Room for improvement in capturing cancer family history in a gynecologic oncology outpatient setting.

The literature demonstrates that the quality of cancer family history (CFH) as currently collected in the outpatient setting is inadequate to assess disease risk. Prior to implementation of a web-based application for cancer family history collection, we aimed to review the quality of collected CFH in a gynecologic oncology outpatient clinic and determine contributing patient factors. Medical records were reviewed for 200 new patients presenting between 4/2019-7/2019. CFH was collected during the patient interview and evaluated for inclusion of eight elements based on standards set by the genetics community. Univariate and multivariable linear regression analyses were utilized to evaluate the effect of patient characteristics on the number of relatives included in the CFH. Among our cohort of 200 patients, CFH was documented for 185 patients (92.5%). On univariate analysis, patients with a family history of cancer and prior genetic testing had significantly greater median number of relatives included in the CFH. On multivariable analysis, patients with family members with cancer had significantly more relatives included. Our data are consistent with the literature, suggesting that the current collection methods may not adequately capture all measures of a high quality CFH. Patients reporting no family history of cancer and those without prior genetic testing were least likely to have CFH that included key quality elements and these patients might benefit from health information technology CFH collection tools.

Concurrent mapping of multiple epigenetic marks and co-occupancy using ACT2-seq.

BACKGROUND: Genome-wide profiling of epigenetic marks is a core technology in molecular genetics. Co-occupancy of different epigenetic marks or protein factors at the same genomic locations must often be inferred from multiple independently collected data sets. However, this strategy does not provide direct evidence of co-enrichment in the same cells due to the existence of cellular heterogeneity. To address this issue, we have developed a technique termed ACT2-seq that is capable of concurrently profiling multiple epigenetic marks in a single biological sample. In addition to reducing the numbers of samples required for experiments, ACT2-seq is capable of mapping co-occupancy of epigenetic factors on chromatin. This strategy provides direct evidence of co-enrichment without requiring complex single-molecule, single-cell, or magnetic bead-based approaches. RESULTS: We concurrently profiled pairs of two epigenetic marks using ACT2-seq as well as three marks in individual samples. Data obtained using ACT2-seq were found to be reproducible and robust. ACT2-seq was capable of cleanly partitioning concurrently mapped data sets that exhibited distinct enrichment patterns. Using ACT2-seq, we identified distinct relationships between co-occupancy of specific histone modifications and gene expression patterns. CONCLUSIONS: We conclude that ACT2-seq presents an attractive option for epigenomic profiling due to its ease of use, potential for reducing sample and sequencing costs, and ability to simultaneously profile co-occupancy of multiple histone marks and/or chromatin-associated proteins.

CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the CSF levels of chitinase proteins during the presymptomatic and early symptomatic phases of amyotrophic lateral sclerosis (ALS). METHODS: CSF samples were obtained from 16 controls, 55 individuals at-risk for ALS (including 18 carrying a mutation in C9ORF72, 33 in SOD1), 12 ALS patients, and 7 phenoconverters (individuals diagnosed with ALS during follow-up). At-risk individuals and phenoconverters were enrolled through the Pre-fALS study, which includes individuals carrying an ALS-associated gene mutation without disease manifestations at initial assessment. Longitudinal CSF collections, where possible, took place every 3-12 months for ALS patients and every 1-2 years for others. CSF levels of chitotriosidase 1 (CHIT1), chitinase-3-like protein 1 (CHI3L1, YKL-40) and chitinase-3-like protein 2 (CHI3L2, YKL-39) were measured by ELISA, along with CHIT1 activity. Longitudinal changes in at-risk individuals and phenoconverters were fitted to linear mixed effects models. RESULTS: Slowly rising levels of CHIT1 were observed over time in the at-risk individuals (slope 0.059 log10 [CHIT1] per year, P < 0.001). Among phenoconverters, CHIT1 levels and activity rose more sharply (0.403 log10 [CHIT1] per year, P = 0.005; 0.260 log10 [CHIT1 activity] per year, P = 0.007). Individual levels of both CHI3L1 and CHI3L2 remained relatively stable over time in all participant groups. INTERPRETATION: The CHIT1 neuroinflammatory response is a feature of the late presymptomatic to early symptomatic phases of ALS. This study does not suggest a long prodrome of upregulated glial activity in ALS pathogenesis, but strengthens the place of CHIT1 as part of a panel of biomarkers to objectively assess the impact of immune-modulatory therapeutic interventions in ALS.

Endoscopic scar assessment after colorectal endoscopic mucosal resection scars: when is biopsy necessary (EMR Scar Assessment Project for Endoscope (ESCAPE) trial).

OBJECTIVE: It is unclear whether endoscopic assessment of scars after colorectal endoscopic mucosal resection (EMR) has to include biopsies, even if endoscopy is negative. Vice versa, endoscopic diagnosis of recurrent adenoma may not require biopsy before endoscopic reinterventions. We prospectively analysed various endoscopic modalities in the diagnosis of recurrence following EMR. DESIGN: We conducted a prospective study of patients undergoing colonoscopy after EMR of large (≥20 mm) colorectal neoplasia. Endoscopists predicted recurrence and confidence level with four imaging modes: high-definition white light (WL) and narrow-band imaging (NBI) with and without near focus (NF). Separately, 26 experienced endoscopists assessed offline images. RESULTS: Two hundred and thirty patients with 255 EMR scars were included. The prevalence of recurrent adenoma was 24%. Diagnostic values were high for all modes (negative predictive value (NPV) ≥97%, positive predictive value (PPV) ≥81%, sensitivity ≥90%, specificity ≥93% and accuracy ≥93%). In high-confidence cases, NBI with NF had NPV of 100% (95% CI 98% to 100%) and sensitivity of 100% (95% CI 93% to 100%). Use of clips at initial EMR increased diagnostic inaccuracy (adjusted OR=1.68(95% CI 1.01 to 2.75)). In offline assessment, specificity was high for all imaging modes (mean: ≥93% (range: 55%-100%)), while sensitivity was significantly higher for NBI-NF (82%(72%-93%)%)) compared with WL (69%(38%-86%); p<0.001), WL-NF (68%(55%-83%); p<0.001) and NBI (71%(59%-90%); p<0.001). CONCLUSION: Our study demonstrates very high sensitivity and accuracy for all four imaging modalities, especially NBI with NF, for diagnosis of recurrent neoplasia after EMR. Our data strongly suggest that in cases of high confidence negative optical diagnosis based on NBI-NF, no biopsy is needed to confirm absence of recurrence during colorectal EMR follow-up. A high confidence positive optical diagnosis can lead to immediate resection of any suspicious area. In all cases of low confidence, biopsy is still required. TRIAL REGISTRATION NUMBER: NCT02668198.

Chloroquine and nanoparticle drug delivery: A promising combination.

Clinically approved cancer therapies include small molecules, antibodies, and nanoparticles. There has been major progress in the treatment of several cancer types over recent decades. However, many challenges remain for optimal use of conventional and nanoparticle-based therapies in oncology including poor drug delivery, rapid clearance, and drug resistance. The antimalarial agent chloroquine has been found to mitigate some of these challenges by modulating cancer cells and the tissue microenvironment. Particularly, chloroquine was recently found to reduce immunological clearance of nanoparticles by resident macrophages in the liver, leading to increased tumor accumulation of nanodrugs. Additionally, chloroquine has been shown to improve drug delivery and efficacy through normalization of tumor vasculature and suppression of several oncogenic and stress-tolerance pathways, such as autophagy, that protect cancer cells from cytotoxic agents. This review will discuss the use of chloroquine as combination therapy to improve cancer treatment.