THE ADDED VALUE OF BLOOD GLUCOSE MONITORING IN HIGH-RISK INDIVIDUALS UNDERGOING PANCREATIC CANCER SURVEILLANCE.

OBJECTIVES: The study aimed to investigate the added value of blood glucose monitoring in high-risk individuals (HRIs) participating in pancreatic cancer surveillance. METHODS: HRIs with a CDKN2A/p16 germline pathogenic variant (PV) participating in pancreatic cancer surveillance were included in this study. Multivariable logistic regression was performed to assess the relationship between new-onset diabetes (NOD) and pancreatic ductal adenocarcinoma (PDAC). To quantify the diagnostic performance of NOD as a marker for PDAC, receiver operating characteristic curve with area under the curve (AUC) was computed. RESULTS: In total, 220 HRIs were included between 2000-2019. Median age was 61 (IQR 53-71) years and 62.7% of participants were female. During the study period, 26 (11.8%) HRIs developed NOD, of whom 5 (19.2%) later developed PDAC. The other 23 (82.1%) PDAC cases remained NOD-free. Multivariable analysis showed no statistically significant relationship between NOD and PDAC (OR 1.21; 95% CI, 0.39-3.78) and four out of five PDAC cases appeared to have NOD within three months before diagnosis. Furthermore, NOD did not differentiate between HRIs with- and without PDAC (AUC 0.54; 95% CI, 0.46-0.61). CONCLUSIONS: In this study we found no added value for longitudinal glucose monitoring in CDKN2A PV carriers participating in an imaging-based pancreatic cancer surveillance program.

Aspects and outcomes of surveillance for individuals at high-risk of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths and is associated with a poor prognosis. The majority of these cancers are detected at a late stage, contributing to the bad prognosis. This underscores the need for novel, enhanced early detection strategies to improve the outcomes. While population-based screening is not recommended due to the relatively low incidence of PDAC, surveillance is recommended for individuals at high risk for PDAC due to their increased incidence of the disease. However, the outcomes of pancreatic cancer surveillance in high-risk individuals are not sorted out yet. In this review, we will address the identification of individuals at high risk for PDAC, discuss the objectives and targets of surveillance, outline how surveillance programs are organized, summarize the outcomes of high-risk individuals undergoing pancreatic cancer surveillance, and conclude with a future perspective on pancreatic cancer surveillance and novel developments.

Surveillance for Pancreatic Cancer in High-Risk Individuals Leads to Improved Outcomes: A Propensity Score-Matched Analysis.

BACKGROUND & AIMS: Recent pancreatic cancer surveillance programs of high-risk individuals have reported improved outcomes. This study assessed to what extent outcomes of pancreatic ductal adenocarcinoma (PDAC) in patients with a CDKN2A/p16 pathogenic variant diagnosed under surveillance are better as compared with patients with PDAC diagnosed outside surveillance. METHODS: In a propensity score matched cohort using data from the Netherlands Cancer Registry, we compared resectability, stage, and survival between patients diagnosed under surveillance with non-surveillance patients with PDAC. Survival analyses were adjusted for potential effects of lead time. RESULTS: Between January 2000 and December 2020, 43,762 patients with PDAC were identified from the Netherlands Cancer Registry. Thirty-one patients with PDAC under surveillance were matched in a 1:5 ratio with 155 non-surveillance patients based on age at diagnosis, sex, year of diagnosis, and tumor location. Outside surveillance, 5.8% of the patients had stage I cancer, as compared with 38.7% of surveillance patients with PDAC (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04-0.19). In total, 18.7% of non-surveillance patients vs 71.0% of surveillance patients underwent a surgical resection (OR, 10.62; 95% CI, 4.56-26.63). Patients in surveillance had a better prognosis, reflected by a 5-year survival of 32.4% and a median overall survival of 26.8 months vs 4.3% 5-year survival and 5.2 months median overall survival in non-surveillance patients (hazard ratio, 0.31; 95% CI 0.19-0.50). For all adjusted lead times, survival remained significantly longer in surveillance patients than in non-surveillance patients. CONCLUSION: Surveillance for PDAC in carriers of a CDKN2A/p16 pathogenic variant results in earlier detection, increased resectability, and improved survival as compared with non-surveillance patients with PDAC.

Cost-effectiveness of pancreas surveillance: The CDKN2A-p16-Leiden cohort.

