Citations

Abstract The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. We developed cMethDNA, a quantitative multiplexed methylation-specific PCR assay for a panel of ten genes, consisting of novel and known breast cancer hypermethylated markers identified by mining our previously reported study of DNA methylation patterns in breast tissue (103 cancer, 21 normal on the Illumina HumanMethylation27 Beadchip) and then validating the 10-gene panel in The Cancer Genome Atlas project breast cancer methylome database. For cMethDNA, a fixed physiologic level (50 copies) of artificially constructed, standard nonhuman reference DNA specific for each gene is introduced in a constant volume of serum (300 μL) before purification of the DNA, facilitating a sensitive, specific, robust, and quantitative assay of tumor DNA, with broad dynamic range. Cancer-specific methylated DNA was detected in training (28 normal, 24 cancer) and test (27 normal, 33 cancer) sets of recurrent stage IV patient sera with a sensitivity of 91% and a specificity of 96% in the test set. In a pilot study, cMethDNA assay faithfully reflected patient response to chemotherapy (N = 29). A core methylation signature present in the primary breast cancer was retained in serum and metastatic tissues collected at autopsy two to 11 years after diagnosis of the disease. Together, our data suggest that the cMethDNA assay can detect advanced breast cancer, and monitor tumor burden and treatment response in women with metastatic breast cancer. Cancer Res; 74(8); 2160–70. ©2014 AACR.

Abstract Rationale Provider decisions about patients to be discharged from the intensive care unit (ICU) are often based on subjective intuition, sometimes leading to premature discharge and early readmission. The Stability and Work Load Index for Transfer (SWIFT) score, as a risk stratification tool, has moderate ability to predict patients at risk of ICU readmission. Objectives To describe findings following the incorporation of the SWIFT score into the discharge workflow of a medical ICU. Methods The study involved 5,293 consecutive patients discharged alive from the medical ICU of an academic medical center. The SWIFT score and associated percentage risk for readmission were incorporated into daily rounds for purpose of discharge decision-making. We measured readmission rates before and after implementation and observed changes in provider discharge decisions for individual patients after SWIFT discussions. Measurements and Main Results Baseline (n = 1,906) and implementation (n = 1,938) cohorts differed with respect to APACHE III scores (P = 0.03). In the implementation cohort, 26.2% of subjects had SWIFT scores greater than 15 and thus were predicted to have a higher risk of unplanned readmissions. In this high-risk group, 25% had SWIFT discussed in their discharge planning. There was modification of provider discharge decisions in 108 (30%) of cases in which the SWIFT was discussed. SWIFT score values above a prespecified cutoff of 15 were associated with physician tendency to prolong ICU stay or to discharge to a monitored setting (P < 0.001). There was no difference in 24-hour or 7-day readmission rates between the baseline and implementation cohorts (1.9 vs. 2.4%, P = 0.24; 6.5 vs. 7.4%, P = 0.26, respectively) even after adjustment for severity of illness. Conclusions Using the SWIFT score as an adjunct to clinical judgment, physicians modified their discharge decisions in one-third of subjects. Introducing such tools into the discharge workflow may present change management challenges that limit the evaluation of their impact on readmission rates and other relevant ICU outcomes.

ABSTRACTBACKGROUND AND PURPOSEHypertrophic olivary degeneration (HOD) is an uncommon type of transneuronal degeneration. Case reports and case series described in the literature provide a foundation of our current knowledge of HOD. These reports have described HOD most frequently to be unilateral and occurring in association with lesions in the dentato‐rubro‐olivary pathway. Our purpose was to evaluate the rate of bilateral versus unilateral HOD in a large case series.METHODSA retrospective review was performed to identify patients in which the phrase “hypertrophic olivary degeneration” occurred in the radiology report. A diagnosis of HOD was confirmed on imaging if there was focal hyperintensity on T2‐weighted images confined to either or both inferior olivary nuclei.RESULTSA total of 102 patients had findings consistent with HOD. Of these, 76% had findings bilaterally. In 44%, a lesion could not be identified to explain HOD. Bilateral HOD was common in both lesional and nonlesional group, though more common in the nonlesional group.CONCLUSIONThis study demonstrates that HOD is frequently bilateral. In slightly over 50% of patients with HOD, a lesion can be identified. In just under 50% patients with HOD, a lesion could not be identified and in these cases HOD was present bilaterally in the majority.

