%% Papers Published
@article{fds372739,
Author = {Lange, J and Zhao, Y and Gogebakan, KC and Olivas-Martinez, A and Ryser,
MD and Gard, CC and Etzioni, R},
Title = {Test sensitivity in a prospective cancer screening program:
A critique of a common proxy measure.},
Journal = {Stat Methods Med Res},
Volume = {32},
Number = {6},
Pages = {1053-1063},
Year = {2023},
Month = {June},
url = {http://dx.doi.org/10.1177/09622802221142529},
Abstract = {The true sensitivity of a cancer screening test, defined as
the frequency with which the test returns a positive result
if the cancer is present, is a key indicator of diagnostic
performance. Given the challenges of directly assessing test
sensitivity in a prospective screening program, proxy
measures for true sensitivity are frequently reported. We
call one such proxy empirical sensitivity, as it is given by
the observed ratio of screen-detected cancers to the sum of
screen-detected and interval cancers. In the setting of the
canonical three-state Markov model for progression from
preclinical onset to clinical diagnosis, we formulate a
mathematical relationship for how empirical sensitivity
varies with the screening interval and the mean preclinical
sojourn time and identify conditions under which empirical
sensitivity exceeds or falls short of true sensitivity. In
particular, when the inter-screening interval is short
relative to the mean sojourn time, empirical sensitivity
tends to exceed true sensitivity, unless true sensitivity is
high. The Breast Cancer Surveillance Consortium (BCSC) has
reported an estimate of 0.87 for the empirical sensitivity
of digital mammography. We show that this corresponds to a
true sensitivity of 0.82 under a mean sojourn time of 3.6
years estimated based on breast cancer screening trials.
However, the BCSC estimate of empirical sensitivity
corresponds to even lower true sensitivity under more
contemporary, longer estimates of mean sojourn time.
Consistently applied nomenclature that distinguishes
empirical sensitivity from true sensitivity is needed to
ensure that published estimates of sensitivity from
prospective screening studies are properly
interpreted.},
Doi = {10.1177/09622802221142529},
Key = {fds372739}
}
@article{fds369224,
Author = {Byng, D and Thomas, SM and Rushing, CN and Lynch, T and McCarthy, A and Francescatti, AB and Frank, ES and Partridge, AH and Thompson, AM and Retèl, VP and van Harten, WH and Grimm, LJ and Hyslop, T and Hwang, ES and Ryser, MD},
Title = {Surveillance Imaging after Primary Diagnosis of Ductal
Carcinoma in Situ.},
Journal = {Radiology},
Volume = {307},
Number = {1},
Pages = {e221210},
Year = {2023},
Month = {April},
url = {http://dx.doi.org/10.1148/radiol.221210},
Abstract = {Background Guidelines recommend annual surveillance imaging
after diagnosis of ductal carcinoma in situ (DCIS).
Guideline adherence has not been characterized in a
contemporary cohort. Purpose To identify uptake and
determinants of surveillance imaging in women who underwent
treatment for DCIS. Materials and Methods A stratified
random sample of women who underwent breast-conserving
surgery for primary DCIS between 2008 and 2014 was
retrospectively selected from 1330 facilities in the United
States. Imaging examinations were recorded from date of
diagnosis until first distant recurrence, death, loss to
follow-up, or end of study (November 2018). Imaging after
treatment was categorized into 10 12-month periods
starting 6 months after diagnosis. Primary outcome was
per-period receipt of asymptomatic surveillance imaging
(mammography, MRI, or US). Secondary outcome was diagnosis
of ipsilateral invasive breast cancer. Multivariable
logistic regression with repeated measures and generalized
estimating equations was used to model receipt of imaging.
Rates of diagnosis with ipsilateral invasive breast cancer
were compared between women who did and those who did not
undergo imaging in the 6-18-month period after diagnosis
using inverse probability-weighted Kaplan-Meier estimators.
Results A total of 12 559 women (median age, 60 years;
IQR, 52-69 years) were evaluated. Uptake of surveillance
imaging was 75% in the first period and decreased over time
(P < .001). Across the first 5 years after treatment, 52% of
women participated in consistent annual surveillance.
Surveillance was lower in Black (adjusted odds ratio [OR],
0.80; 95% CI: 0.74, 0.88; P < .001) and Hispanic (OR, 0.82;
95% CI: 0.72, 0.94; P = .004) women than in White women.
Women who underwent surveillance in the first period had a
higher 6-year rate of diagnosis of invasive cancer (1.6%;
95% CI: 1.3, 1.9) than those who did not (1.1%; 95% CI: 0.7,
1.4; difference: 0.5%; 95% CI: 0.1, 1.0; P = .03).
Conclusion Half of women did not consistently adhere to
imaging surveillance guidelines across the first 5 years
after treatment, with racial disparities in adherence rates.
© RSNA, 2023 Supplemental material is available for this
article. See also the editorial by Rahbar and Dontchos in
this issue.},
Doi = {10.1148/radiol.221210},
Key = {fds369224}
}
@article{fds370133,
Author = {Etzioni, R and Gulati, R and Owens, L and Lange, J and Ryser,
MD},
Title = {Opportunity for interception as a driver of benefit in
cancer early detection: implications for multi-cancer early
detection testing.},
Journal = {Cancer Prevention Research},
Volume = {16},
Number = {1},
Pages = {6-6},
Year = {2023},
Key = {fds370133}
}
@article{fds357630,
Author = {Fridman, I and Chan, L and Thomas, J and Fish, LJ and Falkovic, M and Brioux, J and Hunter, N and Ryser, DH and Hwang, ES and Pollak, KI and Weinfurt, KP and Ryser, MD},
Title = {A web-based personalized decision support tool for patients
diagnosed with ductal carcinoma in situ: development,
content evaluation, and usability testing.},
Journal = {Breast Cancer Res Treat},
Volume = {192},
Number = {3},
Pages = {517-527},
Year = {2022},
Month = {April},
url = {http://dx.doi.org/10.1007/s10549-022-06512-8},
Abstract = {PURPOSE: Patients diagnosed with ductal carcinoma in situ
(DCIS) face trade-offs when deciding among different
treatments, including surgery, radiation, and endocrine
therapy. A less chosen option is active monitoring. While
evidence from clinical trials is not yet available,
observational studies show comparable results for active
monitoring and immediate treatment on cancer outcomes in
select subgroups of patients. We developed and tested a
web-based decision support tool (DST) to help patients
explore current knowledge about DCIS and make an informed
choice. METHODS: The DST, an interactive web application,
was informed by literature reviews and formative work with
patients, breast surgeons, and health communication experts.
We conducted iterative interviews to evaluate the DST
content among women with and without a history of breast
cancer, as well as breast cancer experts. For usability
testing, we conducted an online survey among women with and
without a history of breast cancer. RESULTS: For content
evaluation, 5 women with and 10 women without a history of
DCIS were interviewed. The sample included 11 White and 4
non-White women, with a mean age of 64 years. The expert
sample consisted of 5 attendings and a physician assistant.
The feedback was used to add, clarify, or reorganize
information in the DST. For usability testing, 22
participants with a mean age of 61 years were recruited
including 15 White and 7 Black women and 6 women with a
history of DCIS. The mean usability score was 3.7 out of 5.
Most participants (86%) found that the DST provided unbiased
information about treatments. To improve usability, we
reduced the per-page content and added navigation cues.
CONCLUSION: Content and usability evaluation showed that the
DST helps patients explore trade-offs of active monitoring
and immediate treatment. By adopting a personalized
approach, the tool will enable informed decisions aligned
with patients' values and expectations.},
Doi = {10.1007/s10549-022-06512-8},
Key = {fds357630}
}
@article{fds363082,
Author = {Ryser, MD and Lange, J and Inoue, LYT and O'Meara, ES and Gard, C and Miglioretti, DL and Bulliard, J-L and Brouwer, AF and Hwang, ES and Etzioni, RB},
Title = {Estimation of Breast Cancer Overdiagnosis in a U.S. Breast
Screening Cohort.},
Journal = {Ann Intern Med},
Volume = {175},
Number = {4},
Pages = {471-478},
Year = {2022},
Month = {April},
url = {http://dx.doi.org/10.7326/M21-3577},
Abstract = {BACKGROUND: Mammography screening can lead to
overdiagnosis-that is, screen-detected breast cancer that
would not have caused symptoms or signs in the remaining
lifetime. There is no consensus about the frequency of
breast cancer overdiagnosis. OBJECTIVE: To estimate the rate
of breast cancer overdiagnosis in contemporary mammography
practice accounting for the detection of nonprogressive
cancer. DESIGN: Bayesian inference of the natural history of
breast cancer using individual screening and diagnosis
records, allowing for nonprogressive preclinical cancer.
Combination of fitted natural history model with life-table
data to predict the rate of overdiagnosis among
screen-detected cancer under biennial screening. SETTING:
Breast Cancer Surveillance Consortium (BCSC) facilities.
PARTICIPANTS: Women aged 50 to 74 years at first mammography
screen between 2000 and 2018. MEASUREMENTS: Screening
mammograms and screen-detected or interval breast cancer.