BACKGROUND: CDKN2A-p16-Leiden mutation carriers have a high lifetime risk of developing pancreatic ductal adenocarcinoma (PDAC), with very poor survival. Surveillance may improve prognosis. OBJECTIVE: To assess the cost-effectiveness of surveillance, as compared to no surveillance. METHODS: In 2000, a surveillance program was initiated at Leiden University Medical Center with annual MRI and optional endoscopic ultrasound. Data were collected on the resection rate of screen-detected tumors and on survival. The Kaplan-Meier method and a parametric cure model were used to analyze and compare survival. Based on the surveillance and survival data from the screening program, a state-transition model was constructed to estimate lifelong outcomes. RESULTS: A total of 347 mutation carriers participated in the surveillance program. PDAC was detected in 31 patients (8.9%) and the tumor could be resected in 22 patients (71.0%). Long-term cure among patients with resected PDAC was estimated at 47.1% (p < 0.001). The surveillance program was estimated to reduce mortality from PDAC by 12.1% and increase average life expectancy by 2.10 years. Lifelong costs increased by €13,900 per patient, with a cost-utility ratio of €14,000 per quality-adjusted life year gained. For annual surveillance to have an acceptable cost-effectiveness in other settings, lifetime PDAC risk needs to be 10% or higher. CONCLUSION: The tumor could be resected in most patients with a screen-detected PDAC. These patients had considerably better survival and as a result annual surveillance was found to be cost-effective.

Pancreatic Cancer Surveillance in Carriers of a Germline CDKN2A Pathogenic Variant: Yield and Outcomes of a 20-Year Prospective Follow-Up.

PURPOSE: Pancreatic cancer surveillance in high-risk individuals may lead to detection of pancreatic ductal adenocarcinoma (PDAC) at an earlier stage and with improved survival. This study evaluated the yield and outcomes of 20 years of prospective surveillance in a large cohort of individuals with germline pathogenic variants (PVs) in CDKN2A. METHODS: Prospectively collected data were analyzed from individuals participating in pancreatic cancer surveillance. Surveillance consisted of annual magnetic resonance imaging with magnetic resonance cholangiopancreatography and optional endoscopic ultrasound. RESULTS: Three hundred forty-seven germline PV carriers participated in surveillance and were followed for a median of 5.6 (interquartile range 2.3-9.9) years. A total of 36 cases of PDAC were diagnosed in 31 (8.9%) patients at a median age of 60.4 (interquartile range 51.3-64.1) years. The cumulative incidence of primary PDAC was 20.7% by age 70 years. Five carriers (5 of 31; 16.1%) were diagnosed with a second primary PDAC. Thirty (83.3%) of 36 PDACs were considered resectable at the time of imaging. Twelve cases (12 of 36; 33.3%) presented with stage I disease. The median survival after diagnosis of primary PDAC was 26.8 months, and the 5-year survival rate was 32.4% (95% CI, 19.1 to 54.8). Individuals with primary PDAC who underwent resection (22 of 31; 71.0%) had an overall 5-year survival rate of 44.1% (95% CI, 27.2 to 71.3). Nine (2.6%; 9 of 347) individuals underwent surgery for a suspected malignant lesion, which proved to not be PDAC, and this included five lesions with low-grade dysplasia. CONCLUSION: This long-term surveillance study demonstrates a high incidence of PDAC in carriers of a PV in CDKN2A. This provides evidence that surveillance in such a high-risk population leads to detection of early-stage PDAC with improved resectability and survival.

Neoadjuvant Treatment with Angiogenesis-Inhibitor Dovitinib Prior to Local Therapy in Hepatocellular Carcinoma: A Phase II Study.