Background The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories. Methods The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference. Results Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9–100%), and the mean specificity was 98.0% (87.5–100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories. Conclusions Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.

Severely comminuted fractures of the metatarsal bones with significant bone and soft-tissue loss have commonly subjected patients to proximal amputation procedures. We describe two patients who experienced high-energy traumatic injuries to their limbs that resulted in significant destruction of their first and second metatarsal bones with overlying soft-tissue trauma not amenable to local coverage. In both cases, a vascularized free fibular osteocutaneous flap was used to reconstruct the metatarsal bone defect and traumatized soft tissues so that a proximal amputation was avoided. At an average of 14 months of follow-up, both patients had recovered well and regained independent ambulation, with one patient being able to play soccer. We show that the free fibular osteoseptocutaneous flap is useful in reconstructing significant metatarsal bone defects and in avoiding amputations in this patient population. The skin component of the flap may be used to fill soft-tissue losses, and the fibula bone may be osteotomized so that more than one ray may be reconstructed. (J Am Podiatr Med Assoc 101(6): 531–536, 2011)

Objectives The goal of this study was to determine whether intra-articular administration of the potentially anti-fibrotic agent decorin influences the expression of genes involved in the fibrotic cascade, and ultimately leads to less contracture, in an animal model. Methods A total of 18 rabbits underwent an operation on their right knees to form contractures. Six limbs in group 1 received four intra-articular injections of decorin; six limbs in group 2 received four intra-articular injections of bovine serum albumin (BSA) over eight days; six limbs in group 3 received no injections. The contracted limbs of rabbits in group 1 were biomechanically and genetically compared with the contracted limbs of rabbits in groups 2 and 3, with the use of a calibrated joint measuring device and custom microarray, respectively. Results There was no statistical difference in the flexion contracture angles between those limbs that received intra-articular decorin versus those that received intra-articular BSA (66° vs 69°; p = 0.41). Likewise, there was no statistical difference between those limbs that received intra-articular decorin versus those who had no injection (66° vs 72°; p = 0.27). When compared with BSA, decorin led to a statistically significant increase in the mRNA expression of 12 genes (p < 0.01). In addition, there was a statistical change in the mRNA expression of three genes, when compared with those without injection. Conclusions In this model, when administered intra-articularly at eight weeks, 2 mg of decorin had no significant effect on joint contractures. However, our genetic analysis revealed a significant alteration in several fibrotic genes. Cite this article: Bone Joint Res 2014;3:82–8.

BACKGROUNDThe authors examined the “real‐world” effectiveness of rituximab (R) maintenance therapy (R‐maintenance) compared with observation after R‐based induction therapy in patients with previously untreated follicular lymphoma (FL) in the United States.METHODSThe National LymphoCare Study is a prospective, multicenter, observational study that enrolled > 2700 untreated patients with FL diagnosed from 2004 to 2007 at 265 sites in the United States. Among these, patients who achieved at least stable disease after R‐based induction therapy were eligible for the current analysis. Patients who initiated R‐maintenance within 215 days of completing induction therapy were categorized as the R‐maintenance group, and those who did not initiate therapy during this period were categorized as the observation group. The objective of the current study was to determine the effect of R‐maintenance on progression‐free survival (PFS), time to next treatment (TTNT), and overall survival (OS).RESULTSA total of 1439 patients completed R‐based induction therapy, 1186 of whom met all inclusion criteria (541 patients received R‐maintenance and 645 patients were observed). Characteristics that were found to be predictive of receiving R‐maintenance were histology grade (1/2), Ann Arbor stage of disease (III/IV), geographic region (region other than the West), and practice setting (community practice). With a median follow‐up of 5.7 years, R‐maintenance was associated with superior PFS (hazards ratio [HR], 0.68; 95% confidence interval [95% CI], 0.56‐0.84 [P = .0003]) and TTNT (HR, 0.66; 95% CI, 0.52‐0.84 [P = .0007]). No significant difference in OS was observed (HR, 0.81; 95% CI, 0.58‐1.14 [P = .23]).CONCLUSIONSR‐maintenance in patients with FL and at least stable disease after R‐based induction therapy provided significantly longer PFS and TTNT in comparison with observation, but no significant difference in OS was observed with 5‐years of follow‐up. This comparative effectiveness study aligns with the results of randomized trials suggesting that similar outcomes occur with R‐maintenance in FL with the treatment variations observed in clinical practice. Cancer 2014;120:1830–1837. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.