Citations

Background: Quantitative magnetic resonance (qMR) can be used to measure macromolecules in tissues and is a potential method of observing early cartilage changes in the development of posttraumatic osteoarthritis. Hypothesis/Purpose: We hypothesized that specific patient and surgical factors affecting cartilage matrix composition after anterior cruciate ligament (ACL) reconstruction (ACLR) can be detected using T1ρ and T2 relaxation times. Our purpose was to demonstrate this ability in a multicenter feasibility study. Study Design: Case series; Level of evidence, 4. Methods: A total of 54 patients who underwent ACLR underwent bilateral MRI at baseline before surgery and 6 months postoperatively. Operative findings were recorded. T1ρ and T2 relaxation times were calculated for 6 cartilage regions: the medial femur, lateral femur, medial tibia, lateral tibia, patella, and trochlea. A paired t test compared relaxation times at baseline and 6 months, univariate regression identified regions that influenced patient-reported outcome measures, and analysis of covariance was used to determine the surgical factors that resulted in elevated relaxation times at 6 months. Results: The injured knee had significantly prolonged T1ρ and T2 relaxation times in the tibiofemoral compartment at baseline and 6 months but had shorter values in the patellofemoral compartment compared with the uninjured knee. Prolonged T1ρ and T2 times at 6 months were noted for both the injured and uninjured knees. At 6 months, prolongation of T1ρ and T2 times in the tibial region was associated with lower patient-reported outcome measures. ACLR performed within 30 days of injury had significantly shorter T1ρ times in the tibial regions, and lateral meniscal tears treated with repair had significantly shorter T1ρ times than those treated with excision. Conclusion: Prolonged relaxation times in multiple regions demonstrate how the injury affects the entire joint after an ACL tear. Changes observed in the uninjured knee may be caused by increased loading during rehabilitation, especially in the patellofemoral articular cartilage and distal femur. Relaxation times in the tibial regions may be predictive of patient symptoms at 6 months. These same regions are affected by surgical timing as early as 30 days after injury, but this may partially be reflective of the severity of the preoperative injury and the choice of treatment of meniscal tears.

Background: Digital workstations with high-resolution monitors are replacing standard radiographs for image evaluation and interpretation. Radiographic angles in the foot have been evaluated for interobserver and intraobserver reliability with plain films, but use of digital workstations has not been validated. Because the 1-2 intermetatarsal (IM) and hallux valgus (HV) angles help determine the most appropriate bunion procedure, the reliability of these measurements is important. Methods: The HV and 1-2 IM angles were evaluated on preoperative radiographs of 25 patients who subsequently underwent bunion procedures. A standardized technique using a film marker and goniometer on plain film was compared with use of a mouse and computerized angle measurement software at a digital workstation. Three foot and ankle surgeons conducted these measurements at various intervals. Completion of three readings of each radiograph in each format by each observer totaled 1,800 measurements. Results: Computerized measurement gave better overall reliability. For the HV angle, inter-observer agreement (measurements within 2 degrees) improved from 66% with plain films to 81% with the digital workstation (p < 0.001). Intraobserver agreement increased from 72% to 80%. The 1-2 IM angle was similarly reliable with both methods for inter- and intraobserver agreement. Conclusions: This study validates the use of computer-assisted angle measurement on digital radiographs for assessment of HV and 1-2 IM angles. Computerized measurement may result in more reliable readings because it eliminates the error inherent with use of a goniometer and facilitates adjustment of radiographic lines on the computer to ensure correct alignment.

Context.— The diagnosis and grading of acute cellular and antibody-mediated rejection (AMR) in lung allograft biopsies is important because rejection can lead to acute graft dysfunction and/or failure and may contribute to chronic graft failure. While acute cellular rejection is well defined histologically, no reproducible specific features of AMR are currently identified. Therefore, a combination of clinical features, serology, histopathology, and immunologic findings is suggested for the diagnosis of AMR. Objective.— To describe the perspective of members of the Pulmonary Pathology Society (PPS) on the workup of lung allograft transbronchial biopsy and the diagnosis of acute cellular rejection and AMR in lung transplant. Data Sources.— Reports by the International Society for Heart and Lung Transplantation (ISHLT), experience of members of PPS who routinely review lung allograft biopsies, and search of literature database (PubMed). Conclusions.— Acute cellular rejection should be assessed and graded according to the 2007 working formulation of the ISHLT. As currently no specific features are known for AMR in lung allografts, the triple test (clinical allograft dysfunction, donor-specific antibodies, pathologic findings) should be used for its diagnosis. C4d staining might be performed when morphologic, clinical, and/or serologic features suggestive of AMR are identified.