BACKGROUND: Hepatocellular carcinoma (HCC) recurrence rates following locoregional treatment are high. As multireceptor tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFRs) are effective in advanced HCC, we assessed the efficacy and safety of neoadjuvant systemic treatment with dovitinib in early- and intermediate-stage HCC. MATERIALS AND METHODS: Twenty-four patients with modified Child-Pugh class A early- and intermediate-stage HCC received neoadjuvant oral dovitinib 500 mg daily (5 days on/2 days off) for 4 weeks, followed by locoregional therapy. Primary endpoints were objective response rates and intratumoral blood flow changes. Secondary endpoints were safety, pharmacodynamical plasma markers of VEGFR-blockade, time to progression (TTP), and overall survival (OS). RESULTS: Modified RECIST overall response rate was 48%, including 13% complete remission, and despite dose reduction/interruption in 83% of patients, intratumoral perfusion index decreased significantly. Grade 3-4 adverse events, most frequently (on-target) hypertension (54%), fatigue (25%), and thrombocytopenia (21%), occurred in 88% of patients. Plasma VEGF-A, VEGF-D, and placental growth factor increased significantly, whereas sTie-2 decreased, consistent with VEGFR-blockade. Following neoadjuvant dovitinib, all patients could proceed to their original planned locoregional treatment. No delayed toxicity occurred. Seven patients (three early, four intermediate stage) underwent orthotopic liver transplant after median 11.4 months. Censoring at transplantation, median TTP and OS were 16.8 and 34.8 months respectively; median cancer-specific survival was not reached. CONCLUSION: Already after a short 4-week dovitinib treatment period, intratumoral blood flow reduction and modest antitumor responses were observed. Although these results support use of systemic neoadjuvant strategies, the poor tolerability indicates that dovitinib dose adaptations are required in HCC. IMPLICATIONS FOR PRACTICE: Orthotopic liver transplantation may cure early and intermediate-stage hepatocellular carcinoma. Considering the expected waiting time >6 months because of donor liver scarcity, there is an unmet need for effective neoadjuvant downsizing strategies. Angiogenesis inhibition by dovitinib does not negatively affect subsequent invasive procedures, is safe to administer immediately before locoregional therapy, and may provide a novel treatment approach to improve patient outcomes if tolerability in patients with hepatocellular carcinoma can be improved by therapeutic drug monitoring and personalized dosing.

Feasibility of Velocity-Selective Arterial Spin Labeling in Breast Cancer Patients for Noncontrast-Enhanced Perfusion Imaging.

BACKGROUND: Dynamic contrast-enhanced (DCE) MRI is the most sensitive method for detection of breast cancer. However, due to high costs and retention of intravenously injected gadolinium-based contrast agent, screening with DCE-MRI is only recommended for patients who are at high risk for developing breast cancer. Thus, a noncontrast-enhanced alternative to DCE is desirable. PURPOSE: To investigate whether velocity selective arterial spin labeling (VS-ASL) can be used to identify increased perfusion and vascularity within breast lesions compared to surrounding tissue. STUDY TYPE: Prospective. POPULATION: Eight breast cancer patients. FIELD STRENGTH/SEQUENCE: A 3 T; VS-ASL with multislice single-shot gradient-echo echo-planar-imaging readout. ASSESSMENT: VS-ASL scans were independently assessed by three radiologists, with 3-25 years of experience in breast radiology. Scans were scored on lesion visibility and artifacts, based on a 3-point Likert scale. A score of 1 corresponded to "lesions being distinguishable from background" (lesion visibility), and "no or few artifacts visible, artifacts can be distinguished from blood signal" (artifact score). A distinction was made between mass and nonmass lesions (based on BI-RADS lexicon), as assessed in the standard clinical exam. STATISTICAL TESTS: Intra-class correlation coefficient (ICC) for interobserver agreement. RESULTS: The ICC was 0.77 for lesion visibility and 0.84 for the artifact score. Overall, mass lesions had a mean score of 1.27 on lesion visibility and 1.53 on the artifact score. Nonmass lesions had a mean score of 2.11 on lesion visibility and 2.11 on the artifact score. DATA CONCLUSION: We have demonstrated the technical feasibility of bilateral whole-breast perfusion imaging using VS-ASL in breast cancer patients. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Magnetic Resonance Thrombus Imaging to Differentiate Acute from Chronic Portal Vein Thrombosis.

