240 patients filed a complaint to the NPE, of which 101 were granted compensation. The odds ratio for a claim being granted following a hamstring graft was 2.9 compared to that of a BPTB graft (p = 0.002) The most common reason for compensation was a hospital-acquired infection in 39 patients (38.6%) followed by inadequate surgical technique (27, 26.7%) and delayed diagnosis (13, 12.9%). Of the 39 patients with infection, 27 had received a hamstring graft and six a BPTB graft (two patients were not reconstructed, data missing for three patients). Of the 27 patients who were granted compensation due to inadequate surgical technique, 24 had received a hamstring graft and three a BPTB graft. CONCLUSION: Infection and inadequate surgical technique are the most common causes for granted compensation from the NPE following ACL injury. Hamstring grafts have a threefold risk of complication that yields compensation from the NPE compared to BPTB grafts. This information is relevant for patients and surgeons when choosing graft type. The trend of increased use of BPTB grafts is warranted based on the results from this study. LEVEL OF EVIDENCE: Level III.

Integrative clustering reveals a novel split in the luminal A subtype of breast cancer with impact on outcome.

BACKGROUND: Breast cancer is a heterogeneous disease at the clinical and molecular level. In this study we integrate classifications extracted from five different molecular levels in order to identify integrated subtypes. METHODS: Tumor tissue from 425 patients with primary breast cancer from the Oslo2 study was cut and blended, and divided into fractions for DNA, RNA and protein isolation and metabolomics, allowing the acquisition of representative and comparable molecular data. Patients were stratified into groups based on their tumor characteristics from five different molecular levels, using various clustering methods. Finally, all previously identified and newly determined subgroups were combined in a multilevel classification using a "cluster-of-clusters" approach with consensus clustering. RESULTS: Based on DNA copy number data, tumors were categorized into three groups according to the complex arm aberration index. mRNA expression profiles divided tumors into five molecular subgroups according to PAM50 subtyping, and clustering based on microRNA expression revealed four subgroups. Reverse-phase protein array data divided tumors into five subgroups. Hierarchical clustering of tumor metabolic profiles revealed three clusters. Combining DNA copy number and mRNA expression classified tumors into seven clusters based on pathway activity levels, and tumors were classified into ten subtypes using integrative clustering. The final consensus clustering that incorporated all aforementioned subtypes revealed six major groups. Five corresponded well with the mRNA subtypes, while a sixth group resulted from a split of the luminal A subtype; these tumors belonged to distinct microRNA clusters. Gain-of-function studies using MCF-7 cells showed that microRNAs differentially expressed between the luminal A clusters were important for cancer cell survival. These microRNAs were used to validate the split in luminal A tumors in four independent breast cancer cohorts. In two cohorts the microRNAs divided tumors into subgroups with significantly different outcomes, and in another a trend was observed. CONCLUSIONS: The six integrated subtypes identified confirm the heterogeneity of breast cancer and show that finer subdivisions of subtypes are evident. Increasing knowledge of the heterogeneity of the luminal A subtype may add pivotal information to guide therapeutic choices, evidently bringing us closer to improved treatment for this largest subgroup of breast cancer.

Subtype-specific micro-RNA expression signatures in breast cancer progression.

Robust markers of invasiveness may help reduce the overtreatment of in situ carcinomas. Breast cancer is a heterogeneous disease and biological mechanisms for carcinogenesis vary between subtypes. Stratification by subtype is therefore necessary to identify relevant and robust signatures of invasive disease. We have identified microRNA (miRNA) alterations during breast cancer progression in two separate datasets and used stratification and external validation to strengthen the findings. We analyzed two separate datasets (METABRIC and AHUS) consisting of a total of 186 normal breast tissue samples, 18 ductal carcinoma in situ (DCIS) and 1,338 invasive breast carcinomas. Validation in a separate dataset and stratification by molecular subtypes based on immunohistochemistry, PAM50 and integrated cluster classifications were performed. We propose subtype-specific miRNA signatures of invasive carcinoma and a validated signature of DCIS. miRNAs included in the invasive signatures include downregulation of miR-139-5p in aggressive subtypes and upregulation of miR-29c-5p expression in the luminal subtypes. No miRNAs were differentially expressed in the transition from DCIS to invasive carcinomas on the whole, indicating the need for subtype stratification. A total of 27 miRNAs were included in our proposed DCIS signature. Significant alterations of expression included upregulation of miR-21-5p and the miR-200 family and downregulation of let-7 family members in DCIS samples. The signatures proposed here can form the basis for studies exploring DCIS samples with increased invasive potential and serum biomarkers for in situ and invasive breast cancer.

