Introducing extended consultations for patients with severe mental illness in general practice: Results from the SOFIA feasibility study.

BACKGROUND: People with a severe mental illness (SMI) have shorter life expectancy and poorer quality of life compared to the general population. Most years lost are due to cardiovascular disease, respiratory disease, and various types of cancer. We co-designed an intervention to mitigate this health problem with key stakeholders in the area, which centred on an extended consultations for people with SMI in general practice. This study aimed to1) investigate general practitioners' (GPs) experience of the feasibility of introducing extended consultations for patients with SMI, 2) assess the clinical content of extended consultations and how these were experienced by patients, and 3) investigate the feasibility of identification, eligibility screening, and recruitment of patients with SMI. METHODS: The study was a one-armed feasibility study. We planned that seven general practices in northern Denmark would introduce extended consultations with their patients with SMI for 6 months. Patients with SMI were identified using practice medical records and screened for eligibility by the patients' GP. Data were collected using case report forms filled out by practice personnel and via qualitative methods, including observations of consultations, individual semi-structured interviews, a focus group with GPs, and informal conversations with patients and general practice staff. RESULTS: Five general practices employing seven GPs participated in the study, which was terminated 3 ½ month ahead of schedule due to the COVID-19 pandemic. General practices attempted to contact 57 patients with SMI. Of these, 38 patients (67%) attended an extended consultation, which led to changes in the somatic health care plan for 82% of patients. Conduct of the extended consultations varied between GPs and diverged from the intended conduct. Nonetheless, GPs found the extended consultations feasible and, in most cases, beneficial for the patient group. In interviews, most patients recounted the extended consultation as beneficial. DISCUSSION: Our findings suggest that it is feasible to introduce extended consultations for patients with SMI in general practice, which were also found to be well-suited for eliciting patients' values and preferences. Larger studies with a longer follow-up period could help to assess the long-term effects and the best implementation strategies of these consultations.

The SOFIA pilot trial: a cluster-randomized trial of coordinated, co-produced care to reduce mortality and improve quality of life in people with severe mental illness in the general practice setting.

BACKGROUND: People with severe mental illness (SMI) have an increased risk of premature mortality, predominantly due to somatic health conditions. Evidence indicates that primary and tertiary prevention and improved treatment of somatic conditions in patients with SMI could reduce this excess mortality. This paper reports a protocol designed to evaluate the feasibility of a coordinated co-produced care program (SOFIA model, a Danish acronym for Severe Mental Illness and Physical Health in General Practice) in the general practice setting to reduce mortality and improve quality of life in patients with severe mental illness. METHODS: The SOFIA pilot trial is designed as a cluster randomized controlled trial targeting general practices in two regions in Denmark. We aim to include 12 practices, each of which is instructed to recruit up to 15 community-dwelling patients aged 18 and older with SMI. Practices will be randomized by a computer in a ratio of 2:1 to deliver a coordinated care program or usual care during a 6-month study period. A randomized algorithm is used to perform randomization. The coordinated care program includes educational training of general practitioners and their clinical staff educational training of general practitioners and their clinical staff, which covers clinical and diagnostic management and focus on patient-centered care of this patient group, after which general practitioners will provide a prolonged consultation focusing on individual needs and preferences of the patient with SMI and a follow-up plan if indicated. The outcomes will be parameters of the feasibility of the intervention and trial methods and will be assessed quantitatively and qualitatively. Assessments of the outcome parameters will be administered at baseline, throughout, and at end of the study period. DISCUSSION: If necessary the intervention will be revised based on results from this study. If delivery of the intervention, either in its current form or after revision, is considered feasible, a future, definitive trial to determine the effectiveness of the intervention in reducing mortality and improving quality of life in patients with SMI can take place. Successful implementation of the intervention would imply preliminary promise for addressing health inequities in patients with SMI. TRIAL REGISTRATION: The trial was registered in Clinical Trials as of November 5, 2020, with registration number NCT04618250 . Protocol version: January 22, 2021; original version.

Commentary on a combined approach to the problem of developing biomarkers for the prediction of spontaneous preterm labor that leads to preterm birth.