Introduction Timely diagnosis and treatment of portal vein thrombosis (PVT) is crucial to prevent morbidity and mortality. However, current imaging tests cannot always accurately differentiate acute from chronic (nonocclusive) PVT. Magnetic resonance noncontrast thrombus imaging (MR-NCTI) has been shown to accurately differentiate acute from chronic venous thrombosis at other locations and may also be of value in the diagnostic management of PVT. This study describes the first phase of the Rhea study (NTR 7061). Our aim was to select and optimize MR-NCTI sequences that would be accurate for differentiation of acute from chronic PVT. Study Design The literature was searched for different MRI sequences for portal vein and acute thrombosis imaging. The most promising sequences were tested in a healthy volunteer followed by one patient with acute PVT and two patients with chronic PVT, all diagnosed on (repetitive) contrast-enhanced computed tomography (CT) venography to optimize the MR-NCTI sequences. All images were evaluated by an expert panel. Results Several MR-NCTI sequences were identified and tested. Differentiation of acute from chronic PVT was achieved with 3D T1 TFE (three-dimensional T1 turbo field echo) and 3D T1 Dixon FFE (three-dimensional T1 fast field echo) sequences with best image quality. The expert panel was able to confirm the diagnosis of acute PVT on the combined two MR-NCTI sequences and to exclude acute PVT in the two patients with chronic PVT. Conclusion Using 3D T1 TFE and 3D T1 Dixon FFE sequences, we were able to distinguish acute from chronic PVT. This clinical relevant finding will be elucidated in clinical studies to establish their test performance.

Long-term Evaluation of Allogeneic Bone Marrow-derived Mesenchymal Stromal Cell Therapy for Crohn's Disease Perianal Fistulas.

BACKGROUND AND AIMS: The long-term safety and efficacy of allogeneic bone marrow-derived mesenchymal stromal cell [bmMSC] therapy in perianal Crohn's disease [CD] fistulas is unknown. We aimed to provide a 4-year clinical evaluation of allogeneic bmMSC treatment of perianal CD fistulas. METHODS: A double-blind dose-finding study for local bmMSC therapy in 21 patients with refractory perianal fistulising Crohn's disease was performed at the Leiden University Medical Center in 2012-2014. All patients treated with bmMSCs [1 x 107 bmMSCs cohort 1, n = 5; 3 × 107 bmMSCs cohort 2, n = 5; 9 × 107 bmMSCs cohort 3, n = 5] were invited for a 4-year evaluation. Clinical events were registered, fistula closure was evaluated, and anti-human leukocyte antigen [HLA] antibodies were assessed. Patients were also asked to undergo a pelvic magnetic resonance imaging [MRI] and rectoscopy. RESULTS: Thirteen out of 15 patients [87%] treated with bmMSCs were available for long-term follow-up. Two non-MSC related malignancies were observed. No serious adverse events thought to be related to bmMSC therapy were found. In cohort 2 [n = 4], all fistulas were closed 4 years after bmMSC therapy. In cohort 1 [n = 4] 63%, and in cohort 3 [n = 5] 43%, of the fistulas were closed, respectively. In none of the patients anti-HLA antibodies could be detected 24 weeks and 4 years after therapy. Pelvic MRI showed significantly smaller fistula tracts after 4 years. CONCLUSIONS: Allogeneic bmMSC therapy for CD-associated perianal fistulas is also in the long-term a safe therapy. In bmMSC-treated patients, fistulas with closure at Week 24 were still closed after 4 years.

Dilemmas in the management of screen-detected lesions in patients at high risk for pancreatic cancer.

In 3-5 % of all cases of pancreatic ductal adenocarcinoma (PDAC), hereditary factors influence etiology. While surveillance of high-risk individuals may improve the prognosis, this study describes two very different outcomes in patients with screen-detected lesions. In 2000, a surveillance program of carriers of a CDKN2A/p16-Leiden-mutation consisting of annual MRI was initiated. Patients with a suspected pancreatic lesion undergo CT-scan and Endoscopic Ultrasound, and surgery is offered when a lesion is confirmed. In 2015, two patients with a screen-detected solid lesion were identified. In both patients, lesions were visible on MRI and CT scan, while the EUS was unremarkable. Surgical resection of the head of the pancreas resulted in nearly fatal complications in the first patient. This patient was shown to have a benign lesion. In contrast, timely identification of an early cancer in the second patient was accompanied by an uneventful postoperative course. These cases underline the risks inherent to a PDAC prevention program. All patients should be fully informed about the possible outcomes before joining a surveillance program.

Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients With Crohn's Disease.

