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.
To ...test whether doxycycline inhibits AAA progression in humans.
Randomized, placebo-controlled, double-blind trial. (Dutch Trial Registry: NTR 1345) SETTING: 14 Dutch hospitals.
286 patients with small AAAs between October 2008 and June 2011.
Daily dose of 100 mg of doxycycline (n = 144) or placebo (n = 142) for 18 months.
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.
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 (Kaplan–Meier 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).
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.
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.
The Netherlands Organisation for Health Research and Development, and the NutsOhra Fund.
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 × 107 (n = 5, group 1), 3 × 107 (n = 5, group 2), or 9 × 107 (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 × 107 MSCs appeared to promote healing of perianal fistulas. ClinicalTrials.gov ID NCT01144962.
Abstract
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.
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.
Considering the scarcity of liver donors and expected waiting time to liver transplantation, there is an unmet need for effective neoadjuvant downsizing strategies. This article reports on the safety and efficacy of neoadjuvant dovitinib in patients with hepatocellular carcinoma eligible for locoregional treatment.
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.
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).
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).
Screening results were somewhat worse in BRCA1 mutation carriers, but 6-year survival was high in all risk groups.
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
.
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.
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.
This long-term surveillance study demonstrates a high incidence of PDAC in carriers of a PV in
. This provides evidence that surveillance in such a high-risk population leads to detection of early-stage PDAC with improved resectability and survival.
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
The purpose of this study was to evaluate the role of contrast-enhanced dynamic MRI in predicting the disease activity of Crohn's disease.
Forty-eight patients in two hospitals who had clinically ...suspected exacerbation of Crohn's disease were included in this study. In three levels of thickened small-bowel wall, axial dynamic T1-weighted sequences were performed every 4-6 sec for a total duration of 2-3 min after contrast administration; static T1-weighted turbo spin-echo sequences were acquired both before and after contrast administration. The slope of enhancement, enhancement ratio, time to enhancement, enhancement time, and thickness of the small-bowel wall were determined. These MRI results were compared with overall clinical grade, Crohn's disease activity index (CDAI), and Van Hees activity index. Clinical grade was based on clinical information, physical findings, laboratory studies, endoscopy, surgery, and other imaging studies. Spearman's correlation coefficient and p values were determined per hospital. Fisher's z-transformation was applied before pooling the correlation coefficients from both hospitals.
The enhancement ratio based on the static series showed significant correlation with the clinical grade (r = 0.29, p = 0.045), CDAI (r =0.31, p = 0.033), and Van Hees activity index (r = 0.36, p = 0.016). The enhancement ratio based on the dynamic series correlated significantly with the CDAI (r = 0.38, p = 0.016). Wall thickness correlated significantly with clinical grade (r = 0.47, p = 0.003) and Van Hees activity index (r = 0.41, p = 0.007).
These data suggest that the enhancement ratio of bowel wall after IV administration of gadodiamide and bowel wall thickness are weak to moderate indicators of the severity of Crohn's disease.
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.
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.
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.
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.
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Patients at high risk of pancreatic cancer who were diagnosed in a screening program had a notably better survival than patients diagnosed in the general population.
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.
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.
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.
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.
BRCA1 and BRCA2 mutation carriers may benefit from different screening protocols, for example, below the age of 40.
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