INTRODUCTION: Globally, preterm birth has replaced congenital malformation as the major cause of perinatal mortality and morbidity. The reduced rate of congenital malformation was not achieved through a single biophysical or biochemical marker at a specific gestational age, but rather through a combination of clinical, biophysical and biochemical markers at different gestational ages. Since the aetiology of spontaneous preterm birth is also multifactorial, it is unlikely that a single biomarker test, at a specific gestational age will emerge as the definitive predictive test. METHODS: The Biomarkers Group of PREBIC, comprising clinicians, basic scientists and other experts in the field, with a particular interest in preterm birth have produced this commentary with short, medium and long-term aims: i) to alert clinicians to the advances that are being made in the prediction of spontaneous preterm birth; ii) to encourage clinicians and scientists to continue their efforts in this field, and not to be disheartened or nihilistic because of a perceived lack of progress and iii) to enable development of novel interventions that can reduce the mortality and morbidity associated with preterm birth. RESULTS: Using language that we hope is clear to practising clinicians, we have identified 11 Sections in which there exists the potential, feasibility and capability of technologies for candidate biomarkers in the prediction of spontaneous preterm birth and how current limitations to this research might be circumvented. DISCUSSION: The combination of biophysical, biochemical, immunological, microbiological, fetal cell, exosomal, or cell free RNA at different gestational ages, integrated as part of a multivariable predictor model may be necessary to advance our attempts to predict sPTL and PTB. This will require systems biological data using "omics" data and artificial intelligence/machine learning to manage the data appropriately. The ultimate goal is to reduce the mortality and morbidity associated with preterm birth.

Toxicity and efficacy of lomustine and bevacizumab in recurrent glioblastoma patients.

The combination of lomustine and bevacizumab is a commonly used salvage treatment for recurrent glioblastoma (GBM). We investigated the toxicity and efficacy of lomustine plus bevacizumab (lom-bev) in a community-based patient cohort and made a comparison to another frequently used combination therapy consisting of irinotecan plus bevacizumab (iri-bev). Seventy patients with recurrent GBM were treated with lomustine 90 mg/m2 every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Toxicity was registered and compared to the toxicity observed in 219 recurrent GBM patients who had previously been treated with irinotecan 125 mg/m2 and bevacizumab 10 mg/kg every 2 weeks. The response rate was 37.1% for lom-bev and 30.1% for iri-bev. Median progression-free survival (PFS) was 23 weeks for lom-bev and 21 weeks for iri-bev (p = 0.9). Overall survival (OS) was 37 weeks for lom-bev and 32 weeks for iri-bev (p = 0.5). Lom-bev caused a significantly higher frequency of thrombocytopenia (11.4% grade 3-4) compared to iri-bev (3.5% grade 3-4). Iri-bev patients had more gastrointestinal toxicity with regard to nausea, vomiting, diarrhea, constipation and stomatitis. Within the limitations of the study lom-bev is a well-tolerated treatment for recurrent GBM, although hematological toxicity may be a dose limiting factor. No significant differences between lom-bev and iri-bev were observed with regard to PFS or OS. The differences in toxicity profiles between lom-bev and iri-bev could guide treatment decision in recurrent GBM therapy as efficacy is equal and no predictive factors for efficacy exist.

Randomised feasibility study of a more liberal haemoglobin trigger for red blood cell transfusion compared to standard practice in anaemic cancer patients treated with chemotherapy.

OBJECTIVES: The primary objective of this feasibility study was to identify quality of life (QoL) scores and symptom scales as tools for measuring patient-reported outcomes (PRO) associated with haemoglobin level in chemotherapy-treated cancer patients. Secondary objectives included comparing QoL and symptoms between randomisation arms. BACKGROUND: Anaemia in cancer patients undergoing chemotherapy is associated with decreased QoL. One treatment option is red blood cell transfusion (RBCT). However, the optimal haemoglobin trigger for transfusion is unknown. METHODS: Patients were randomised to a haemoglobin trigger for RBCT of either < 9·7 g dL-1 (arm A) or < lower normal level, female: 11·5 g dL-1 , male: 13·1 g dL-1 (arm B). Four PROs were used: Functional Assessment of Cancer Therapy-General (FACT-G) and the FACT-Anaemia (FACT-An), a Numeric Rating Scale on symptoms of anaemia and self-reported Performance Status (PS). The association between haemoglobin and PRO variables was assessed using a linear mixed model with random effects. RESULTS: A total of 133 patients were enrolled, of which 86 patients received RBCT (28 in arm A, 58 in arm B). Baseline questionnaires were filled out in 79·7% of cases. Haemoglobin levels were significantly correlated with FACT-An, FACT-An Total Outcome Index (TOI), Functional Well-Being, fatigue and PS. Improvement on several PRO variables was observed in both arms after RBCT, with clinically minimal important differences observed in FACT-G, Physical Well-Being, FACT-An, FACT-An TOI, fatigue and dyspnoea. CONCLUSIONS: QoL scores of physical and functional domains as well as self-reported anaemia-related symptoms correlated well with haemoglobin level in chemotherapy-treated cancer patients.