BACKGROUND & AIMS: Patients with perianal fistulizing Crohn's disease have a poor prognosis because these lesions do not heal well. We evaluated the effects of local administration of bone marrow-derived mesenchymal stromal cells (MSCs) to these patients from healthy donors in a double-blind, placebo-controlled study. METHODS: Twenty-one patients with refractory perianal fistulizing Crohn's disease were randomly assigned to groups given injections of 1 × 10(7) (n = 5, group 1), 3 × 10(7) (n = 5, group 2), or 9 × 10(7) (n = 5, group 3) MSCs, or placebo (solution with no cells, n = 6), into the wall of curettaged fistula, around the trimmed and closed internal opening. The primary outcome, fistula healing, was determined by physical examination 6, 12, and 24 weeks later; healing was defined as absence of discharge and <2 cm of fluid collection-the latter determined by magnetic resonance imaging at week 12. All procedures were performed at Leiden University Medical Center, The Netherlands, from June 2012 through July 2014. RESULTS: No adverse events were associated with local injection of any dose of MSCs. Healing at week 6 was observed in 3 patients in group 1 (60.0%), 4 patients in group 2 (80.0%), and 1 patient in group 3 (20.0%), vs 1 patient in the placebo group (16.7%) (P = .08 for group 2 vs placebo). At week 12, healing was observed in 2 patients in group 1 (40.0%), 4 patients in group 2 (80.0%), and 1 patient in group 3 (20.0%), vs 2 patients in the placebo group (33.3%); these effects were maintained until week 24 and even increased to 4 (80.0%) in group 1. At week six, 4 of 9 individual fistulas had healed in group 1 (44.4%), 6 of 7 had healed in group 2 (85.7%), and 2 of 7 had healed in group 3 (28.6%) vs 2 of 9 (22.2%) in the placebo group (P = .04 for group 2 vs placebo). At week twelve, 3 of 9 individual fistulas had healed in group 1 (33.3%), 6 of 7 had healed in group 2 (85.7%), 2 of 7 had healed in group 3 (28.6%), and 3 of 9 had healed in the placebo group (33.3%). These effects were stable through week 24 and even increased to 6 of 9 (66.7%) in group 1 (P = .06 group 2 vs placebo, weeks 12 and 24). CONCLUSIONS: Local administration of allogeneic MSCs was not associated with severe adverse events in patients with perianal fistulizing Crohn's disease. Injection of 3 × 10(7) MSCs appeared to promote healing of perianal fistulas. ClinicalTrials.gov ID NCT01144962.

Value of Magnetic Resonance Cholangiopancreatography in Assessment of Nonanastomotic Biliary Strictures After Liver Transplantation.

UNLABELLED: Nonanastomotic biliary strictures (NAS) remain a frequent complication after orthotopic liver transplantation (OLT). The aim of this study was to evaluate whether magnetic resonance cholangiopancreatography (MRCP) could be used to detect NAS and to grade the severity of biliary strictures. METHODS: In total, 58 patients after OLT from 2 Dutch transplantation centers in whom endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography and MRCP were performed within less than 6 months apart were included in the study. Of these patients, 41 had NAS and 17 were without NAS based on endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography and follow-up. Four radiologists-2 from each center-used an adapted validated classification-termed "Leiden Biliary Stricture Classification" "(LBSC)-to evaluate the MRCP examinations independently. In this classification, NAS severity is assessed in 4 hepatobiliary regions. Interobserver agreement of the severity score for each region was calculated with the κ statistics. RESULTS: Optimal cutoff value of the LBSC to detect the presence of NAS with MRCP was calculated at 3 points or greater for all readers. Applying this cutoff sensitivity for each reader was greater than 90%, with a specificity of 50% to 82%, positive predictive value of 86% to 91%, and negative predictive value of 80% to 100%. The MRCP performance was better in evaluation of the intrahepatic than of the extrahepatic bile ducts. The additional value of MRCP for grading severity of NAS was limited. CONCLUSIONS: The MRCP with the LBSC is a reliable tool to detect or exclude NAS after OLT. Currently, MRCP cannot be used to reliably grade the severity of these strictures.

Optical mammography using diffuse optical spectroscopy for monitoring tumor response to neoadjuvant chemotherapy in women with locally advanced breast cancer.

