Abstract
Objectives
Current protocols for processing multiple prostate biopsy cores per case are uneconomical and cumbersome. Tissue fragmentation and loss compromise cancer diagnosis. We sought to ...study an alternate method to improve processing and diagnosis of prostate cancer.
Methods
Two sets of sextant biopsy specimens from near-identical locations were obtained ex vivo from 48 prostate specimens. One set was processed in the standard fashion while the other was processed using the BxChip, a proprietary biomimetic matrix that accommodates six cores on a single chip. Parameters including grossing, embedding, sectioning and reading time, length of tissue, and degree of fragmentation were compared.
Results
A significant reduction (more than threefold) in preanalytical and analytical time was observed using the multiplex method. Nonlinear fragmentation was absent, in contrast to standard processing.
Conclusions
The BxChip reduced tissue fragmentation and increased efficiency of prostate biopsy diagnosis. It also resulted in overall cost savings and significantly increased tissue length.
Prostate Biopsy Processing Murugan, Paari; Shukla, Dip; Morocho, Jennifer ...
American journal of clinical pathology,
11/2019, Letnik:
152, Številka:
6
Journal Article
Recenzirano
Abstract
Objectives
Current protocols for processing multiple prostate biopsy cores per case are uneconomical and cumbersome. Tissue fragmentation and loss compromise cancer diagnosis. We sought to ...study an alternate method to improve processing and diagnosis of prostate cancer.
Methods
Two sets of sextant biopsy specimens from near-identical locations were obtained ex vivo from 48 prostate specimens. One set was processed in the standard fashion while the other was processed using the BxChip, a proprietary biomimetic matrix that accommodates six cores on a single chip. Parameters including grossing, embedding, sectioning and reading time, length of tissue, and degree of fragmentation were compared.
Results
A significant reduction (more than threefold) in preanalytical and analytical time was observed using the multiplex method. Nonlinear fragmentation was absent, in contrast to standard processing.
Conclusions
The BxChip reduced tissue fragmentation and increased efficiency of prostate biopsy diagnosis. It also resulted in overall cost savings and significantly increased tissue length.
Abstract only
e15069
Background: Recent clinical guidelines for expansion of molecular testing of oncogenic RAS mutations in colorectal carcinoma have led to increased identification of mutations in ...this patient population. The clinical characteristics of NRAS-mutated colorectal carcinoma have not been well established because of the lower prevalence of these mutations (< 6%) as compared to oncogenic KRAS mutations. Here, we report the discovery of a novel internal tandem duplication (ITD) mutation of NRAS, which disrupts the Switch II domain in an index case of a patient with widely disseminated colorectal cancer. Methods: Hotspot next generation sequencing of a brain metastasis using a clinical solid tumor panel identified this novel NRAS ITD and a TP53 missense mutation (p.P275F). Whole exome sequencing of the primary tumor and two metastatic lesions (lung and brain) was performed to identify other genetic factors potentially driving the disease. Results: The above approach confirmed that the NRAS ITD and TP53 mutation were conserved between the primary tumor and both metastatic tumors and identified an additional pathogenic mutation in CSMD1 (a tumor suppressor gene). No other clearly pathogenic driver mutations were identified. Structural biology and biochemical analyses demonstrated that the inserted 15 amino acids prevented binding to GAP protein, leading to sustained RAS activation and increased interaction with RAF to stimulate downstream MAPK activation. Conclusions: These genomic and biochemical studies indicate that a novel NRAS ITD was the primary driver mutation of this aggressive colorectal carcinoma. Identical or similar ITDs in NRAS and KRAS may also drive other forms of colorectal cancer and other aggressive malignancies and represent a new subset of RAS-driven drug-resistant cancers.