Hybrid Capture 2 and cobas human papillomavirus assays perform similarly on SurePath samples from women with abnormalities.

OBJECTIVE: In two laboratories (Departments of Pathology, Copenhagen University Hospitals of Herlev and Hvidovre), we compared cobas and Hybrid Capture 2 (HC2) human papillomavirus (HPV) assays using SurePath® samples from women with atypical squamous cells of undetermined significance (ASCUS) at ≥30 years and women after treatment of cervical intraepithelial neoplasia (CIN). METHODS: Samples from 566 women with ASCUS and 411 women after treatment were routinely tested with HC2 and, thereafter, with cobas. Histological outcomes were retrieved from the Danish Pathology Data Base. We calculated the overall agreement between the assays, and compared their sensitivity and specificity for ≥CIN2. RESULTS: In women with ASCUS, HC2 and cobas testing results were similar in the two laboratories. The overall agreement was 91% (95% CI, 88-93). After CIN treatment, the overall agreement was 87% (95% CI, 82-91) at Herlev and 88% (95% CI, 82-92) at Hvidovre. There were no significant differences in the sensitivity for ≥CIN2 between the two tests [Herlev, 98% (95% CI, 89-100) for HC2 versus 94% (95% CI, 82-99) for cobas; Hvidovre, 97% (95% CI, 83-100) for HC2 versus 100% (95% CI, 88-100) for cobas]. The differences were also not significant for specificity. CONCLUSIONS: In women with the studied well-defined clinical indications for HPV testing, cobas and HC2 performed similarly in terms of the detection of HPV and ≥CIN2.

Inflammation and uPAR-Expression in Colorectal Liver Metastases in Relation to Growth Pattern and Neo-adjuvant Therapy.

Proteolytic activity and inflammation in the tumour microenvironment affects cancer progression. In colorectal cancer (CRC) liver metastases it has been observed that three different immune profiles are present, as well as proteolytic activity, determined by the expression of urokinase-type plasminogen activator (uPAR).The main objectives of this study were to investigate uPAR expression and the density of macrophages (CD68) and T cells (CD3) as markers of inflammation in resected CRC liver metastases, where patients were neo-adjuvantly treated with chemotherapy with or without the angiogenesis inhibitor bevacizumab. Chemonaive patients served as a control group. The markers were correlated to growth patterns (GP) of liver metastases, i.e. desmoplastic, pushing and replacement GP. It was hypothesised that differences in proteolysis and inflammation could reflect tumour specific growth and therapy related changes in the tumour microenvironment. In chemonaive patients, a significantly higher level of uPAR was observed in desmoplastic liver metastases in comparison to pushing GP (p = 0.01) or replacement GP (p = 0.03). A significantly higher density of CD68 was observed in liver metastases with replacement GP in comparison to those with pushing GP (p = 0.01). In liver metastases from chemo treated patients, CD68 density was significantly higher in desmoplastic GP in comparison to pushing GP (p = 0.03). In chemo and bevacizumab treated patients only a significant lower CD3 expression was observed in liver metastases with a mixed GP than in those with desmoplastic (p = 0.01) or pushing GP (p = 0.05). Expression of uPAR and the density of macrophages at the tumour margin of liver metastasis differ between GP in the untreated patients. A higher density of T cells was observed in the bevacizumab treated patients, when desmoplastic and pushing metastases were compared to liver metastases with a mix of the GP respectively, however no specific correlations between the immune markers of macrophages and T cells or GP of liver metastases could be demonstrated.