PURPOSE: Diffuse optical spectroscopy (DOS) has the potential to enable monitoring of tumor response during chemotherapy, particularly in the early stages of treatment. This study aims to assess feasibility of DOS for monitoring treatment response in HER2-negative breast cancer patients receiving neoadjuvant chemotherapy (NAC) and compare DOS with tumor response assessment by MRI. EXPERIMENTAL DESIGN: Patients received NAC in six cycles of 3 weeks. In addition to standard treatment monitoring by dynamic contrast enhanced MRI (DCE-MRI), DOS scans were acquired after the first, third, and last cycle of chemotherapy. The primary goal was to assess feasibility of DOS for early assessment of tumor response. The predictive value of DOS and DCE-MRI compared with pathologic response was assessed. RESULTS: Of the 22 patients, 18 patients had a partial or complete tumor response at pathologic examination, whereas 4 patients were nonresponders. As early as after the first chemotherapy cycle, a significant difference between responders and nonresponders was found using DOS (HbO2 86% ± 25 vs. 136% ± 25, P = 0.023). The differences between responders and nonresponders continued during treatment (halfway treatment, HbO2 68% ± 22 vs. 110% ± 10, P = 0.010). Using DCE-MRI, a difference between responders and nonresponders was found halfway treatment (P = 0.005) using tumor volume measurement calculations. CONCLUSIONS: DOS allows for tumor response assessment and is able to differentiate between responders and nonresponders after the first chemotherapy cycle and halfway treatment. In this study, DOS was equally effective in predicting tumor response halfway treatment compared with DCE-MRI. Therefore, DOS may be used as a novel imaging modality for (early) treatment monitoring of NAC.

Variation in precursor lesions of pancreatic cancer among high-risk groups.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are currently offered to high-risk individuals aiming to detect precursor lesions or PDAC at an early stage. We assessed differences in frequency and behavior of precursor lesions and PDAC between two high-risk groups. EXPERIMENTAL DESIGN: Individuals with a p16-Leiden germline mutation (N = 116; median age 54 years) and individuals from familial pancreatic cancer (FPC) families (N = 125; median age 47 years) were offered annual surveillance by MRI and magnetic resonance cholangiopancreatography (MRCP) with or without endoscopic ultrasound (EUS) for a median surveillance period of 34 months (0-127 months) or 36 months (0-110 months), respectively. Detailed information was collected on pancreatic cystic lesions detected on MRCP and precursor lesions in surgical specimens of patients who underwent pancreatic surgery. RESULTS: Cystic lesions were more common in the FPC cohort (42% vs. 16% in p16-Leiden cohort), whereas PDAC was more common in the p16-Leiden cohort (7% vs. 0.8% in FPC cohort). Intraductal papillary mucinous neoplasm (IPMN) was a common finding in surgical specimens of FPC-individuals, and was only found in two patients of the p16-Leiden cohort. In the p16-Leiden cohort, a substantial proportion of cystic lesions showed growth or malignant transformation during follow-up, whereas in FPC individuals most cystic lesions remain stable. CONCLUSION: In p16-Leiden mutation carriers, cystic lesions have a higher malignant potential than in FPC-individuals. On the basis of these findings, a more intensive surveillance program may be considered in this high-risk group.

Reliability and differentiation of pelvic floor muscle electromyography measurements in healthy volunteers using a new device: the Multiple Array Probe Leiden (MAPLe).

AIMS: A new multiple electrode probe, the Multiple Array Probe Leiden (MAPLe), has been developed for biofeedback registration of the individual pelvic floor musculature (PFM). The aim was to determine the reliability and differentiation of electromyography (EMG) signals measured with the MAPLe in healthy volunteers. METHODS: Two hundred twenty nine healthy volunteers not seeking treatment or using medication for symptoms of prolapse, lower urinary tract, bowel, pain, and/or sexual function related to pelvic floor dysfunction were qualified to participate. Subjects were asked to perform five tasks: rest, maximum voluntary contractions, endurance, cough, and valsalva. Mean EMG values per electrode were registered. Test-retest reliability was assessed using linear mixed model with random subject effects. One-way ANOVA tests were performed to detect differences between groups. RESULTS: Magnetic resonance imaging (MRI) showed that each of the electrodes could be related nearest to the individual muscles. For test-retest, the intraclass correlation ranged from 0.53 to 0.91. The MAPLe showed significant differences in average EMG values between men and women, and between nulliparous and parous, pre- and prostmenpausal women. Significant differences were seen between the left and right sides of the pelvic floor. In addition, the activity nearest to the individual pelvic floor muscles (external anal sphincter (EAS), puborectalis muscle, bulbospongiosus, ischiocavernosus and the pubococcygeus muscle) could be determined. CONCLUSIONS: The MAPLe is a reliable instrument measuring the EMG signals of the different sides and levels nearest to the pelvic floor musculature and is capable to differentiate between men and women, nulliparous, parous, pre- and postmenopausal. The findings of this study have implications for the diagnosis and treatment of pelvic floor dysfunction in the future.