RESULTS: The cohort included 35 986 women, 82 677
mammograms, and 718 breast cancer diagnoses. Among all
preclinical cancer cases, 4.5% (95% uncertainty interval
[UI], 0.1% to 14.8%) were estimated to be nonprogressive. In
a program of biennial screening from age 50 to 74 years,
15.4% (UI, 9.4% to 26.5%) of screen-detected cancer cases
were estimated to be overdiagnosed, with 6.1% (UI, 0.2% to
20.1%) due to detecting indolent preclinical cancer and 9.3%
(UI, 5.5% to 13.5%) due to detecting progressive preclinical
cancer in women who would have died of an unrelated cause
before clinical diagnosis. LIMITATIONS: Exclusion of women
with first mammography screen outside BCSC. CONCLUSION: On
the basis of an authoritative U.S. population data set, the
analysis projected that among biennially screened women aged
50 to 74 years, about 1 in 7 cases of screen-detected cancer
is overdiagnosed. This information clarifies the risk for
breast cancer overdiagnosis in contemporary screening
practice and should facilitate shared and informed decision
making about mammography screening. PRIMARY FUNDING SOURCE:
National Cancer Institute.},
Doi = {10.7326/M21-3577},
Key = {fds363082}
}
@article{fds367148,
Author = {Schapiro, D and Yapp, C and Sokolov, A and Reynolds, SM and Chen, Y-A and Sudar, D and Xie, Y and Muhlich, J and Arias-Camison, R and Arena, S and Taylor, AJ and Nikolov, M and Tyler, M and Lin, J-R and Burlingame, EA and Human Tumor Atlas Network, and Chang, YH and Farhi, SL and Thorsson,
V and Venkatamohan, N and Drewes, JL and Pe'er, D and Gutman, DA and Herrmann, MD and Gehlenborg, N and Bankhead, P and Roland, JT and Herndon, JM and Snyder, MP and Angelo, M and Nolan, G and Swedlow, JR and Schultz, N and Merrick, DT and Mazzili, SA and Cerami, E and Rodig, SJ and Santagata, S and Sorger, PK},
Title = {MITI minimum information guidelines for highly multiplexed
tissue images.},
Journal = {Nat Methods},
Volume = {19},
Number = {3},
Pages = {262-267},
Year = {2022},
Month = {March},
url = {http://dx.doi.org/10.1038/s41592-022-01415-4},
Abstract = {The imminent release of tissue atlases combining
multi-channel microscopy with single cell sequencing and
other omics data from normal and diseased specimens creates
an urgent need for data and metadata standards that guide
data deposition, curation and release. We describe a Minimum
Information about highly multiplexed Tissue Imaging (MITI)
standard that applies best practices developed for genomics
and other microscopy data to highly multiplexed tissue
images and traditional histology.},
Doi = {10.1038/s41592-022-01415-4},
Key = {fds367148}
}
@article{fds367149,
Author = {Schmitz, RSJM and van den Belt-Dusebout, SW and Cresta, C and Liu,
Y-H and Schaapveld, M and Clements, K and Timbres, J and Byng, DT and Ryser, MD and Ren, Y and Lynch, T and Hyslop, T and Menegaz, B and Collyar,
D and Hwang, S and Thompson, A and Sawyer, E and Wesseling, J and Lips, EH and Schmidt, MK},
Title = {Abstract P1-22-02: Subsequent risk of ipsilateral breast
events in a multinational DCIS cohort of 48.619 patients: A
meta-analysis within the PRECISION consortium},
Journal = {Cancer Research},
Volume = {82},
Number = {4_Supplement},
Publisher = {American Association for Cancer Research
(AACR)},
Year = {2022},
Month = {February},
url = {http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-22-02},
Abstract = {<jats:title>Abstract</jats:title> <jats:p>Background: The
PRECISION (PREvent ductal Carcinoma In Situ Invasive
Overtreatment Now) CRUK Grand Challenge project focusses on
discriminating hazardous from indolent ductal carcinoma in
situ (DCIS). Aim of these analyses is to identify factors
associated with a lower or higher risk of developing
invasive breast cancer after an initial DCIS diagnosis.
Knowledge of these factors is crucial in our quest to
reducing overtreatment for women with DCIS. Many
clinicopathological features are hypothesized to be
important factors affecting the risk of a subsequent breast
lesion. Most studies performed so far are from trial or
single country studies, we now present an integrated
analysis of four different cohorts from three
countries.Methods: Four cohorts from the three countries
participating in PRECISION were identified. A population
based cohort from the Netherlands cancer registry (Dutch
cohort); a population based, prospective, screening cohort
from the United Kingdom (Sloane cohort); a single center
cohort from MD Anderson Cancer Center (MDACC) and a subset
of DCIS patients abstracted from a population based National
Cancer Database Special Study cohort (NCDB subset) in the
United States. Patient-level data from these cohorts were
combined for this analysis. Subsequent ipsilateral invasive
breast cancer (iIBC) and subsequent ipsilateral DCIS (iDCIS)
were assessed at five and ten years by Kaplan Meier
analysis. The cumulative incidence of iIBC was assessed in
three treatment groups: breast conserving surgery only
(BCS), breast conserving surgery with radiotherapy (BCS+RT)
and mastectomy (MST). Cumulative incidence of iDCIS was
assessed in patients receiving BCS or BCS+RT. Additionally,
cumulative incidences were calculated for iIBC and IDCIS in
patients who received endocrine treatment (ET) after BCS or
BCS+RT versus patients who did not receive ET. All
cumulative incidences were calculated with death as
competing risk. Results: The joint PRECISION cohort
consisted of 48,619 patients, diagnosed between 1999 and
2017. Median follow-up was 7.4 years (0.6-17.9). In
preliminary analyses, Kaplan Meier curves showed broadly
similar risks in iIBC and iDCIS between the four different
cohorts. The cumulative incidence of iIBC was 1.6% at five
years and 3.5% at 10 years. Five-year cumulative incidence
of iIBC was highest in patients receiving BCS (3.4%)
compared with patients receiving BCS+RT or MST (1.3%). The
cumulative incidence of iDCIS was 1.7% at 5 years and 2.4%
at 10 years. Five-year cumulative incidence of iDCIS was
higher in patients receiving BCS (3.5%) compared to patients
receiving BCS+RT (1.9%). In univariate analyses, the effect
of ET on cumulative incidence of both iIBC and iDCIS was
modest, especially with respect to radiotherapy. Conclusion:
Overall, 5- and 10-year incidence of an ipsilateral in situ
or invasive breast lesion was low and similar between the
four different cohorts. The incidence of iIBC and iDCIS was
higher in patients receiving BCS, compared to women
receiving BCS+RT or MST.</jats:p> <jats:p>Table 1.Cohort and
patient characteristicsDutch Cohort Sloane MDACCNCDB
subsetTotal CohortN=18,995N=8,425N=1,820N=19,379N=48,619Cohort
descriptionProspectiveNoYesNoNoPopulation basedYesYesNo,
single centerYesScreening and non-screeningYesScreening
onlyYesYesMean (min - max)Mean (min - max)Mean (min -
max)Mean (min-max)Mean (min-max)Age diagnosis DCIS58.3
(21-94)59.8 (46-88)55.6 (20-90)59.7 (20-98)59.0 (20-98)Year
of diagnosis (range)1999-20152003-20121999-20172007-20151999-2017Follow-up
in years10.4 (0.5-21.1)5.3 (0.5-9.7)8.7 (0.25-17.8)5.8
(0.5-10.7)7.6 (0.25-2.1)N (%)N (%)N (%)N (%)N (%)GradeGrade
12,844 (15.0)784 (9.3)141 (7.8)3,158 (16.3)6,927 (14.3)Grade
25,952 (31.3)2,328 (27.6)737 (40.5)6,844 (35.3)15,861
(32.6)Grade 38,944 (47.1)5,305 (62.9)933 (51.3)7,848
(40.5)23,030 (47.3)Unknown grade1,255 (6.6)8 (0.1)9
(0.5)1,529 (7.9)2,801 (5.8)Type of surgeryBreast conserving
surgery (BCS)11,790 (62.1)5,830 (69.2)1,031 (56.7)14,504
(74.8)33,155 (68.2)Mastectomy (MST)7,205 (37.9)2,595
(30.8)789 (43.4)4,875 (25.2)15,464 (31.8)Adjuvant
treatmentRadiotherapy (RT)9,650 (50.8)3,418 (40.6)762
(41.9)10,620 (54.8)24,450 (50.3)Endocrine treatmentNA1,151
(13.6)999 (54.9)8,849 (45.7)10,999 (37.0)5 years Cumulative
IncidencesiIBC1.4%2.3%1.6%1.7%1.6%iDCIS1.5%2.0%1.6%1.7%1.7%Vital
statusAlive16,472 (86.7)8,147 (96.7)1,668 (91.7)18,161
(93.7)44,448 (91.4)Deceased2,523 (13.3)278 (3.3)152
(8.4)1,218 (6.3)4,171 (8.6)This work was supported by Cancer
Research UK and by KWF Dutch Cancer Society
(ref.C38317/A24043)</jats:p> <jats:p>Citation Format: Renée
SJM Schmitz, Sandra W van den Belt-Dusebout, Chiara Cresta,
Yat-Hee Liu, Michael Schaapveld, Karen Clements, Jasmine
Timbres, Danalyn T Byng, Marc D Ryser, Yi Ren, Thomas Lynch,
Terry Hyslop, Brian Menegaz, Deborah Collyar, Shelley Hwang,
Alastair Thompson, Elinor Sawyer, Jelle Wesseling, Esther H
Lips, Marjanka K Schmidt, Grand Challenge PRECISION
consortium. Subsequent risk of ipsilateral breast events in
a multinational DCIS cohort of 48.619 patients: A
meta-analysis within the PRECISION consortium [abstract].