Tetranectin positive expression in tumour tissue leads to longer survival in Danish women with ovarian cancer. Results from the 'Malova' ovarian cancer study.

The primary objective of this study was to analyse Tetranectin (TN) expression in tumour tissues and TN serum concentration in 758 women with epithelial ovarian tumours. The second was to evaluate, whether TN tissue expression levels correlate with clinico-pathological parameters and prognosis of the disease. Using tissue arrays we analysed the expression levels in tissues from 166 women with borderline ovarian tumours (BOTs) and 592 women with ovarian cancer (OC). A panel of three antibodies was used for immunohistochemistry: a polyclonal and two monoclonal antibodies. Serum TN was measured using the polyclonal antibody A-371. Univariate survival analyses stratified for chemotherapy showed that positive tissue TN as demonstrated by the polyclonal antibody indicated a significantly longer overall survival (OS) (p = 0.0001) as well as cancer specific survival (CSS) (p < 0.0001). High serum TN was likewise found to imply longer OS (p < 0.0001) and CSS (p < 0.0001), whereas tissue staining with the two monoclonal antibodies failed to demonstrate any significant correlation with either survival type. Univariate Kaplan-Meier survival analysis performed on all OC cases showed a significantly longer OS (p = 0.0009) and CSS (p = 0.0006) for women with TN positive tumour tissue and in women with high serum TN levels (p < 0.0001 for both). However, in the multivariate Cox regression analysis, only serum TN was found to be an independent prognostic factor for OS (p = 0.01) and not for CSS (p = 0.08). In conclusion, our results predict that a positive TN expression of both tumour tissue and serum points to a more favourable outcome for OC patients.

Growth pattern of colorectal liver metastasis as a marker of recurrence risk.

Despite improved therapy of advanced colorectal cancer, the median overall survival (OS) is still low. A surgical removal has significantly improved survival, if lesions are entirely removed. The purpose of this retrospective explorative study was to evaluate the prognostic value of histological growth patterns (GP) in chemonaive and patients receiving neo-adjuvant therapy. Two-hundred-fifty-four patients who underwent liver resection of colorectal liver metastases between 2007 and 2011 were included in the study. Clinicopathological data and information on neo-adjuvant treatment were retrieved from patient and pathology records. Histological GP were evaluated and related to recurrence free and OS. Kaplan-Meier curves, log-rank test and Cox regression analysis were used. The 5-year OS was 41.8% (95% CI 33.8-49.8%). Growth pattern evaluation of the largest liver metastasis was possible in 224 cases, with the following distribution: desmoplastic 63 patients (28.1%); pushing 77 patients (34.4%); replacement 28 patients (12.5%); mixed 56 patients (25.0%). The Kaplan-Meier analyses demonstrated that patients resected for liver metastases with desmoplastic growth pattern had a longer recurrence free survival (RFS) than patients resected for non-desmoplastic liver metastases (p=0.05). When patients were stratified according to neo-adjuvant treatment in the multivariate Cox regression model, hazard ratios for RFS compared to desmoplastic were: pushing (HR=1.37, 95% CI 0.93-2.02, p=0.116), replacement (HR=2.16, 95% CI 1.29-3.62, p=0.003) and mixed (HR=1.70, 95% CI 1.12-2.59, p=0.013). This was true for chemonaive patients as well as for patients who received neo-adjuvant treatment.

Prospective multi-centre randomised trial comparing induction of labour with a double-balloon catheter versus dinoprostone.

This randomised controlled study compared the efficacy of double-balloon catheter versus vaginal prostaglandin E2 (dinoprostone) for induction of labour. In total, 825 pregnant women with cephalic presentation and an unfavourable cervix undergoing induction for conventional indications were randomised to double-balloon or vaginal dinoprostone (3 mg) groups. There was a significantly higher failure rate for labour induction in the balloon group (relative risk: 1.25, 95% confidence interval [CI]: 1.02-1.49). Median induction time was 27.3 h in the balloon group and 29.8 h in the dinoprostone group (difference not significant). After 24 h, 55.3% had given birth in the balloon group versus 54.3% in the dinoprostone group. Additional oxytocin stimulation was used more often in the balloon (46%) compared with that in the dinoprostone (34%) (relative risk: 1.34 (95%CI 1.16 -1.54) group. Caesarean section rates and neonatal outcome were similar. Overall, the two methods for induction were comparable with regard to efficacy and safety.

Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia.

The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.

Renal impairment and late toxicity in germ-cell cancer survivors.

BACKGROUND: Treatment with bleomycin-etoposide-cisplatin (BEP) impairs renal function and increases the risk of late cardiovascular disease (CVD) and death. We investigated the influence of BEP on glomerular filtration rate (GFR) and assessed the importance of GFR changes on CVD and death in a large cohort of germ-cell cancer survivors. PATIENTS AND METHODS: BEP-treated patients (N = 1206) were identified in the Danish DaTeCa database, and merged with national registers to identify late toxicity. GFR were measured (51Cr-EDTA clearance) before and after treatment and at 1, 3 and 5-year follow-up. The influence of BEP on GFR was evaluated with a linear mixed model. Risk factors for late toxicity were identified by a landmark analysis adjusting for covariates. The cohort was compared with the background population with standardized hospitalization/mortality rates. RESULTS: GFR changed (ΔGFR) -11.3%, -15.4% and -25.9% after three, four and five+ cycles of BEP. For patients with impaired renal function before treatment the changes were 4.3%, 0.0% and -12.8%, respectively. During follow-up a significant rebound of GFR was documented. Compared with the background population, all patients, irrespective of renal function, had an increased risk of CVD and death. This risk depended on chronic kidney disease stage before treatment but not after treatment. ΔGFR had no influence on risk of late toxicity [death: hazard ratio (HR) 1.06, P = 0.50; CVD: HR 0.97, P = 0.61]. CONCLUSIONS: Renal function after BEP is closely related to number of cycles, but the changes in GFR are partly reversible and have no impact on risk of CVD or death.

A randomized pilot study on single-port versus conventional laparoscopic rectal surgery: effects on postoperative pain and the stress response to surgery.

BACKGROUND: Potential benefits of single-port laparoscopic surgery may include improved cosmetic results, less postoperative pain, surgical trauma and faster recovery. Results of randomized prospective studies with a focus on single-port rectal surgery have not yet been presented. The aim of the present study was to compare single-port and conventional laparoscopic surgery for rectal cancer in terms of short-term outcomes including postoperative pain and trauma-induced changes in certain bioactive substances. METHODS: Patients with non-metastasized rectal cancer were prospectively randomized to single-port (n = 20) or conventional laparoscopic rectal surgery (n = 20). Postoperative pain was assessed at rest, at coughing and during mobilization, with a numeric pain ranking score and was recorded at 6 h after the operation and subsequently every morning daily for 4 days. Levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tissue inhibitor of metalloproteinases-1 (TIMP-1) were determined. Blood samples were collected preoperatively (baseline), and 6, 24, 48, 72 and 96 h after skin incision. RESULTS: Pain scores were significantly reduced in the single-port group on postoperative days 2, 3 and 4 during coughing and mobilization. In addition, the patients in the single-port group suffered significantly less pain at rest at 6 h after surgery and on postoperative days 1, 3 and 4. The levels of the three markers increased significantly after surgery. The increase was similar between groups for plasma IL-6 and TIMP-1 at all time points, while the CRP levels were significantly lower in the single-port group at 6 (p < 0.001) and 24 h (p < 0.05) after skin incision. Abdominal incisions lengths were significantly shorter in the single-port group (p = 0.001). There was no significant difference between groups in operating time and blood loss, morbidity or mortality rate. The short-term oncological outcome in the two groups was similar. CONCLUSIONS: Single-port rectal surgery may reduce postoperative pain. Although CRP levels were lower at some time points, results of the present randomized, pilot study suggest that the trauma-induced inflammatory response of single-port operations may be similar to the trauma-induced inflammatory response of conventional laparoscopic surgery.

Prognostic significance of circulating intact and cleaved forms of urokinase plasminogen activator receptor in inoperable chemotherapy treated cholangiocarcinoma patients.