Doxycycline for stabilization of abdominal aortic aneurysms: a randomized trial.

BACKGROUND: Doxycycline inhibits formation and progression of abdominal aortic aneurysms (AAAs) in preclinical models of the disease, but it is unclear whether and how this observation translates to humans. OBJECTIVE: To test whether doxycycline inhibits AAA progression in humans. DESIGN: Randomized, placebo-controlled, double-blind trial. (Dutch Trial Registry: NTR 1345) SETTING: 14 Dutch hospitals. PATIENTS: 286 patients with small AAAs between October 2008 and June 2011. INTERVENTION: Daily dose of 100 mg of doxycycline (n = 144) or placebo (n = 142) for 18 months. MEASUREMENTS: The primary outcome measure was aneurysm growth at 18 months, as estimated by repeated single-observer ultrasonography. Secondary outcomes included growth at 6 and 12 months and the need for elective surgery. RESULTS: Mean aneurysm diameter (approximately 43 mm) and other baseline characteristics were similar in both groups. Doxycycline treatment was associated with increased aneurysm growth (4.1 mm in the doxycycline group vs. 3.3 mm in the placebo group at 18 months; difference, 0.8 mm [95% CI, 0.1 to 1.4 mm]; P = 0.016 mm). Twenty-one patients receiving doxycycline and 22 patients receiving placebo had elective surgical repair (Kaplan­Meier estimates were 16.1% for those receiving doxycycline and 16.5% for those receiving placebo; difference, -0.4% [CI, -9.3% to 8.5%]; P = 0.83). Time to repair was similar in the groups (P = 0.92). LIMITATIONS: This study focuses on patients with small AAAs. As such, whether the data can be extrapolated to larger AAAs (>55 mm) is unclear. The high number of elective repairs (n = 43) was unanticipated. Moreover, the study did not follow patients who withdrew because of an adverse effect. CONCLUSION: This trial found that 18 months of doxycycline therapy did not reduce aneurysm growth and did not influence the need for AAA repair or time to repair. PRIMARY FUNDING SOURCE: The Netherlands Organisation for Health Research and Development, and the NutsOhra Fund.

Differences in natural history between breast cancers in BRCA1 and BRCA2 mutation carriers and effects of MRI screening-MRISC, MARIBS, and Canadian studies combined.

BACKGROUND: It is recommended that BRCA1/2 mutation carriers undergo breast cancer screening using MRI because of their very high cancer risk and the high sensitivity of MRI in detecting invasive cancers. Clinical observations suggest important differences in the natural history between breast cancers due to mutations in BRCA1 and BRCA2, potentially requiring different screening guidelines. METHODS: Three studies of mutation carriers using annual MRI and mammography were analyzed. Separate natural history models for BRCA1 and BRCA2 were calibrated to the results of these studies and used to predict the impact of various screening protocols on detection characteristics and mortality. RESULTS: BRCA1/2 mutation carriers (N = 1,275) participated in the studies and 124 cancers (99 invasive) were diagnosed. Cancers detected in BRCA2 mutation carriers were smaller [80% ductal carcinoma in situ (DCIS) or ≤10 mm vs. 49% for BRCA1, P < 0.001]. Below the age of 40, one (invasive) cancer of the 25 screen-detected cancers in BRCA1 mutation carriers was detected by mammography alone, compared with seven (three invasive) of 11 screen-detected cancers in BRCA2 (P < 0.0001). In the model, the preclinical period during which cancer is screen-detectable was 1 to 4 years for BRCA1 and 2 to 7 years for BRCA2. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening. CONCLUSIONS: Our studies suggest substantial mortality benefits in using MRI to screen BRCA1/2 mutation carriers aged 25 to 60 years but show important clinical differences in natural history. IMPACT: BRCA1 and BRCA2 mutation carriers may benefit from different screening protocols, for example, below the age of 40.

BRCA1-associated breast cancers present differently from BRCA2-associated and familial cases: long-term follow-up of the Dutch MRISC Screening Study.