In: Proceedings of the 2021 San Antonio Breast Cancer
Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia
(PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr
P1-22-02.</jats:p>},
Doi = {10.1158/1538-7445.sabcs21-p1-22-02},
Key = {fds367149}
}
@article{fds367150,
Author = {Grimm, LJ and Rahbar, H and Abdelmalak, M and Hall, AH and Ryser,
MD},
Title = {Ductal Carcinoma in Situ: State-of-the-Art
Review.},
Journal = {Radiology},
Volume = {302},
Number = {2},
Pages = {246-255},
Year = {2022},
Month = {February},
url = {http://dx.doi.org/10.1148/radiol.211839},
Abstract = {Ductal carcinoma in situ (DCIS) is a nonobligate precursor
of invasive cancer, and its detection, diagnosis, and
management are controversial. DCIS incidence grew with the
expansion of screening mammography programs in the 1980s and
1990s, and DCIS is viewed as a major driver of overdiagnosis
and overtreatment. For pathologists, the diagnosis and
classification of DCIS is challenging due to undersampling
and interobserver variability. Understanding the progression
from normal breast tissue to DCIS and, ultimately, to
invasive cancer is limited by a paucity of natural history
data with multiple proposed evolutionary models of DCIS
initiation and progression. Although radiologists are
familiar with the classic presentation of DCIS as
asymptomatic calcifications at mammography, the expanded
pool of modalities, advanced imaging techniques, and image
analytics have identified multiple potential biomarkers of
histopathologic characteristics and prognosis. Finally,
there is growing interest in the nonsurgical management of
DCIS, including active surveillance, to reduce overtreatment
and provide patients with more personalized management
options. However, current biomarkers are not adept at
enabling identification of occult invasive disease at biopsy
or accurately predicting the risk of progression to invasive
disease. Several active surveillance trials are ongoing and
are expected to better identify women with low-risk DCIS who
may avoid surgery.},
Doi = {10.1148/radiol.211839},
Key = {fds367150}
}
@article{fds370457,
Author = {Schmitz, RS and van den Belt-Dusebout, AW and Clements, K and Ren, Y and Cresta, C and Timbres, J and Liu, Y-H and Byng, D and Lynch, T and Menegaz,
B and Collyar, D and Hyslop, T and Schaapveld, M and Sawyer, E and Hwang,
SE and Thompson, A and Ryser, MD and Wesseling, J and Lips, EH and Schmidt,
MK},
Title = {Subsequent invasive breast cancer risk after DCIS treatment
in multinational PRECISION consortium cohorts comprising
48,576 patients},
Journal = {Cancer Research},
Volume = {82},
Number = {12},
Year = {2022},
Key = {fds370457}
}
@article{fds359358,
Author = {Murgas, KA and Ma, Y and Shahidi, LK and Mukherjee, S and Allen, AS and Shibata, D and Ryser, MD},
Title = {A Bayesian hierarchical model to estimate DNA methylation
conservation in colorectal tumors.},
Journal = {Bioinformatics},
Volume = {38},
Number = {1},
Pages = {22-29},
Year = {2021},
Month = {December},
url = {http://dx.doi.org/10.1093/bioinformatics/btab637},
Abstract = {MOTIVATION: Conservation is broadly used to identify
biologically important (epi)genomic regions. In the case of
tumor growth, preferential conservation of DNA methylation
can be used to identify areas of particular functional
importance to the tumor. However, reliable assessment of
methylation conservation based on multiple tissue samples
per patient requires the decomposition of methylation
variation at multiple levels. RESULTS: We developed a
Bayesian hierarchical model that allows for variance
decomposition of methylation on three levels:
between-patient normal tissue variation, between-patient
tumor-effect variation and within-patient tumor variation.
We then defined a model-based conservation score to identify
loci of reduced within-tumor methylation variation relative
to between-patient variation. We fit the model to
multi-sample methylation array data from 21 colorectal
cancer (CRC) patients using a Monte Carlo Markov Chain
algorithm (Stan). Sets of genes implicated in CRC
tumorigenesis exhibited preferential conservation,
demonstrating the model's ability to identify functionally
relevant genes based on methylation conservation. A pathway
analysis of preferentially conserved genes implicated
several CRC relevant pathways and pathways related to
neoantigen presentation and immune evasion. Our findings
suggest that preferential methylation conservation may be
used to identify novel gene targets that are not
consistently mutated in CRC. The flexible structure makes
the model amenable to the analysis of more complex
multi-sample data structures. AVAILABILITY AND
IMPLEMENTATION: The data underlying this article are
available in the NCBI GEO Database, under accession code
GSE166212. The R analysis code is available at
https://github.com/kevin-murgas/DNAmethylation-hierarchicalmodel.
SUPPLEMENTARY INFORMATION: Supplementary data are available
at Bioinformatics online.},
Doi = {10.1093/bioinformatics/btab637},
Key = {fds359358}
}
@article{fds358880,
Author = {van Seijen, M and Lips, EH and Fu, L and Giardiello, D and van
Duijnhoven, F and de Munck, L and Elshof, LE and Thompson, A and Sawyer,
E and Ryser, MD and Hwang, ES and Schmidt, MK and Elkhuizen, PHM and Grand
Challenge PRECISION Consortium, and Wesseling, J and Schaapveld,
M},
Title = {Long-term risk of subsequent ipsilateral lesions after
surgery with or without radiotherapy for ductal carcinoma in
situ of the breast.},
Journal = {Br J Cancer},
Volume = {125},
Number = {10},
Pages = {1443-1449},
Year = {2021},
Month = {November},
url = {http://dx.doi.org/10.1038/s41416-021-01496-6},
Abstract = {BACKGROUND: Radiotherapy (RT) following breast-conserving
surgery (BCS) for ductal carcinoma in situ (DCIS) reduces
ipsilateral breast event rates in clinical trials. This
study assessed the impact of DCIS treatment on a 20-year
risk of ipsilateral DCIS (iDCIS) and ipsilateral invasive
breast cancer (iIBC) in a population-based cohort. METHODS:
The cohort comprised all women diagnosed with DCIS in the
Netherlands during 1989-2004 with follow-up until 2017.
Cumulative incidence of iDCIS and iIBC following BCS and
BCS + RT were assessed. Associations of DCIS treatment
with iDCIS and iIBC risk were estimated in multivariable Cox
models. RESULTS: The 20-year cumulative incidence of any
ipsilateral breast event was 30.6% (95% confidence interval
(CI): 28.9-32.6) after BCS compared to 18.2% (95% CI
16.3-20.3) following BCS + RT. Women treated with
BCS compared to BCS + RT had higher risk of developing
iDCIS and iIBC within 5 years after DCIS diagnosis (for
iDCIS: hazard ratio (HR)age < 50 3.2 (95% CI 1.6-6.6);
HRage ≥ 50 3.6 (95% CI 2.6-4.8) and for iIBC: HRage<50
2.1 (95% CI 1.4-3.2); HRage ≥ 50 4.3 (95% CI
3.0-6.0)). After 10 years, the risk of iDCIS and iIBC no
longer differed for BCS versus BCS + RT (for iDCIS:
HRage < 50 0.7 (95% CI 0.3-1.5); HRage ≥ 50 0.7
(95% CI 0.4-1.3) and for iIBC: HRage < 50 0.6 (95% CI
0.4-0.9); HRage ≥ 50 1.2 (95% CI 0.9-1.6)).
CONCLUSION: RT is associated with lower iDCIS and iIBC risk
up to 10 years after BCS, but this effect wanes
thereafter.},
Doi = {10.1038/s41416-021-01496-6},
Key = {fds358880}
}
@article{fds367151,
Author = {Byng, D and Retel, VP and van Harten, W and Rushing, CN and Thomas, SM and Lynch, T and McCarthy, A and Francescatti, AB and Frank, ES and Partridge, AH and Thompson, AM and Grimm, L and Hyslop, T and Hwang,
E-SS and Ryser, MD},
Title = {Disparities in surveillance imaging after breast conserving
surgery for primary DCIS.},
Journal = {Journal of Clinical Oncology : Official Journal of the
American Society of Clinical Oncology},
Volume = {39},
Number = {15_suppl},
Pages = {6516-6516},
Publisher = {American Society of Clinical Oncology (ASCO)},
Year = {2021},
Month = {May},
url = {http://dx.doi.org/10.1200/jco.2021.39.15_suppl.6516},
Abstract = {<jats:p> 6516 </jats:p><jats:p> Background: Due to the
elevated risk of ipsilateral invasive breast cancer (iIBC)
after diagnosis with primary ductal carcinoma in situ
(DCIS), professional guidelines recommend surveillance
screening within 6-12 months (mo) after completion of
initial local treatment and annually thereafter. To
characterize adherence to these guidelines, we explored
longitudinal patterns of utilization and factors associated
with the use of surveillance imaging (mammography, MRI,
ultrasound) for women with primary DCIS treated with breast
conserving surgery (BCS) ± radiotherapy (RT) within 6 mo of
diagnosis. Methods: A treatment-stratified random sample of
patients diagnosed with screen-detected and biopsy-confirmed
DCIS in 2008-15 was selected from 1,330 Commission on
Cancer-accredited facilities (up to 20/site) in the US. All
imaging exams coded as asymptomatic were collected from 6 mo
up to 10 years (yr) post-diagnosis. Time was defined
according to 12-mo long surveillance periods. To be included
in a given surveillance period, women had to be alive and
free of a new breast cancer diagnosis through the end of the
period. Women were classified as “consistent” screeners
if they had at least one surveillance screen during each
period, for the first 5 yr post-treatment or until
censoring, whichever occurred first. Repeated measures
multivariable logistic regression with generalized
estimating equations was used to model receipt of
surveillance breast imaging over time. The model included
clinical and socioeconomic features. Results: The final
analytic cohort contained 12,559 women; 8,989 (71.6%)
received RT after BCS. Median age was 60 yr (interquartile
range: 52-69) and median follow-up was 5.6 yr (95%
confidence interval [CI] 5.6-5.7). Among women who received
BCS (instead of BCS+RT), 62.5% (79.7%) underwent
surveillance imaging within 6-18 mo after diagnosis. 38.7%
(54.0%) were categorized as “consistent” screeners.