BACKGROUND: High levels of intact and cleaved forms of the urokinase-type plasminogen activator receptor (uPAR) in both tissue and blood are associated with poor survival in several cancer diseases. The prognostic significance of uPAR in cholangiocarcinoma is unknown. The aims of this study were to determine if pre-treatment serum levels of uPAR forms and a decrease in levels during chemotherapy are predictive of survival in patients with inoperable cholangiocarcinoma. DESIGN AND METHODS: Patients with inoperable cholangiocarcinoma were consecutively included in the training set (n=108). A test set included patients from a different hospital using similar treatment guidelines (n=60). Serum levels of the different uPAR forms were determined using time-resolved fluorescence immunoassays (TR-FIA). The Cox proportional hazards model was used for the uni- and multivariate survival analyses. RESULTS: Baseline level of uPAR(I-III)+uPAR(II-III) was an independent predictor of survival (HR=2.08, 95% CI:1.46-2.97, p<0.0001). Applying the linear predictor from the training set to the test set, it was validated that uPAR(I-III)+uPAR(II-III) predicted overall survival (p=0.049). A high level of uPAR(I-III)+uPAR(II-III) after 2cycles of chemotherapy was associated with poor survival (HR=1.79, 95% CI:1.08-2.97, p=0.023, n=57). This predictor, however, was not significant in the test set (p=0.21, 26 events in 27 patients). CONCLUSION: The baseline level of uPAR(I-III)+uPAR(II-III) is a predictor of survival in inoperable cholangiocarcinoma patients.

Pretransplant C-reactive protein as A prognostic marker in allogeneic stem cell transplantation.

We evaluated the prognostic role of baseline levels of C-reactive protein (CRP) as well as CRP levels during conditioning in patients undergoing myeloablative allogeneic stem cell transplantation (SCT). Furthermore, we studied the impact of baseline clinical factors and conditioning regimens on CRP levels in the same period. We conducted a population-based retrospective study of 349 patients undergoing SCT at the National Danish SCT centre between January 2000 and January 2009. CRP levels increased significantly during the conditioning and peaked at day -3 before infusion of the graft. Elevated CRP was associated with older age, non-malignant disease, reduced pretransplant Karnofsky score and high-risk leukaemia. By univariate and multivariate analyses, increased CRP levels (>10 mg/l) before the start of treatment (day -7) and at the day of graft infusion (day 0) were associated with decreased overall survival [HR 1.35 (95%CL) (1.18-1.54); P < 0.0001] and increased treatment-related mortality [1.5 (1.24-1.82); P < 0.0001]. Similar findings were seen for mean CRP levels during the conditioning. CRP was not associated with risk of relapse or aGvHD in multivariate analysis. This study suggests that increased CRP levels before and during the conditioning are associated with baseline clinical factors and that elevated pretransplant CRP levels predict a poorer survival in SCT.

Prdm5 suppresses Apc(Min)-driven intestinal adenomas and regulates monoacylglycerol lipase expression.

PRDM proteins are tissue-specific transcription factors often deregulated in diseases, particularly in cancer where different members have been found to act as oncogenes or tumor suppressors. PRDM5 is a poorly characterized member of the PRDM family for which several studies have reported a high frequency of promoter hypermethylation in cancer types of gastrointestinal origin. We report here the characterization of Prdm5 knockout mice in the context of intestinal carcinogenesis. We demonstrate that loss of Prdm5 increases the number of adenomas throughout the murine small intestine on an Apc(Min) background. By using the genome-wide ChIP-seq (chromatin immunoprecipitation (ChIP) followed by DNA sequencing) and transcriptome analyses we identify loci encoding proteins involved in metabolic processes as prominent PRDM5 targets and characterize monoacylglycerol lipase (Mgll) as a direct PRDM5 target in human colon cancer cells and in Prdm5 mutant mouse intestines. Moreover, we report the downregulation of PRDM5 protein expression in human colon neoplastic lesions. In summary, our data provide the first causal link between Prdm5 loss and intestinal carcinogenesis, and uncover an extensive and novel PRDM5 target repertoire likely facilitating the tumor-suppressive functions of PRDM5.

Risk of biochemical recurrence and positive surgical margins in patients with pT2 prostate cancer undergoing radical prostatectomy.