The oncogene RAS is one of the most widely studied proteins in cancer biology, and mutant active RAS is a driver in many types of solid tumors and hematological malignancies. Yet the biological ...effects of different RAS mutations and the tissue-specific clinical implications are complex and nuanced. Here, we identified an internal tandem duplication (ITD) in the switch II domain of NRAS from a patient with extremely aggressive colorectal carcinoma. Results of whole-exome DNA sequencing of primary and metastatic tumors indicated that this mutation was present in all analyzed metastases and excluded the presence of any other clear oncogenic driver mutations. Biochemical analysis revealed increased interaction of the RAS ITD with Raf proto-oncogene Ser/Thr kinase (RAF), leading to increased phosphorylation of downstream MAPK/ERK kinase (MEK)/extracellular signal–regulated kinase (ERK). The ITD prevented interaction with neurofibromin 1 (NF1)–GTPase–activating protein (GAP), providing a mechanism for sustained activity of the RAS ITD protein. We present the first crystal structures of NRAS and KRAS ITD at 1.65–1.75 Å resolution, respectively, providing insight into the physical interactions of this class of RAS variants with its regulatory and effector proteins. Our in-depth bedside-to-bench analysis uncovers the molecular mechanism underlying a case of highly aggressive colorectal cancer and illustrates the importance of robust biochemical and biophysical approaches in the implementation of individualized medicine.
1. Participants will demonstrate a greater understanding of rule-based natural language processing as a method to assess palliative and end-of-life care quality.
2. Participants will broadly explore ...how to apply the rule-based natural language processing technology to serious illness research.
Natural language processing (NLP) for end-of-life care (EOLC) quality measurement has not yet been used in children with serious illness. In a single-center cohort of childhood cancer decedents, we established a feasible, scalable approach to measure EOLC quality, using rule-based NLP.
Data on end-of-life care (EOLC) quality, assessed through evidence-based process measures (EOLC-PMs), are difficult to obtain. Natural language processing (NLP) enables efficient EOLC quality measurement and has not yet been used in children with serious illness.
To validate a pediatric-specific EOLC-PM keyword library and evaluate EOLC-PM attainment among childhood cancer decedents.
In a single-center cohort of children with cancer who died between 2014-2022, we examined the content of all clinical notes from electronic health records in the last six months of life, using rule-based NLP software. Upon iterative refinement of a keyword library, we identified documentation of five EOLC-PMs: goals of care discussions, code status limitations, hospice discussions, palliative care consultation, and preferred location of death. We assessed performance of NLP methods, compared to gold standard manual chart abstraction. We then piloted NLP to characterize proportions of decedents with documented EOLC-PMs and timing of first documentation relative to death.
Among 101 decedents, nearly half were minorities Hispanic/Latinx (24%), non-Hispanic Black/African American (20%) or female (48%). Our keyword library ultimately achieved robust performance statistics (for all EOLC-PMs, F1 statistic=1). In the last six months of life, most decedents had documented goals of care discussions (83%), code status limitations (83%), and hospice discussions (74%). First documentation of EOLC-PMs occurred an average of 61, 41, and 58 days before death, respectively. Some decedents had documented palliative care consultations (49%), which occurred an average of 72 days before death. Few decedents had documented discussions regarding preferred location of death (36%), occurring an average of 38 days before death.
A high proportion of decedents attained specified EOLC-PMs more than 30 days prior to death.
In establishing use of this technology at a single site, we discovered that rule-based NLP is a feasible, scalable approach to measuring EOLC quality for children with cancer.
Innovative technologies/Pediatrics
Acute allograft rejection appears to be associated with increases in QT/QTc intervals.
To determine the relationship between acute allograft rejection and electrocardiogram changes in patients ...undergoing an orthotopic heart transplant.
The study population comprised 220 adult patients undergoing heart transplant and enrolled in the NEW HEART study. Electrocardiograms obtained within 72 hours of endomyocardial biopsy were analyzed; electrocardiograms obtained fewer than 10 days after transplant surgery were excluded. Repeated-measures analysis was performed with statistical models including effects for rejection severity (mild and moderate/severe) and time trends independent of rejection status.
The 151 male and 69 female transplant recipients (mean age SD, 54 13 years) had 969 biopsy/electrocardiogram pairs: 677 with no rejection, 280 with mild rejection, and 12 with moderate/severe rejection. Moderate to severe organ rejection was associated with significant increases in QRS duration (
< .001), QT (
= .009), QTc (
= .003), and PR interval (
= .03), as well as increased odds of right bundle block branch (
= .002) and fascicular block (
= .009) occurring.