Compared to white women, Black women were less likely to
receive surveillance screening after treatment for primary
DCIS (odds ratio [OR] 0.85, 95% CI 0.77-0.94). Hispanic
ethnicity had a similar association (OR 0.86, 95% CI
0.74-0.99) compared to non-Hispanic ethnicity. Women with
private insurance, compared to government insurance, were
more likely to receive screening (OR 1.20, 95% CI
1.11-1.30). Prognostic tumor features indicative of a higher
risk of subsequent iIBC, including higher grade, presence of
comedonecrosis, and hormone receptor-negative DCIS, were not
associated with screening uptake. Conclusions: Despite
guidelines recommending annual surveillance imaging, many
women with primary DCIS do not undergo regular imaging after
BCS. The findings from this US-based study suggest that
disparities in screening uptake are associated with
race/ethnicity and insurance status rather than prognostic
tumor features. </jats:p>},
Doi = {10.1200/jco.2021.39.15_suppl.6516},
Key = {fds367151}
}
@article{fds357629,
Author = {Chan, L and Fridman, I and Grant, J and Hwang, ES and Weinfurt, K and Ryser, MD},
Title = {USING PAIRWISE SIMULATED OUTCOMES TO IMPROVE THE
UNDERSTANDING OF THE STATISTICAL DIFFERENCES BETWEEN TWO
RISK DISTRIBUTIONS},
Journal = {Medical Decision Making : an International Journal of the
Society for Medical Decision Making},
Volume = {41},
Number = {4},
Pages = {E284-E286},
Year = {2021},
Key = {fds357629}
}
@article{fds366619,
Author = {Ryser, MD and Rushing, CN and Thomas, SM and Lynch, T and McCarthy, A and Mohammed, ZA and Francescatti, AB and Frank, ES and Partridge, AH and Thompson, AM and Hyslop, T and Hwang, ES},
Title = {Ipsilateral invasive cancer risk after diagnosis with ductal
carcinoma in situ in patients with and without index
surgery: The effects of endocrine therapy and radiation
treatment},
Journal = {Cancer Research},
Volume = {81},
Number = {4},
Year = {2021},
Key = {fds366619}
}
@article{fds352569,
Author = {Butt, J and Blot, WJ and Visvanathan, K and Le Marchand and L and Wilkens,
LR and Chen, Y and Sesso, HD and Teras, L and Ryser, MD and Hyslop, T and Wassertheil-Smoller, S and Tinker, LF and Potter, JD and Song, M and Berndt, SI and Waterboer, T and Pawlita, M and Epplein,
M},
Title = {Auto-antibodies to p53 and the Subsequent Development of
Colorectal Cancer in a U.S. Prospective Cohort
Consortium.},
Journal = {Cancer Epidemiol Biomarkers Prev},
Volume = {29},
Number = {12},
Pages = {2729-2734},
Year = {2020},
Month = {December},
url = {http://dx.doi.org/10.1158/1055-9965.EPI-20-0780},
Abstract = {BACKGROUND: Auto-antibodies to tumor suppressor p53 are
found in a subset of patients with colorectal cancer. A
recent prospective study in the United States has reported a
significant 1.8-fold increased odds for colorectal cancer
development with prediagnostic seropositivity to p53. In
this study, we sought to examine this association in a U.S.
colorectal cancer cohort consortium to evaluate the
potential utility of p53 auto-antibodies as an early
biomarker for colorectal cancer. METHODS: Auto-antibodies to
p53 were measured in prediagnostic blood samples of 3,702
incident colorectal cancer cases and 3,702 controls, matched
by age, race, and sex, from 9 U.S. prospective cohorts. The
association of seropositivity to p53 with colorectal cancer
risk, overall and by time between blood draw and diagnosis,
was determined by conditional logistic regression. RESULTS:
Overall, 5% of controls and 7% of cases were seropositive to
p53, resulting in a statistically significant 33% increased
colorectal cancer risk [odds ratio (OR), 1.33; 95%
confidence interval (CI), 1.09-1.61]. By follow-up time, the
association was only significant with colorectal cancer
diagnoses within 4 years after blood draw (OR, 2.27; 95% CI,
1.62-3.19), but not thereafter (OR, 0.97; 95% CI,
0.76-1.24). CONCLUSIONS: In this large consortium of
prospective cohorts, we found that prediagnostic
seropositivity to tumor suppressor p53 was significantly
associated with an over 2-fold increased odds of developing
colorectal cancer within 4 years after blood draw. IMPACT:
Our finding suggests that p53 seropositivity may not be a
useful predictor of long-term colorectal cancer risk;
however, it might be considered as a marker to aid in the
early diagnosis of colorectal cancer.},
Doi = {10.1158/1055-9965.EPI-20-0780},
Key = {fds352569}
}
@article{fds352570,
Author = {Brouwer, AF and He, K and Chinn, SB and Mondul, AM and Chapman, CH and Ryser, MD and Banerjee, M and Eisenberg, MC and Meza, R and Taylor,
JMG},
Title = {Time-varying survival effects for squamous cell carcinomas
at oropharyngeal and nonoropharyngeal head and neck sites in
the United States, 1973-2015.},
Journal = {Cancer},
Volume = {126},
Number = {23},
Pages = {5137-5146},
Year = {2020},
Month = {December},
url = {http://dx.doi.org/10.1002/cncr.33174},
Abstract = {BACKGROUND: Anatomical site is strongly associated with head
and neck cancer etiology, and etiology and patient
sociodemographic characteristics are prognostic factors for
survival. It is not known whether the effects of these
predictors persist over the postdiagnosis period or are
strongest proximal to the time of diagnosis. METHODS: Using
survival times and causes of death for 180,434 patients with
head and neck cancer in the Surveillance, Epidemiology, and
End Results cancer registry (1973-2015), the empirical
cumulative incidences of cancer-specific death and
other-cause death were calculated with a competing risks
framework, and the time-dependent effects (hazard ratios) of
anatomical tumor site (oropharynx, oral cavity, or
hypopharynx/larynx), age, sex, race, and year of diagnosis
on cancer-specific death and other-cause death, stratified
by tumor stage, were estimated. RESULTS: All effects were
significantly time-varying (P < .001). Patients with
nonoropharyngeal cancer had a higher hazard of
cancer-specific death but a similar cumulative fraction of
deaths because of a higher rate of death from other causes.
Cancer-specific survival has not changed for patients with
nonoropharyngeal cancer over the past decades but has
improved since 2000 for patients with oropharyngeal cancer.
The effects of age and sex on cancer survival were strongest
proximal to the diagnosis, whereas the effect of race
persisted over time. CONCLUSIONS: Recent improvements in
survival for patients with oropharyngeal cancer may be due
more to an increasing fraction of cancers attributable to
human papillomavirus than to increasing treatment
effectiveness. The prognostic strength of anatomical site
and other predictors changes over the postdiagnosis period.
LAY SUMMARY: It is generally assumed that the effects of
tumor and personal characteristics on the survival of
patients with head and neck cancer are fixed over time, but
this study shows that many factors are most important only
in the first few years after diagnosis. Also, recent
improvements in the survival of patients with head and neck
cancer appear to benefit only patients with cancers of the
oropharynx. The improvements may be due more to an
increasing fraction of cancers caused by human
papillomavirus (which generally have better outcomes) than
to advances in head and neck cancer treatment
overall.},
Doi = {10.1002/cncr.33174},
Key = {fds352570}
}
@article{fds355730,
Author = {Rodriguez-Homs, LG and Hammill, BG and Ryser, MD and Phillips, HR and Mosca, PJ},
Title = {Relationship Between HCAHPS Scores and Survey Response Rate
Is Linked to Hospital Size.},
Journal = {J Patient Exp},
Volume = {7},
Number = {6},
Pages = {1543-1548},
Year = {2020},
Month = {December},
url = {http://dx.doi.org/10.1177/2374373520932458},
Abstract = {Patient experience is an important dimension of health care
quality and is assessed using the standard Hospital Consumer
Assessment of Healthcare Providers and Systems (HCAHPS)
survey for inpatients. The HCAHPS scores may vary based on
survey response rate and hospital size. The objective of
this study was to describe the association between survey
response rate and HCAHPS scores and examine whether the
relationship varies based on hospital size. Medicare's
Hospital Compare publicly reported HCAHPS data were used.