BACKGROUND AND OBJECTIVE: To investigate risk factors associated with positive surgical margins (PSM) and biochemical recurrence (BR) in organ confined tumors (pT2) after radical prostatectomy (RP) for localized prostate cancer (PCa). METHODS: Between 1995 and 2011, 1,649 patients underwent RP at our institution. The study includes the 1,133 consecutive patients with pT2 tumors at final histopathology. Logistic regression analysis was used for risk of PSM. Risk of BR, defined as the first PSA ≥ 0.2 ng/ml, was analyzed with Kaplan-Meier and Cox regression analysis. RESULTS: Median follow-up was 3.6 years (range: 0.5-15.5 years). In logistic regression, NS surgery was independently associated with an increased risk of pT2 PSM (OR = 1.68, 95% CI: 1.3-2.0, P = 0.01) relative to non-NS surgery. NS surgery was not independently associated with BR but the interaction of PSM and NS surgery trended (P = 0.08) to increase the risk of BR compared to PSM and non-NS surgery. CONCLUSION: Several factors influence the risk of pT2 PSMs in radical prostatectomy. In our cohort pT2 PSM is associated with NS surgery and trend to increase risk of BR compared to non-NS surgery. The optimal selection of candidates for NS surgery is still not clear.

Duodenal surveillance improves the prognosis after duodenal cancer in familial adenomatous polyposis.

AIM: Duodenal adenomatosis in familial adenomatous polyposis results in a cancer risk that increases with age. Endoscopic surveillance has been recommended, but the effect has not yet been documented. The aim of this study was to present the results of long-term duodenal surveillance and to evaluate the risk of cancer development. METHOD: Follow up of patients in a previous study with gastroduodenoscopy in 1990-2010. Statistical analysis included the χ(2) test, actuarial method and Kaplan-Meier analysis. RESULTS: Among 304 patients, 261 (86%) had more than one endoscopy. The median follow up was 14 (interquartile range, 9-17) years. The cumulative lifetime risk of duodenal adenomatosis was 88% (95% CI, 84-93), and of Spigelman stage IV was 35% (95% CI, 25-45). The Spigelman stage improved in 32 (12%) patients, remained unchanged in 88 (34%) and worsened in 116 (44%). Twenty (7%) patients had duodenal cancer at a median age of 56 (range, 44-82) years. The cumulative cancer incidence was 18% at 75 years of age (95% CI, 8-28) and increased with increasing Spigelman stage at the index endoscopy to 33% in Spigelman stage IV (P < 0.0001). The median overall survival was 6.4 years (95% CI, 1.7 to not estimated): 8 years after a screen-detected cancer vs 0.8 years (95% CI, 0.03-1.7) after a symptomatic cancer (P < 0.0001). The location of the mutation in the APC gene did not influence the risk of developing Spigelman stage IV (P = 0.46) or duodenal cancer (P = 0.83). CONCLUSION: The risk of duodenal cancer in familial adenomatous polyposis is considerable, and regular surveillance and cancer prophylactic surgery result in a significantly improved prognosis.

Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) genotypes in colorectal cancer.

Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) are key factors of the lectin pathway of complement activation. Polymorphisms of the MBL2 and MASP-2 genes affect serum levels of MBL and MASP-2. In patients with colorectal cancer (CRC), the MBL and MASP-2 serum levels are increased and high MASP-2 levels are associated with recurrence and poor survival, whereas low MBL levels predict post-operative pneumonia. It is not known whether these associations are genetically based. In this study, the MBL and MASP-2 genotypes are investigated in 593 patients with CRC and 348 healthy controls. The potential association between genetic profile and infections, recurrence and survival is evaluated. Four single-nucleotide polymorphisms (SNPs) of MBL2 were analysed using TaqMan assays, with characterization of MBL2 wildtype A, variants B, C and D and alleles H/L, Y/X and P/Q. The SNP D120G for MASP-2 was determined. Serum levels of MBL and MASP-2 were measured. The MBL2 and MASP-2 genotype distribution was similar among patients with CRC and healthy controls and MBL2 genotype significantly associated with MBL concentration in serum (P<0.0001). No significant association between MBL2/MASP-2 genotype and post-operative infectious complications (P=0.33 and 0.22), recurrent cancer or survival (P=0.74 and P=0.61 respectively) was found. Thus, the increased serum levels of MBL and MASP-2 found in patients with CRC are not explained for by genetic profiles. In contrast to what has been demonstrated for serum levels of MBL and MASP-2, the genotypes do not predict disease course of the CRC patients.