Moderate to severe acute allograft rejection was associated with electrocardiographic changes after transplant surgery. Studies are needed to assess the value of computerized electrocardiogram measurement algorithms for detecting acute allograft rejection.
Background:
Little attention has focused on gender differences in cardiac comorbidities and outcomes in patients undergoing orthotropic heart transplant.
Objective:
The objective of this study was to ...investigate gender differences at baseline and during follow-up among heart transplant patients.
Methods:
An observational cohort within the NEW HEART study was evaluated to determine gender differences in relation to age, coexisting cardiac comorbidities, and outcomes. Differences were assessed by t-test, Fisher’s exact test, and logistic regression analysis.
Results:
Male transplant recipients (n = 238) were significantly older than female recipients (n = 92), with a greater percentage over 60 years of age (45% vs. 24%, p = 0.0006). Males were more likely to have hypertension (63% vs. 49%, p = 0.034), dyslipidemia (62% vs. 45%, p = 0.006), a history of smoking (52% vs. 35%, p = 0.009), and diabetes (42% vs. 21%, p = 0.0002). Analysis of endomyocardial biopsies obtained during the 1-year follow-up period demonstrated that women averaged more episodes of acute rejection than men (3.9 vs. 3.0, p = 0.009). While most episodes of rejection were mild, women were more likely than men to have episodes of moderate or severe rejection (14% vs. 5%, p = 0.012) and to be hospitalized for acute rejection (15% vs. 6%, p = 0.013). There were no significant differences in mortality.
Conclusions:
Men were more likely than women to be older and to have diabetes, dyslipidemia, hypertension, and a history of smoking. Women were more likely to experience moderate or severe allograft rejection and to be hospitalized for acute rejection. Future investigation of the reasons for these gender differences is warranted and may improve clinical care of women undergoing cardiac transplantation.
This is a case of a 43-year-old black male with no history of hypertension, diabetes, dyslipidemia, or smoking. The subject underwent an OHT for worsening heart failure due to an idiopathic ...cardiomyopathy. Three endomyocardial biopses acquired during the first 8 months following transplant surgery did not show acute allograph rejection and the QTc was not prolonged on electrocardiogram (ECG). However, a 2R rejection was noted on an endomyocardial biopsy acquired 9 months following transplant surgery which correlated with prolongation of the QTc to 518 ms on an ECG obtained the following day and to 577 ms on an ECG acquired 11 days later. In the two months following this episode of acute allograph rejection, the endomyocardial biopses showed no rejection and the QTc interval returned to normal. Upon review of pre and post rejection ECGs, prolongation of the QTc was only observed following a positive endomyocardial biopsy (Fig. 1). Conclusion: Noninvasive ECG monitoring may not be an early biomarker for predicting OHT rejection.
Previous studies have suggested that acute allograft rejection is associated with increases in QT/QTc.
This study sought to determine the relationship between acute allograft rejection and ECG ...changes in patients undergoing an orthotopic heart transplant.
The study population consisted of 220 adult heart transplant patients enrolled in the NEW HEART Study. ECGs performed within 72h of endomyocardial biopsy were analyzed with ECGs obtained <10days following transplant surgery excluded. Repeated measures analysis was performed with statistical models including effects for rejection severity (mild and moderate/severe) and time trends independent of rejection status.
Among the 151 male and 69 female transplant recipients (age 54±13), there were 969 biopsy/ECG pairs: 677 with no rejection, 280 with mild rejection, and 12 with moderate/severe rejection. Moderate/severe rejection was associated with significant increases in QRS duration (p<0.0001), QT (p=0.009), QTc (p=0.003), and PR interval (p=0.03), as well as increased odds of right bundle block branch (p=0.002) and fascicular block (p=0.009).
Moderate/severe acute allograft rejection is associated with ECG changes following transplant surgery. Future studies are needed to assess the value of computerized ECG measurement algorithms for detecting acute allograph rejection.
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