Pearson correlation, controlling for number of staffed beds,
and linear regression models were used for the analysis.
Hospitals were grouped into quartiles based on number of
staffed beds to delineate the effect of increasing hospital
size on the relationship between survey response rate and
HCAHPS scores. A significant association between HCAHPS
survey response rate and all examined HCAHPS domain scores
was observed. The effect size across HCAHPS domains varied
based on hospital size. The relationship between HCAHPS
score and survey response rate differed significantly
between hospitals in the smallest and largest size quartiles
for discharge information, nurse communication, and hospital
quietness. While a causal relationship cannot be inferred
from this study, the response rate could be a direct and/or
indirect driver of HCAHPS scores. Future research should be
aimed to further explore the basis of this relationship and
to determine how it may inform the interpretation of HCAHPS
results.},
Doi = {10.1177/2374373520932458},
Key = {fds355730}
}
@article{fds354107,
Author = {Epplein, M and Le Marchand and L and Cover, TL and Song, M and Blot, WJ and Peek, RM and Teras, LR and Visvanathan, K and Chen, Y and Sesso, HD and Zeleniuch-Jacquotte, A and Berndt, SI and Potter, JD and Ryser, MD and Haiman, CA and Wassertheil-Smoller, S and Tinker, LF and Waterboer,
T and Butt, J},
Title = {Association of Combined Sero-Positivity to Helicobacter
pylori and Streptococcus gallolyticus with Risk of
Colorectal Cancer.},
Journal = {Microorganisms},
Volume = {8},
Number = {11},
Year = {2020},
Month = {October},
url = {http://dx.doi.org/10.3390/microorganisms8111698},
Abstract = {Previously, we found that risk of colorectal cancer (CRC) is
increased in individuals with serum antibody response to
both Helicobacter pylori (HP) Vacuolating Cytotoxin (VacA)
toxin or Streptococcus gallolyticus (SGG) pilus protein
Gallo2178. In the present analysis, we tested the hypothesis
that combined seropositivity to both antigens is a better
indicator of CRC risk than seropositivity to single
antigens. We used multiplex serologic assays to analyze
pre-diagnostic serum for antibody responses from 4063
incident CRC cases and 4063 matched controls from 10 US
cohorts. To examine whether combined SGG Gallo2178 and HP
VacA sero-status was associated with CRC risk, we used
conditional logistic regression models to estimate odds
ratios (ORs) and 95% confidence intervals (CIs). Compared to
dual sero-negative individuals, there was no increased risk
for individuals sero-positive to SGG Gallo2178 only (OR:
0.93; 95% CI: 0.66-1.31) or to HP VacA only (OR: 1.08; 95%
CI: 0.98-1.19). However, dual sero-positive individuals had
a >50% increased odds of developing CRC (OR: 1.54; 95% CI:
1.16-2.04), suggesting an interaction between antibody
responses to these two pathogens and CRC risk (pinteraction
= 0.06). In conclusion, this study suggests that dual
sero-positivity to HP VacA and SGG Gallo2178 is an indicator
of increased risk of CRC.},
Doi = {10.3390/microorganisms8111698},
Key = {fds354107}
}
@article{fds352571,
Author = {Shehata, MN and Rahbar, H and Flanagan, MR and Kilgore, MR and Lee, CI and Ryser, MD and Lowry, KP},
Title = {Risk for Upgrade to Malignancy After Breast Core Needle
Biopsy Diagnosis of Lobular Neoplasia: A Systematic Review
and Meta-Analysis.},
Journal = {Journal of the American College of Radiology :
Jacr},
Volume = {17},
Number = {10},
Pages = {1207-1219},
Year = {2020},
Month = {October},
url = {http://dx.doi.org/10.1016/j.jacr.2020.07.036},
Abstract = {PURPOSE: Lobular neoplasia (LN) detected on breast core
needle biopsy is frequently managed with surgical excision
because of concern for undersampled malignancy. The authors
performed a systematic review and meta-analysis to estimate
the risk for upgrade to malignancy in the setting of
imaging-concordant classic LN diagnosed on core biopsy.
METHODS: PubMed and Embase were searched for original
articles published from 1998 to 2020 that reported rates of
upgrade to malignancy for classic LN, including atypical
lobular hyperplasia (ALH) and classic lobular carcinoma in
situ (LCIS). Two reviewers extracted study data and assessed
the following quality criteria: exclusion of variant LCIS,
exclusion of imaging-discordant lesions, and outcome
reporting for ≥70% of lesions. For studies meeting all
criteria, pooled risks for upgrade to any malignancy
(invasive carcinoma or ductal carcinoma in situ) and
invasive malignancy for all LN, ALH, and LCIS were estimated
using random-effects models. RESULTS: For 65 full-text
articles included in the review, the risk for upgrade to any
malignancy ranged from 0% to 45%. Among the 16 studies that
met all quality criteria for the meta-analysis, pooled
risks for upgrade to any malignancy were 3.1% (95%
confidence interval [CI], 1.8%-5.2%) for all LN, 2.5% (95%
CI, 1.6%-3.9%) for ALH, and 5.8% (95% CI, 2.9%-11.3%) for
LCIS. Risks for upgrade to invasive malignancy were 1.3%
(95% CI, 0.7%-2.4%) for all LN, 0.4% (95% CI, 0.0%-4.2%) for
ALH, and 3.5% (95% CI, 2.0%-5.9%) for LCIS. CONCLUSIONS: The
risk for upgrade to malignancy for LN found on breast biopsy
is low. Imaging surveillance can likely be offered as an
alternative to surgical management for LN, particularly for
ALH.},
Doi = {10.1016/j.jacr.2020.07.036},
Key = {fds352571}
}
@article{fds350404,
Author = {Williamson, T and Ryser, MD and Ubel, PA and Abdelgadir, J and Spears,
CA and Liu, B and Komisarow, J and Lemmon, ME and Elsamadicy, A and Lad,
SP},
Title = {Withdrawal of Life-supporting Treatment in Severe Traumatic
Brain Injury.},
Journal = {Jama Surg},
Volume = {155},
Number = {8},
Pages = {723-731},
Year = {2020},
Month = {August},
url = {http://dx.doi.org/10.1001/jamasurg.2020.1790},
Abstract = {IMPORTANCE: There are limited data on which factors affect
the critical and complex decision to withdraw
life-supporting treatment (LST) in patients with severe
traumatic brain injury (sTBI). OBJECTIVE: To determine
demographic and clinical factors associated with the
decision to withdraw LST in patients with sTBI. DESIGN,
SETTING, AND PARTICIPANTS: This retrospective analysis of
inpatient data from more than 825 trauma centers across the
US in the American College of Surgeons Trauma Quality
Improvement Program database from January 2013 to December
2015 included adult patients with sTBI and documentation of
a decision regarding withdrawal of LST (WLST). Data analysis
was conducted in September 2019. MAIN OUTCOMES AND MEASURES:
Factors associated with WLST in sTBI. RESULTS: A total of
37931 patients (9817 women [25.9%]) were included in the
multivariable analysis; 7864 (20.7%) had WLST. Black
patients (4806 [13.2%]; odds ratio [OR], 0.66; 95% CI,
0.59-0.72; P < .001) and patients of other race (4798
[13.2%]; OR, 0.83; 95% CI, 0.76-0.91; P < .001) were
less likely than white patients (26 864 [73.7%]) to have
WLST. Patients from hospitals in the Midwest (OR, 1.12; 95%
CI, 1.04-1.20; P = .002) or Northeast (OR, 1.23; 95% CI,
1.13-1.34; P < .001) were more likely to have WLST than
patients from hospitals in the South. Patients with Medicare
(OR, 1.55; 95% CI, 1.43-1.69; P < .001) and self-pay
patients (OR, 1.36; 95% CI, 1.25-1.47; P < .001) were
more likely to have WLST than patients with private
insurance. Older patients and those with lower Glasgow Coma
Scale scores, higher Injury Severity Scores, or craniotomy
were generally more likely to have WLST. Withdrawal of LST
was more likely for patients with functionally dependent
health status (OR, 1.30; 95% CI, 1.08-1.58; P = .01),
hematoma (OR, 1.19; 95% CI, 1.12-1.27; P < .001),
dementia (OR, 1.29; 95% CI, 1.08-1.53; P = .004), and
disseminated cancer (OR, 2.82; 95% CI, 2.07-3.82;
P < .001) than for patients without these conditions.