Background and objectives Delayed graft function is a form of AKI resulting from ischemia-reperfusion injury. Our aim was to study the effect of delayed graft function on the progression of interstitial fibrosis after deceased donor kidney transplantation. Design, setting, participants, & measurements Our study is a retrospective study of all patients transplanted at our center between July of 2003 and September of 2014 using a kidney from a deceased donor. The primary outcome was the progression of interstitial fibrosis on serial protocol biopsies done during the first year post-transplant. We analyzed the distribution of the change in the Banff interstitial fibrosis (ci) score between the delayed graft function and nondelayed graft function groups for all of the paired biopsies done at time 0 and 12 months post-transplant ( Δ fibrosis). We also performed a linear mixed model analyzing the difference in the slopes for the progression of mean Banff ci score for all of the biopsies done at time 0 and 1, 4, and 12 months post-transplant. Results There were 343 (36.7%) in the delayed graft function group and 591 in the control group. The biopsy rates for the delayed graft function and nondelayed graft function groups at time 0 were 65.3% ( n =224) and 67.0% ( n =396), respectively, and at 12 months, they were 64.4% ( n =221) and 68.4% ( n =404), respectively. Paired biopsies were available for 155 in the delayed graft function group and 283 in the control group. In a risk-adjusted model, Banff ci score >0 on the time 0 biopsy had a higher odds of delayed graft function (odds ratio, 1.70; 95% confidence interval, 1.03 to 2.82). The distribution of the Δ fibrosis between 0 and 12 months was similar in delayed graft function and control groups ( P =0.91). The slopes representing the progression of fibrosis were also similar between the groups ( P =0.66). Conclusions Donor-derived fibrosis may increase the odds of delayed graft function; however, delayed graft function does not seem to increase the progression of fibrosis during the first year after transplantation.

Abstract Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C&gt;T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer–affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair–deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (ORBC = 1.53, ORER+ = 1.73), particularly for the estrogen receptor–positive subset (P &lt; 0.007). Significance: A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers. Cancer Discov; 6(11); 1267–75. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 1197

Context.— Idiopathic pulmonary fibrosis (IPF) is a distinctive clinicopathologic entity and the most common form of progressive diffuse lung scarring in older adults. Idiopathic pulmonary fibrosis manifests histopathologically as the usual interstitial pneumonia pattern. The usual interstitial pneumonia pattern is distinguished by geographically and temporally heterogeneous fibrosis that is peripherally accentuated, often with honeycombing and traction bronchiectasis. Idiopathic pulmonary fibrosis is not the only disease that leads to end-stage lung fibrosis, however, and several other entities may also cause advanced fibrosis. Surgical lung biopsies often present a diagnostic dilemma when they show clear evidence of advanced fibrosis, but the clinical, imaging, and/or histopathologic subcharacteristics suggest something other than IPF. Objective.— To address this dilemma, we review several other fibrotic lung diseases, including connective tissue disease–associated interstitial lung disease, chronic hypersensitivity pneumonitis, advanced pulmonary Langerhans cell histiocytosis, end-stage pulmonary sarcoidosis, Erdheim-Chester disease, Hermansky-Pudlak syndrome, and others, detailing their clinical, radiologic, and histopathologic attributes and emphasizing similarities to and differences from IPF. Data Sources.— Data sources comprised published peer-reviewed literature and personal experience of the authors. Conclusions.— Often, clues in the lung biopsy may offer the first suggestion of a fibrotic lung disease other than IPF, and accurate classification is important for prognosis, treatment, and the development of future therapies.

Abstract Background: Known gene mutations account for approximately 50% of the risk for breast cancer. However, a considerable fraction of heritable risk remains unexplained. Fifteen percent of the risk is accounted for by BRCA1/2 and another 3% by TP53, PTEN, LKB1 and CDH1. CHEK2, ATM, PALB2, BRIP1, RAD51C, RAD51D and BARD1 account for 4%, while SNPs discovered from large multicenter genome-wide association studies explain another 14% of the heritable risk. Founder mutations in the DNA repair pathway genes such as BRCA1 and BRCA2 account for the majority of AJ breast cancer mutations. Methods: We performed exome sequencing of 49 early onset (age &lt;35) breast cancer cases, and 85 BRCA wild type familial breast cancer cases, all of Ashkenazi Jewish (AJ) from the New York City area. A recurrent truncating mutation was then analyzed in 3131 breast cancer cases and 2716 unaffected women of Ashkenazi ancestry from New York and Israel. Using CRISPR and overexpression systems on the human mammary epithelial cell line HMLE, transcript and protein levels were assayed for the mutant and compared to wild-type. Treatment with IlludinS and UVC were performed to assess DNA damage response. Finally, clonogenic survival assay was also performed. Results: Amongst the DNA repair pathway genes, exome sequencing revealed a heterozygous recurrent truncating mutation in ERCC3 (R109X) in 2 of 49 early onset breast cancer cases of AJ ancestry and 4 familial AJ probands. Taqman genotyping in a case control setting from New York and Israel revealed 54 mutation carriers in 3131 cases and 32 in the 2716 controls. In total, there were 60 heterozygotes detected in 3209 cases and 32 in 2716 controls [OR 1.59 (95% CI 1.01-2.50)]; p = 0.02 Fisher one- tailed). Functional studies using CRISPR and overexpression systems on human mammary epithelial cells, show that the mutation results in lower transcript levels and this reduction is effected by nonsense mediated decay of the mutant transcript. Western blotting showed that the mutation resulted in a smaller protein (∼12kDa). Clonogenic assays showed similar survival rate of mutant and wildtype under UVC exposure, however the mutant cell line showed significantly smaller colony size demonstrating a growth disadvantage that was further increased upon DNA damage. Treatment with fungal sesquiterpene IlludinS, a known sensitizer to mutant ERCC3 cell lines, showed drastically reduced survival when compared to the wild type human mammary epithelial cells. Conclusions: We demonstrate that ERCC3 is a moderate risk gene for breast cancer in individuals of Ashkenazi ancestry. ERCC3 is somatically mutated in multiple cancers including breast, ovarian and pancreatic cancers, however its role as a cancer susceptibility gene requires further elucidation. Additional functional and population genetic studies to further characterize this novel ERCC3 variant are underway. Citation Format: Joseph Vijai, Sabine Topka, Kara Maxwell, Vignesh Ravichandran, Tinu Thomas, Danylo Villano, Ann Maria, Pragna Gaddam, Anne Lincoln, Steven Hart, Susan Neuhausen, Mark Robson, Jeffrey Weitzel, Mark Daly, Katherine Nathanson, Fergus Couch, Gadi Rennert, Kenneth Offit. ERCC3 R109X is a moderate risk breast cancer risk variant in Ashkenazi Jews. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 796.