PURPOSE: The Dutch MRI Screening Study on early detection of hereditary breast cancer started in 1999. We evaluated the long-term results including separate analyses of BRCA1 and BRCA2 mutation carriers and first results on survival. PATIENTS AND METHODS: Women with higher than 15% cumulative lifetime risk (CLTR) of breast cancer were screened with biannual clinical breast examination and annual mammography and magnetic resonance imaging (MRI). Participants were divided into subgroups: carriers of a gene mutation (50% to 85% CLTR) and two familial groups with high (30% to 50% CLTR) or moderate risk (15% to 30% CLTR). RESULTS: Our update contains 2,157 eligible women including 599 mutation carriers (median follow-up of 4.9 years from entry) with 97 primary breast cancers detected (median follow-up of 5.0 years from diagnosis). MRI sensitivity was superior to that of mammography for invasive cancer (77.4% v 35.5%; P<.00005), but not for ductal carcinoma in situ. Results in the BRCA1 group were worse compared to the BRCA2, the high-, and the moderate-risk groups, respectively, for mammography sensitivity (25.0% v 61.5%, 45.5%, 46.7%), tumor size at diagnosis≤1 cm (21.4% v 61.5%, 40.9%, 63.6%), proportion of DCIS (6.5% v 18.8%, 14.8%, 31.3%) and interval cancers (32.3% v 6.3%, 3.7%, 6.3%), and age at diagnosis younger than 30 years (9.7% v 0%). Cumulative distant metastasis-free and overall survival at 6 years in all 42 BRCA1/2 mutation carriers with invasive breast cancer were 83.9% (95% CI, 64.1% to 93.3%) and 92.7% (95% CI, 79.0% to 97.6%), respectively, and 100% in the familial groups (n=43). CONCLUSION: Screening results were somewhat worse in BRCA1 mutation carriers, but 6-year survival was high in all risk groups.

Assessment of false-negative cases of breast MR imaging in women with a familial or genetic predisposition.

In order to assess the characteristics of malignant breast lesions those were not detected during screening by MR imaging. In the Dutch MRI screening study(MRISC), a non-randomized prospective multicenter study,women with high familial risk or a genetic predisposition for breast cancer were screened once a year by mammography and MRI and every 6 months with a clinical breast examination (CBE). The false-negative MR examinations were subject of this study and were retrospectively reviewed by two experienced radiologists. From November 1999 until March 2006, 2,157 women were eligible for study analyses. Ninety-seven malignant breast tumors were detected, including 19 DCIS (20%). In 22 patients with a malignant lesion, the MRI was assessed as BI-RADS 1 or 2. One patient was excluded because the examinations were not available for review. Forty-three percent (9/21) of the false-negative MR cases concerned pure ductal carcinoma in situ (DCIS) or DCIS with invasive foci, in eight of them no enhancement was seen at the review. In six patients the features of malignancy were missed or misinterpreted.Small lesion size (n = 3), extensive diffuse contrast enhancement of the breast parenchyma (n = 2),and a technically inadequate examination (n = 1) were other causes of the missed diagnosis. A major part of the false-negative MR diagnoses concerned non-enhancing DCIS, underlining the necessity of screening not only with MRI but also with mammography. Improvement of MRI scanning protocols may increase the detection rate of DCIS. The missed and misinterpreted cases are reflecting the learning curve of a multicenter study.

Pelvic floor muscle lesions at endoanal MR imaging in female patients with faecal incontinence.

To evaluate the frequency and spectrum of lesions of different pelvic floor muscles at endoanal MRI in women with severe faecal incontinence and to study their relation with incontinence severity and manometric findings. In 105 women MRI examinations were evaluated for internal anal sphincter (IAS), external anal sphincter (EAS), puborectal muscle (PM) and levator ani (LA) lesions. The relative contribution of lesions to differences in incontinence severity and manometric findings was studied. IAS (n = 59) and EAS (n = 61) defects were more common than PM (n = 23) and LA (n = 26) defects. PM and LA defects presented mainly with IAS and/or EAS defects (isolated n = 2 and n = 3). EAS atrophy (n = 73) was more common than IAS (n = 19), PM (n = 16) and LA (n = 9) atrophy and presented mainly isolated. PM and LA atrophy presented primarily with EAS atrophy (isolated n = 3 and n = 1). Patients with IAS and EAS lesions had a lower resting and squeeze pressure, respectively; no other associations were found. PM and LA lesions are relatively common in patients with severe faecal incontinence, but the majority of lesions are found in women who also have IAS and/or EAS lesions. Only an association between anal sphincter lesions and manometry was observed.