CONCLUSIONS AND RELEVANCE: Withdrawal of LST is common in
sTBI and socioeconomic factors are associated with the
decision to withdraw LST. These results highlight the many
factors that contribute to decision-making in sTBI and
demonstrate that in a complex and variable disease process,
variation based on race, payment, and region presents as a
potential challenge.},
Doi = {10.1001/jamasurg.2020.1790},
Key = {fds350404}
}
@article{fds350405,
Author = {Chootipongchaivat, S and van Ravesteyn, NT and Li, X and Huang, H and Weedon-Fekjær, H and Ryser, MD and Weaver, DL and Burnside, ES and Heckman-Stoddard, BM and de Koning, HJ and Lee,
SJ},
Title = {Modeling the natural history of ductal carcinoma in situ
based on population data.},
Journal = {Breast Cancer Res},
Volume = {22},
Number = {1},
Pages = {53},
Year = {2020},
Month = {May},
url = {http://dx.doi.org/10.1186/s13058-020-01287-6},
Abstract = {BACKGROUND: The incidence of ductal carcinoma in situ (DCIS)
has increased substantially since the introduction of
mammography screening. Nevertheless, little is known about
the natural history of preclinical DCIS in the absence of
biopsy or complete excision. METHODS: Two well-established
population models evaluated six possible DCIS natural
history submodels. The submodels assumed 30%, 50%, or 80% of
breast lesions progress from undetectable DCIS to
preclinical screen-detectable DCIS; each model additionally
allowed or prohibited DCIS regression. Preclinical
screen-detectable DCIS could also progress to clinical DCIS
or invasive breast cancer (IBC). Applying US population
screening dissemination patterns, the models projected
age-specific DCIS and IBC incidence that were compared to
Surveillance, Epidemiology, and End Results data. Models
estimated mean sojourn time (MST) in the preclinical
screen-detectable DCIS state, overdiagnosis, and the risk of
progression from preclinical screen-detectable DCIS.
RESULTS: Without biopsy and surgical excision, the majority
of DCIS (64-100%) in the preclinical screen-detectable state
progressed to IBC in submodels assuming no DCIS regression
(36-100% in submodels allowing for DCIS regression). DCIS
overdiagnosis differed substantially between models and
submodels, 3.1-65.8%. IBC overdiagnosis ranged 1.3-2.4%.
Submodels assuming DCIS regression resulted in a higher DCIS
overdiagnosis than submodels without DCIS regression. MST
for progressive DCIS varied between 0.2 and 2.5 years.
CONCLUSIONS: Our findings suggest that the majority of
screen-detectable but unbiopsied preclinical DCIS lesions
progress to IBC and that the MST is relatively short.
Nevertheless, due to the heterogeneity of DCIS, more
research is needed to understand the progression of DCIS by
grades and molecular subtypes.},
Doi = {10.1186/s13058-020-01287-6},
Key = {fds350405}
}
@article{fds349460,
Author = {Rozenblatt-Rosen, O and Regev, A and Oberdoerffer, P and Nawy, T and Hupalowska, A and Rood, JE and Ashenberg, O and Cerami, E and Coffey,
RJ and Demir, E and Ding, L and Esplin, ED and Ford, JM and Goecks, J and Ghosh, S and Gray, JW and Guinney, J and Hanlon, SE and Hughes, SK and Hwang, ES and Iacobuzio-Donahue, CA and Jané-Valbuena, J and Johnson, BE and Lau, KS and Lively, T and Mazzilli, SA and Pe'er, D and Santagata, S and Shalek, AK and Schapiro, D and Snyder, MP and Sorger,
PK and Spira, AE and Srivastava, S and Tan, K and West, RB and Williams,
EH and Human Tumor Atlas Network},
Title = {The Human Tumor Atlas Network: Charting Tumor Transitions
across Space and Time at Single-Cell Resolution.},
Journal = {Cell},
Volume = {181},
Number = {2},
Pages = {236-249},
Year = {2020},
Month = {April},
url = {http://dx.doi.org/10.1016/j.cell.2020.03.053},
Abstract = {Crucial transitions in cancer-including tumor initiation,
local expansion, metastasis, and therapeutic
resistance-involve complex interactions between cells within
the dynamic tumor ecosystem. Transformative single-cell
genomics technologies and spatial multiplex in situ methods
now provide an opportunity to interrogate this complexity at
unprecedented resolution. The Human Tumor Atlas Network
(HTAN), part of the National Cancer Institute (NCI) Cancer
Moonshot Initiative, will establish a clinical,
experimental, computational, and organizational framework to
generate informative and accessible three-dimensional
atlases of cancer transitions for a diverse set of tumor
types. This effort complements both ongoing efforts to map
healthy organs and previous large-scale cancer genomics
approaches focused on bulk sequencing at a single point in
time. Generating single-cell, multiparametric, longitudinal
atlases and integrating them with clinical outcomes should
help identify novel predictive biomarkers and features as
well as therapeutically relevant cell types, cell states,
and cellular interactions across transitions. The resulting
tumor atlases should have a profound impact on our
understanding of cancer biology and have the potential to
improve cancer detection, prevention, and therapeutic
discovery for better precision-medicine treatments of cancer
patients and those at risk for cancer.},
Doi = {10.1016/j.cell.2020.03.053},
Key = {fds349460}
}
@article{fds348805,
Author = {Ryser, MD and Mallo, D and Hall, A and Hardman, T and King, LM and Tatishchev, S and Sorribes, IC and Maley, CC and Marks, JR and Hwang,
ES and Shibata, D},
Title = {Minimal barriers to invasion during human colorectal tumor
growth.},
Journal = {Nature Communications},
Volume = {11},
Number = {1},
Pages = {1280},
Year = {2020},
Month = {March},
url = {http://dx.doi.org/10.1038/s41467-020-14908-7},
Abstract = {Intra-tumoral heterogeneity (ITH) could represent clonal
evolution where subclones with greater fitness confer more
malignant phenotypes and invasion constitutes an
evolutionary bottleneck. Alternatively, ITH could represent
branching evolution with invasion of multiple subclones. The
two models respectively predict a hierarchy of subclones
arranged by phenotype, or multiple subclones with shared
phenotypes. We delineate these modes of invasion by merging
ancestral, topographic, and phenotypic information from 12
human colorectal tumors (11 carcinomas, 1 adenoma) obtained
through saturation microdissection of 325 small tumor
regions. The majority of subclones (29/46, 60%) share
superficial and invasive phenotypes. Of 11 carcinomas, 9
show evidence of multiclonal invasion, and invasive and
metastatic subclones arise early along the ancestral trees.
Early multiclonal invasion in the majority of these tumors
indicates the expansion of co-evolving subclones with
similar malignant potential in absence of late bottlenecks
and suggests that barriers to invasion are minimal during
colorectal cancer growth.},
Doi = {10.1038/s41467-020-14908-7},
Key = {fds348805}
}
@article{fds349461,
Author = {Ryser, MD and Hwang, ES},
Title = {Response to Habel and Buist.},
Journal = {J Natl Cancer Inst},
Volume = {112},
Number = {2},
Pages = {216-217},
Year = {2020},
Month = {February},
url = {http://dx.doi.org/10.1093/jnci/djz120},
Doi = {10.1093/jnci/djz120},
Key = {fds349461}
}
@article{fds349462,
Author = {Fridman, I and Kumaresan, V and Vijendra, P and Seshadri, P and Garland,
S and Kim, G and Fagerlin, A and Ubel, PA and Ryser,
MD},
Title = {INFORMATION PROCESSING AND PATIENT DECISION MAKING: A BIG
DATA APPROACH TO TREATMENT CHOICE IN PROSTATE CANCER
PATIENTS},
Journal = {Medical Decision Making : an International Journal of the
Society for Medical Decision Making},
Volume = {40},
Number = {1},
Pages = {E183-E184},
Publisher = {SAGE PUBLICATIONS INC},
Year = {2020},
Month = {January},
Key = {fds349462}
}
@article{fds349463,
Author = {Williamson, T and Ryser, MD and Abdelgadir, J and Lemmon, M and Barks,
MC and Zakare, R and Ubel, PA},
Title = {Surgical decision making in the setting of severe traumatic
brain injury: A survey of neurosurgeons.},
Journal = {Plos One},
Volume = {15},
Number = {3},
Pages = {e0228947},
Year = {2020},
url = {http://dx.doi.org/10.1371/journal.pone.0228947},
Abstract = {BACKGROUND: Surgical decision-making in severe traumatic
brain injury (TBI) is complex. Neurosurgeons weigh risks and
benefits of interventions that have the potential to both
maximize the chance of recovery and prolong suffering.
Inaccurate prognostication can lead to over- or
under-estimation of outcomes and influence treatment
recommendations. OBJECTIVE: To evaluate the impact of
evidence-based risk estimates on neurosurgeon treatment
recommendations and prognostic beliefs in severe TBI.