Abstract Sequencing tests assaying panels of genes or whole exomes are widely available for cancer risk evaluation. However, methods for classification of variants resulting from this testing are not well studied. We evaluated the ability of American College of Medical Genetics and Genomics (ACMG) guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG designated reportable cancer and non-cancer genes, in individuals who met guidelines for hereditary cancer risk evaluation. We performed whole exome sequencing in 404 individuals in 257 families and classified 1640 variants from these genes. Potentially clinically actionable (likely-pathogenic/pathogenic, LP/P) versus nonactionable (VUS/likely-benign/benign) calls were 92% and 88% concordant with locus specific databases and Clinvar, respectively. LP/P mutations were identified in 11 of 25 breast cancer susceptibility genes in 27 BRCA1/2 negative families (11%). Evaluation of 84 additional autosomal dominant cancer susceptibility genes identified LP/P mutations in only four additional families (1.7%), suggesting they do not influence risk in this cohort. However, individuals from nine of 257 families (3.5%) had incidental LP/P mutations in 32 non-cancer disease genes, and 7% of individuals were monoallelic carriers of an LP/P mutation in 39 autosomal recessive cancer syndrome genes. Furthermore, 90% of individuals had at least one VUS. In summary, these data support the clinical utility of ACMG variant classification guidelines. In addition, evaluation of extended panels of cancer genes in breast/ovarian cancer families leads to only an incremental clinical benefit but substantially increases the complexity of the results. Citation Format: Kara N. Maxwell, Steven N. Hart, Joseph Vijai, Kasmintan A. Schrader, Tinu Thomas, Bradley Wubbenhorst, Vignesh Ravichandran, Raymond M. Moore, Chunling Hu, Lucia Guidugli, Brandon Wenz, Thomas P. Slavin, Susan M. Domchek, Mark E. Robson, Csilla Szabo, Susan L. Neuhausen, Jeffrey N. Weitzel, Kenneth Offit, Fergus J. Couch, Katherine L. Nathanson. Evaluation of ACMG guideline classified variants in 180 cancer and incidental non-cancer genes in families with breast/ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5220.

Context Three distinct patterns of pulmonary fibrosis, including usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway-centered fibrosis, can be identified on surgical lung biopsies. Objectives To compare the pathologic definitions, clinical and radiographic presentations, etiologies and differential diagnoses, treatments, and prognoses of usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway-centered fibrosis patterns, and to address the challenges and controversies related to pulmonary fibrosis. Data Sources Data were derived from published literature and clinical experience. Conclusions Although there may be overlap, identification of the dominant form of fibrosis in a particular case can provide a general category of disease and assist in identifying an etiology.

Aims We wanted to improve the quality of histopathology addenda and amendments by introducing standardised nomenclature and procedures. Methods We standardised amendment and addenda definitions, implemented a pathologist visual work tool, and evaluated and quantitated all amendments and addenda for 3 months prior to implementation and 17 months after. Results In the 3-month pre-intervention period, 32 of 979 addenda (3.3%) were misused and 18 of 98 amendments (18.4%) were incorrectly classified. In the 17-month post-intervention period, 57 of 5906 addenda (1.0%) were misused and 54 of 752 amendments (7.2%) were incorrectly classified. These differences were statistically significant (p<0.0001). Conclusions The introduction of standardised nomenclature and a visual work tool significantly improved the quality of histopathology addenda and amendments.