GFRA3 promoter methylation may be associated with decreased postoperative survival in gastric cancer.

BACKGROUND: A large number of epigenetic alterations has been found to be implicated in the etiology of gastric cancer. We have studied the DNA methylation status of 27 500 gene promoter regions in 24 gastric adenocarcinomas from a Norwegian cohort, and aimed at identifying the hypermethylated regions. We have compared our findings to the gene expression in the same tissue, and linked our results to prognosis and survival. METHODS: Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 24 patients following surgical resection of the tumor. Genome-wide DNA methylation profiling of the tumor and matched non-cancerous mucosa was performed. The results were compared to whole transcriptome cDNA microarray analysis of the same material. RESULTS: Most of the gene promoter regions in both types of tissue showed a low degree of methylation, however there was a small, but significant hypermethylation of the tumors. Hierarchical clustering showed separate grouping of the tumor and normal tissue. Hypermethylation of the promoter region of the GFRA3 gene showed a strong correlation to post-operative survival and several of the clinicopathological parameters, however no difference was found between the two main histological types of gastric cancer. There was only a modest correlation between the DNA methylation status and gene expression. CONCLUSIONS: The different DNA methylation clusters of the tumors and normal tissue indicate that aberrant DNA methylation is a distinct feature of gastric cancer, although there is little difference in the overall, and low, methylation levels between the two tissue types. The GFRA3 promoter region showed marked hypermethylation in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance.

Long-term quality of life and functionality after ventral hernia mesh repair.

BACKGROUND: The absence of recurrence and pain are important for good quality of life (QoL) after ventral hernia mesh repair. We wanted to study long-term outcome after laparoscopic (LVHR) and open ventral hernia mesh repair (OVHR) using validated scales to measure QoL and functional outcome. METHODS: We conducted a single-center follow-up study of 194 consecutive patients after LVHR and OVHR between March 2000 and June 2010. Of these, 27 patients (13.9 %) died and 14 (7.2 %) failed to attend their follow-up appointment. Of 153 (78.9 %) patients who attended, 81 (52.9 %) patients had LVHR and 72 (47.1 %) patients had OVHR, including 11 conversions (surgery group). One hundred and twelve patients with non-recurrent ventral hernia were also enrolled consecutively as controls (non-surgery group). Quality of life was measured by the SF-36 short form questionnaire and functional outcome by the Activities Assessment Scale (AAS) with the revised Life Orientation Test to measure the influence of dispositional optimism on pain and functionality. Assessment of pain was done using a 100-mm visual analogue scale ruler anchored by word descriptors. RESULTS: Median time from hernia mesh repair to follow-up was 48 and 52 months after LVHR and OVHR, respectively. There were no long-term differences between LVHR and OVHR measured by SF-36 and AAS. Physical dimensions in SF-36: physical function, restrictions in physical function and bodily pain, were significantly better in the surgery group compared to the non-surgery group, but only for incisional hernia. Recurrence was associated with a significant reduction in QoL in all dimensions of SF-36 in both hernia repair cohorts. Chronic pain and impairment were closely related. Optimistic patients had less impairment than pessimistic patients. CONCLUSION: LVHR and OVHR reduce chronic pain and physical impairment and improve long-term QoL. Hernia recurrence and persistent pain reduce the beneficial effect of hernia surgery. Dispositional optimism can modulate QoL reporting and improve functionality.