Please cite this paper as: Lynch A, Murphy J, Gibbs R, Levine R, Giclas P, Salmon J, Holers V. The interrelationship of complement‐activation fragments and angiogenesis‐related factors in early ...pregnancy and their association with pre‐eclampsia. BJOG 2010; 117:456–462.
Objective To determine the interrelationships during early pregnancy of complement‐activation fragments Bb, C3a and sC5b‐9, and angiogenesis‐related factors placental growth factor (PiGF), soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and soluble endoglin (sEng), and their associations with pre‐eclampsia.
Design Prospective cohort study.
Setting Denver complement study (June 2005–June 2008).
Population A total of 668 pregnant women with singleton gestations, recruited between 10 and 15 weeks of gestation.
Methods Using univariable and multivariable logistic regression analysis, concentrations of complement‐activation fragments and angiogenesis‐related factors were compared between 10 and 15 weeks of gestation in women who subsequently did or did not develop pre‐eclampsia. Interrelationships between these variables were tested using the non‐parametric Spearman rank correlation coefficient.
Main outcome measure Pre‐eclampsia. The association of complement‐activation fragments and angiogenesis‐related factors with obesity was also examined.
Results The mean (±SD) levels of complement Bb in early pregnancy among women who did and did not develop pre‐eclampsia were 0.84 (±0.26) μg/ml and 0.69 (±0.2) μg/ml, respectively (P = 0.001). Concentrations of PiGF were significantly (P = 0.01) lower (31 ± 12 pg/ml) in early pregnancy in the pre‐eclamptic group of women, as compared with the normotensive group (39 ± 32 pg/ml). The adjusted odds ratio (AOR) of Bb and PiGF were 2.1 (CI = 1.4–3.1, P < 0.0003) and 0.2 (CI = 0.07–0.7, P = 0.01), respectively. There was no significant difference in the levels of C3a, sC5b‐9, sFlt‐1 and sEng in early pregnancy among women who developed pre‐eclampsia, compared with women who remained normotensive during pregnancy. Higher levels of Bb (P = 0.0001) and C3a (P = 0.03), and lower levels of sFlt‐1 (P = 0.0002) and sEng (P = 0.0001) were found among women with obesity, compared with non‐obese controls. No meaningful relationships were found between the complement‐activation fragments and the angiogenesis‐related factors.
Conclusions In this cohort during early pregnancy, increased concentrations of complement‐activation factor Bb and lower concentrations of PiGF were associated with the development of pre‐eclampsia later in pregnancy.
Aneurysmal bone cyst is a benign, locally destructive lesion of bone. The rates of local recurrence after curettage have varied widely. Therefore, we performed a retrospective study of patients who ...had had an aneurysmal bone cyst in order to identify the rate of local recurrence and the prognostic factors related to local recurrence after use of contemporary methods of curettage with a high-speed burr.
We reviewed the cases of forty patients who had been managed by the same surgeon for an aneurysmal bone cyst, as diagnosed on the basis of the latest pathological review, between January 1, 1976, and December 31, 1993. The patients were evaluated with regard to age, gender, the duration and type of symptoms, the presence or absence of pathological fracture, the status of the growth plate, the bone and part of the bone that were involved, the type of operative procedure, the outcome, the radiographic stage, the findings on magnetic resonance imaging and computerized tomography (when it became available) and on bone scintigraphy, and histological parameters. The median duration of follow-up was eighty-seven months (range, fifteen to 267 months). According to the criteria of Enneking, no patient had a stage-1 lesion (one with a surrounding rim of cortical bone), twenty-four had a stage-2 lesion (one with a clearly defined border but no cortical bone), and sixteen had a stage-3 lesion (one with no clearly defined border).
Of the forty patients, thirty-four had curettage with use of a high-speed burr. Of these thirty-four, twenty-two had filling of the defect with a cancellous autogenous graft; four, with a cancellous allograft; and three, with polymethylmethacrylate. In five patients, no material was put into the defect. The remaining six patients had resection through the margin of the lesion. Four (12 percent) of the thirty-four patients who had curettage had a local recurrence. No patient who had an excision through the margin of the lesion had a local recurrence. All local recurrences were in skeletally immature girls who were three, four, ten, and eleven years old. Univariate analysis with use of the chi-square, Fisher exact, and Wilcoxon log-rank tests showed that local recurrence was associated only with a young age (p = 0.0036) and open growth plates (p = 0.039). All local recurrences occurred within two years postoperatively, at two, seven, nine, and twenty-four months, and all were treated successfully with a second operation.
Rates of local control of almost 90 percent can be achieved with thorough curettage with use of a mechanical burr and without use of liquid nitrogen, phenol, or other adjuvants in patients who have an aneurysmal bone cyst of an extremity. A young age and open growth plates are associated with an increased risk of local recurrence.
Giant basal cell carcinoma (BCC) of the chest wall is rare and poses challenges related to resection and reconstruction. A 69-year old man presented with giant BCC invading sternum. Wide resection ...and reconstruction with polymethylmethacrylate and mesh was performed. The soft tissue defect was covered with a pedicled omental flap and skin graft. He developed an infection requiring removal of the mesh construct; however, debridement and antibiotics cleared the infection. This case illustrates the locally aggressive nature of this disease and the need for tertiary-level care.