METHODS: In a survey-based randomized experiment, a total of
139 neurosurgeons were presented with two hypothetical
patient with severe TBI and subdural hematoma; the
intervention group received additional evidence-based risk
estimates for each patient. The main outcome was
neurosurgeon treatment recommendation of non-surgical
management. Secondary outcomes included prediction of
functional recovery at six months. RESULTS: In the first
patient scenario, 22% of neurosurgeons recommended
non-surgical management and provision of evidence-based risk
estimates increased the propensity to recommend non-surgical
treatment (odds ratio [OR]: 2.81, 95% CI: 1.21-6.98; p =
0.02). Neurosurgeon prognostic beliefs of 6-month functional
recovery were variable in both control (median 20%, IQR:
10%-40%) and intervention (30% IQR: 10%-50%) groups and
neurosurgeons were less likely to recommend non-surgical
management when they believed prognosis was favorable (odds
ratio [OR] per percentage point increase in 6-month
functional recovery: 0.97, 95% confidence interval [CI]:
0.95-0.99). The results for the second patient scenario were
qualitatively similar. CONCLUSIONS: Our findings show that
the provision of evidence-based risk predictions can
influence neurosurgeon treatment recommendations and
prognostication, but the effect is modest and there remains
large variability in neurosurgeon prognostication.},
Doi = {10.1371/journal.pone.0228947},
Key = {fds349463}
}
@article{fds354106,
Author = {Ryser, MD and Sorribes, IC and Greenwald, M and Wu, E and Hall, A and Mallo, D and King, LM and Hardman, T and Simpson, L and Maley, CC and Marks, JR and Shibata, D and Hwang, ES},
Title = {Inferring the evolutionary dynamics of ductal carcinoma in
situ through multi-regional sequencing and mathematical
modeling.},
Journal = {Cancer Research},
Volume = {80},
Number = {21},
Year = {2020},
Key = {fds354106}
}
@article{fds354108,
Author = {Ryser, MD and Hendrix, L and Thomas, SM and Lynch, T and McCarthy, A and Mohammed, Z and Francescatti, AB and Frank, ES and Partridge, AH and Thompson, AM and Hyslop, T and Hwang, E-SS},
Title = {Ipsilateral invasive cancer risk after diagnosis with ductal
carcinoma in situ (DCIS): Comparison of patients with and
without index surgery.},
Journal = {Journal of Clinical Oncology : Official Journal of the
American Society of Clinical Oncology},
Volume = {38},
Number = {15},
Year = {2020},
Key = {fds354108}
}
@article{fds342717,
Author = {Ryser, MD and Weaver, DL and Zhao, F and Worni, M and Grimm, LJ and Gulati,
R and Etzioni, R and Hyslop, T and Lee, SJ and Hwang,
ES},
Title = {Cancer Outcomes in DCIS Patients Without Locoregional
Treatment.},
Journal = {J Natl Cancer Inst},
Volume = {111},
Number = {9},
Pages = {952-960},
Year = {2019},
Month = {September},
url = {http://dx.doi.org/10.1093/jnci/djy220},
Abstract = {BACKGROUND: The vast majority of women diagnosed with ductal
carcinoma in situ (DCIS) undergo treatment. Therefore, the
risks of invasive progression and competing death in the
absence of locoregional therapy are uncertain. METHODS: We
performed survival analyses of patient-level data from DCIS
patients who did not receive definitive surgery or radiation
therapy as recorded in the US National Cancer Institute's
Surveillance, Epidemiology, and End Results program
(1992-2014). Kaplan-Meier curves were used to estimate the
net risk of subsequent ipsilateral invasive cancer. The
cumulative incidences of ipsilateral invasive cancer,
contralateral breast cancer, and death were estimated using
competing risk methods. RESULTS: A total of 1286 DCIS
patients who did not undergo locoregional therapy were
identified. Median age at diagnosis was 60 years
(inter-quartile range = 51-74 years), with median follow-up
of 5.5 years (inter-quartile range = 2.3-10.6 years).
Among patients with tumor grade I/II (n = 547), the
10-year net risk of ipsilateral invasive breast cancer was
12.2% (95% confidence interval [CI] = 8.6% to 17.1%)
compared with 17.6% (95% CI = 12.1% to 25.2%) among patients
with tumor grade III (n = 244) and 10.1% (95% CI = 7.4%
to 13.8%) among patients with unknown grade (n = 495).
Among all patients, the 10-year cumulative incidences of
ipsilateral invasive cancer, contralateral breast cancer,
and all-cause mortality were 10.5% (95% CI = 8.5% to 12.4%),
3.9% (95% CI = 2.6% to 5.2%), and 24.1% (95% CI = 21.2% to
26.9%), respectively. CONCLUSION: Despite limited data, our
findings suggest that DCIS patients without locoregional
treatment have a limited risk of invasive progression.
Although the cohort is not representative of the general
population of patients diagnosed with DCIS, the findings
suggest that there may be overtreatment, especially among
older patients and patients with elevated
comorbidities.},
Doi = {10.1093/jnci/djy220},
Key = {fds342717}
}
@article{fds345487,
Author = {Ryser, MD and Hendrix, LH and Worni, M and Liu, Y and Hyslop, T and Hwang,
ES},
Title = {Incidence of Ductal Carcinoma In Situ in the United States,
2000-2014.},
Journal = {Cancer Epidemiol Biomarkers Prev},
Volume = {28},
Number = {8},
Pages = {1316-1323},
Year = {2019},
Month = {August},
url = {http://dx.doi.org/10.1158/1055-9965.EPI-18-1262},
Abstract = {BACKGROUND: In absence of definitive molecular risk markers,
clinical management of patients diagnosed with ductal
carcinoma in situ (DCIS) remains largely guided by patient
and tumor characteristics. In this study, we analyzed recent
trends in DCIS incidence and compared them against trends in
mammography use. METHODS: The Surveillance, Epidemiology,
and End Results registry was queried for patients diagnosed
with DCIS from 2000 to 2014 (18 registries). Joinpoint
regression analyses were used to compute age- and
race-stratified trends in age-adjusted incidence of DCIS.
The patterns of DCIS incidence were compared against
mammography utilization data from the National Health
Interview Survey. RESULTS: Between 2000 and 2014, overall
DCIS incidence in the U.S. population was stable (P = 0.24).
Among age groups 20 to 44 years and 45 to 55 years, DCIS
incidence increased by 1.3% (P = 0.001) and 0.6% (P = 0.02)
per year, respectively. Although stable among white women,
DCIS incidence increased among black women and women of
other races by 1.6% (P < 0.001) and 1.0% (P = 0.002) per
year, respectively. Mammography uptake correlated well with
DCIS incidence, with the exception of women ages 40 to 49
years and black women who experienced an increase in DCIS
incidence despite stagnating and decreasing mammography
uptake, respectively. CONCLUSIONS: Overall DCIS incidence
rates have remained stable between 2000 and 2014. However,
subgroup analyses revealed an increase in incidence among
both younger women and black women. IMPACT: DCIS incidence
trends did not correlate with the mammography uptake
patterns, suggesting that etiologic factors other than
screening may be leading to an increased DCIS incidence in
these groups.},
Doi = {10.1158/1055-9965.EPI-18-1262},
Key = {fds345487}
}
@article{fds343483,
Author = {Grimm, LJ and Miller, MM and Thomas, SM and Liu, Y and Lo, JY and Hwang,
ES and Hyslop, T and Ryser, MD},
Title = {Growth Dynamics of Mammographic Calcifications:
Differentiating Ductal Carcinoma in Situ from Benign Breast
Disease.},
Journal = {Radiology},
Volume = {292},
Number = {1},
Pages = {77-83},
Year = {2019},
Month = {July},
url = {http://dx.doi.org/10.1148/radiol.2019182599},
Abstract = {Background Most ductal carcinoma in situ (DCIS) lesions are
first detected on screening mammograms as calcifications.
However, false-positive biopsy rates for calcifications
range from 30% to 87%. Improved methods to differentiate
benign from malignant calcifications are thus needed.
Purpose To quantify the growth rates of DCIS and benign
breast disease that manifest as mammographic calcifications.
Materials and Methods All calcifications (n = 2359) for
which a stereotactic biopsy was performed from 2008 through
2015 at Duke University Medical Center were retrospectively
identified. Mammograms from all cases of DCIS (n = 404) were
reviewed for calcifications that were visible on mammograms
taken at least 6 months before biopsy. Women with at least
one prior mammogram with visible calcifications were age-
and race-matched 1:2 to women with a benign breast biopsy
and calcifications visible on prior mammograms. The long
axis of the calcifications was measured on all mammograms.
Multivariable adjusted linear mixed-effects models estimated
the association of calcification growth rates with patholo
findings. Hierarchical clustering accounted for matching
benign and DCIS groups. Results A total of 74 DCIS
calcifications and 148 benign calcifications were included
for final analysis. The median patient age was 62 years
(interquartile range, 51-71 years). No significant
difference in breast density (P > .05) or number of
available mammograms (P > .05) was detected between groups.
Calcifications associated with DCIS were larger than those
associated with benign breast disease at biopsy (median, 10
mm vs 6 mm, respectively; P < .001). After adjustment, the
relative annual increase in the long-axis length of DCIS
calcifications was greater than that of benign breast
calcifications (96% [95% confidence interval: 72%, 224%] vs
68% [95% confidence interval: 56%, 80%] per year,
respectively; P < .001). Conclusion Ductal carcinoma in situ
calcifications are more extensive at diagnosis and grow
faster in extent than those associated with benign breast
disease. The rate of calcification change may help to
discriminate benign from malignant calcifications. © RSNA,
2019 Online supplemental material is available for this
article.},
Doi = {10.1148/radiol.2019182599},
Key = {fds343483}
}
@article{fds339498,
Author = {Shen, Y and Dong, W and Gulati, R and Ryser, MD and Etzioni,
R},
Title = {Estimating the frequency of indolent breast cancer in
screening trials.},
Journal = {Stat Methods Med Res},
Volume = {28},
Number = {4},
Pages = {1261-1271},
Year = {2019},
Month = {April},
url = {http://dx.doi.org/10.1177/0962280217754232},
Abstract = {Cancer screening can detect cancer that would not have been
detected in a patient's lifetime without screening. Standard
methods for analyzing screening data do not explicitly
account for the possibility that a fraction of tumors may
remain latent indefinitely. We extend these methods by
representing cancers as a mixture of those that progress to
symptoms (progressive) and those that remain latent
(indolent). Given sensitivity of the screening test, we
derive likelihood expressions to simultaneously estimate (1)
the rate of onset of preclinical cancer, (2) the average
preclinical duration of progressive cancers, and (3) the
fraction of preclinical cancers that are indolent.