The ability to analyze multiple single-cell parameters is critical for understanding cellular heterogeneity. Despite recent advances in measurement technology, methods for analyzing high-dimensional ...single-cell data are often subjective, labor intensive and require prior knowledge of the biological system. To objectively uncover cellular heterogeneity from single-cell measurements, we present a versatile computational approach, spanning-tree progression analysis of density-normalized events (SPADE). We applied SPADE to flow cytometry data of mouse bone marrow and to mass cytometry data of human bone marrow. In both cases, SPADE organized cells in a hierarchy of related phenotypes that partially recapitulated well-described patterns of hematopoiesis. We demonstrate that SPADE is robust to measurement noise and to the choice of cellular markers. SPADE facilitates the analysis of cellular heterogeneity, the identification of cell types and comparison of functional markers in response to perturbations.
Follow-up of intracranial aneurysms in autosomal-dominant polycystic kidney disease.
Approximately 8% of autosomal-dominant polycystic kidney disease (ADPKD) patients have intracranial aneurysms. The ...risk of growth and rupture of those discovered by presymptomatic screening is key to the feasibility and success of a screening program. This study was initiated to ascertain this risk.
ADPKD patients were offered screening with magnetic resonance (MR) imaging that included three-dimensional time-of-flight MR angiographic and three-dimensional phase-contrast sequences. Patients with aneurysms were recommended periodic surveillance, initially at 6months and yearly, and less frequently after demonstration of their stability.
Twenty-two saccular and one fusiform aneurysms were detected at the initial screening in 21 patients from 19 families (seven men and 14 women, 47.9 ± 10.6years old). All the saccular aneurysms were small (mean diameter 3.5mm, range 2.0 to 6.5mm) and the majority (77%) in the anterior circulation. Two patients died from unrelated causes without further follow-up. One patient was lost to follow-up. A new 2mm middle cerebral artery aneurysm developed in one patient. One aneurysm increased from a size of 4mm to 5mm after a follow-up of 105months. No aneurysmal development or growth occurred in the remaining 16 patients. No aneurysmal rupture occurred during a mean imaging follow-up of 81months and a mean clinical follow-up of 92months. During the period of the study, two additional ADPKD patients, with three intracranial aneurysms detected elsewhere by presymptomatic MR angiographic screening, were referred for surgical treatment. The larger size of these aneurysms (10, 8, and 8mm) probably reflects referral bias.
Most intracranial aneurysms detected by presymptomatic screening in ADPKD patients are small and in the anterior circulation. The follow-up results do not suggest an increased risk for growth and rupture, compared to those of intracranial aneurysms in the general population. These data do not support widespread screening for intracranial aneurysms in the ADPKD population.
Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as ...compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown.
In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival.
At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval CI, 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group.
Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).
Abstract Several genes and risk factors are associated with Parkinson’s disease (PD). Although many of the genetic markers belong to a common pathway, a unifying pathogenetic mechanism is yet to be ...found. Also, missing heritability analyses have estimated that only part of the genetic influence contributing to PD has been found. Here, we carried out whole-exome sequencing (WES) on 438 Finnish patients with early-onset PD. We also re-analyzed previous data from genome-wide association studies (GWAS) on the same cohort. Variants in the CEL gene/locus were associated with PD in both GWAS and WES analysis. Exome-wide gene-based association tests also identified the MPHOSPH10, TAS2R19 and SERPINA1 genes in the discovery dataset (p<2.5E-6). MPHOSPH10 had estimated odds ratio (OR) of 1.53 and the rs141620200 variant in SERPINA1 had OR of 1.27. We identified several candidate genes, but further investigation is required in order to determine the role of these genes in PD.
Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a ...marker of therapeutic efficacy.
This prospective study involved 53 mCRC patients receiving standard first-line chemotherapy. Both ctDNA and CEA were assessed in plasma collected before treatment, 3 days after treatment and before cycle 2. Computed tomography (CT) scans were carried out at baseline and 8–10 weeks and were centrally assessed using RECIST v1.1 criteria. Tumors were sequenced using a panel of 15 genes frequently mutated in mCRC to identify candidate mutations for ctDNA analysis. For each patient, one tumor mutation was selected to assess the presence and the level of ctDNA in plasma samples using a digital genomic assay termed Safe-SeqS.
Candidate mutations for ctDNA analysis were identified in 52 (98.1%) of the tumors. These patient-specific candidate tissue mutations were detectable in the cell-free DNA from the plasma of 48 of these 52 patients (concordance 92.3%). Significant reductions in ctDNA (median 5.7-fold; P < 0.001) levels were observed before cycle 2, which correlated with CT responses at 8–10 weeks (odds ratio = 5.25 with a 10-fold ctDNA reduction; P = 0.016). Major reductions (≥10-fold) versus lesser reductions in ctDNA precycle 2 were associated with a trend for increased progression-free survival (median 14.7 versus 8.1 months; HR = 1.87; P = 0.266).
ctDNA is detectable in a high proportion of treatment naïve mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response.
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