Simulations demonstrate satisfactory performance of the
estimation approach to identify model parameters subject to
precise specifications of input parameters and adequate
numbers of interval cancers. In application to four breast
cancer screening trials, the estimated indolent fraction
among preclinical cancers varies between 2% and 35% when
assuming 80% test sensitivity and varying specifications for
the earliest time that participants could plausibly have
developed cancer. We conclude that standard methods for
analyzing screening data can be extended to allow some
indolent cancers, but accurate estimation depends on
correctly specifying key inputs that may be difficult to
determine precisely in practice.},
Doi = {10.1177/0962280217754232},
Key = {fds339498}
}
@article{fds339494,
Author = {Ryser, MD and Gulati, R and Eisenberg, MC and Shen, Y and Hwang, ES and Etzioni, RB},
Title = {Identification of the Fraction of Indolent Tumors and
Associated Overdiagnosis in Breast Cancer Screening
Trials.},
Journal = {American Journal of Epidemiology},
Volume = {188},
Number = {1},
Pages = {197-205},
Year = {2019},
Month = {January},
url = {http://dx.doi.org/10.1093/aje/kwy214},
Abstract = {It is generally accepted that some screen-detected breast
cancers are overdiagnosed and would not progress to
symptomatic cancer if left untreated. However, precise
estimates of the fraction of nonprogressive cancers remain
elusive. In recognition of the weaknesses of overdiagnosis
estimation methods based on excess incidence, there is a
need for model-based approaches that accommodate
nonprogressive lesions. Here, we present an in-depth
analysis of a generalized model of breast cancer natural
history that allows for a mixture of progressive and
indolent lesions. We provide a formal proof of global
structural identifiability of the model and use simulation
to identify conditions that allow for parameter estimates
that are sufficiently precise and practically actionable. We
show that clinical follow-up after the last screening can
play a critical role in ensuring adequately precise
identification of the fraction of indolent cancers in a
stop-screen trial design, and we demonstrate that model
misspecification can lead to substantially biased estimates
of mean sojourn time. Finally, we illustrate our findings
using the example of Canadian National Breast Screening
Study 2 (1980-1985) and show that the fraction of indolent
cancers is not precisely identifiable. Our findings provide
the foundation for extended models that account for both in
situ and invasive lesions.},
Doi = {10.1093/aje/kwy214},
Key = {fds339494}
}
@article{fds339945,
Author = {Ryser, MD and Yu, M and Grady, W and Siegmund, K and Shibata,
D},
Title = {Epigenetic Heterogeneity in Human Colorectal Tumors Reveals
Preferential Conservation And Evidence of Immune
Surveillance.},
Journal = {Scientific Reports},
Volume = {8},
Number = {1},
Pages = {17292},
Year = {2018},
Month = {November},
url = {http://dx.doi.org/10.1038/s41598-018-35621-y},
Abstract = {Genomic intratumoral heterogeneity (ITH) is common in
cancers, but the extent of phenotypic ITH is uncertain
because most subclonal mutations are passengers. Since tumor
phenotypes are largely driven by epigenetics, methylomic
analyses can provide insights into phenotypic ITH. Following
this principle, we determined the extent of epigenetic ITH
in 16 human colorectal tumors by comparing the methylomes
from spatially separated regions in each tumor. Methylomes
from opposite tumor sides were similar (Pearson correlation
>0.95) with little evidence of ITH or stepwise selection
during growth, suggesting that the epigenome of a sampled
tumor largely reflects that of its founder cell. Epigenetic
conservation was functional, with higher conservation at
promoters and expressed genes compared to non-coding
regions. Despite epigenomic conservation, RNA expression
varied between individual tumor glands, indicating continued
adaption during growth. Because many promoters and enhancers
were unmethylated, continued adaptation may be due to
phenotypic plasticity. Gene enrichment analyses identified
that interferon signaling and antigen-processing and
presenting pathways were strongly conserved during tumor
growth, suggesting a mechanism for immune evasion. In
summary, our findings suggest that epigenomes are
preferentially conserved during tumor growth and that early
tumor cells are poised for rapid growth, phenotypic
adaptation, and immune evasion.},
Doi = {10.1038/s41598-018-35621-y},
Key = {fds339945}
}
@article{fds338377,
Author = {Ryser, MD and Min, B-H and Siegmund, KD and Shibata,
D},
Title = {Spatial mutation patterns as markers of early colorectal
tumor cell mobility.},
Journal = {Proc Natl Acad Sci U S A},
Volume = {115},
Number = {22},
Pages = {5774-5779},
Year = {2018},
Month = {May},
url = {http://dx.doi.org/10.1073/pnas.1716552115},
Abstract = {A growing body of evidence suggests that a subset of human
cancers grows as single clonal expansions. In such a nearly
neutral evolution scenario, it is possible to infer the
early ancestral tree of a full-grown tumor. We hypothesized
that early tree reconstruction can provide insights into the
mobility phenotypes of tumor cells during their first few
cell divisions. We explored this hypothesis by means of a
computational multiscale model of tumor expansion
incorporating the glandular structure of colorectal tumors.
After calibrating the model to multiregional and single
gland data from 19 human colorectal tumors using approximate
Bayesian computation, we examined the role of early tumor
cell mobility in shaping the private mutation patterns of
the final tumor. The simulations showed that early cell
mixing in the first tumor gland can result in
side-variegated patterns where the same private mutations
could be detected on opposite tumor sides. In contrast,
absence of early mixing led to nonvariegated, sectional
mutation patterns. These results suggest that the patterns
of detectable private mutations in colorectal tumors may be
a marker of early cell movement and hence the invasive and
metastatic potential of the tumor at the start of the
growth. In alignment with our hypothesis, we found evidence
of early abnormal cell movement in 9 of 15 invasive
colorectal carcinomas ("born to be bad"), but in none of 4
benign adenomas. If validated with a larger dataset, the
private mutation patterns may be used for outcome prediction
among screen-detected lesions with unknown invasive
potential.},
Doi = {10.1073/pnas.1716552115},
Key = {fds338377}
}
@article{fds339495,
Author = {Grimm, LJ and Ryser, MD and Hyslop, T},
Title = {Role of Preoperative Variables in Reducing the Rate of
Occult Invasive Disease for Women Considering Active
Surveillance for Ductal Carcinoma In Situ.},
Journal = {Jama Surg},
Volume = {153},
Number = {3},
Pages = {290-291},
Year = {2018},
Month = {March},
url = {http://dx.doi.org/10.1001/jamasurg.2017.5566},
Doi = {10.1001/jamasurg.2017.5566},
Key = {fds339495}
}
@article{fds339496,
Author = {Ryser, MD and Horton, JK and Hwang, ES},
Title = {How Low Can We Go-and Should We? Risk Reduction for
Minimal-Volume DCIS.},
Journal = {Annals of Surgical Oncology},
Volume = {25},
Number = {2},
Pages = {354-355},
Year = {2018},
Month = {February},
url = {http://dx.doi.org/10.1245/s10434-017-6128-4},
Doi = {10.1245/s10434-017-6128-4},
Key = {fds339496}
}
@article{fds339499,
Author = {Grimm, LJ and Ryser, MD and Partridge, AH and Thompson, AM and Thomas,
JS and Wesseling, J and Hwang, ES},
Title = {Surgical Upstaging Rates for Vacuum Assisted Biopsy Proven
DCIS: Implications for Active Surveillance
Trials.},
Journal = {Annals of Surgical Oncology},
Volume = {24},
Number = {12},
Pages = {3534-3540},
Year = {2017},
Month = {November},
url = {http://dx.doi.org/10.1245/s10434-017-6018-9},
Abstract = {PURPOSE: This study was designed to determine invasive
cancer upstaging rates at surgical excision following
vacuum-assisted biopsy of ductal carcinoma in situ (DCIS)
among women meeting eligibility for active surveillance
trials. METHODS: Patients with vacuum-assisted,
biopsy-proven DCIS at a single center from 2008 to 2015 were
retrospectively reviewed. Imaging and pathology reports were
interrogated for the imaging appearance, tumor grade,
hormone receptor status, and presence of comedonecrosis.
Subsequent surgical reports were reviewed for upstaging to
invasive disease. Cases were classified by eligibility
criteria for the COMET, LORIS, and LORD DCIS active
surveillance trials. RESULTS: Of 307 DCIS diagnoses, 15 (5%)
were low, 95 (31%) intermediate, and 197 (64%) high nuclear
grade. The overall upstage rate to invasive disease was 17%
(53/307). Eighty-one patients were eligible for the COMET
Trial, 74 for the LORIS trial, and 10 for the LORD Trial,
although LORIS trial eligibility also included real-time,
multiple central pathology review, including elements not
routinely reported. The upstaging rates to invasive disease
were 6% (5/81), 7% (5/74), and 10% (1/10) for the COMET,
LORIS, and LORD trials, respectively. Among upstaged cancers
(n = 5), four tumors were Stage IA invasive ductal
carcinoma and one was Stage IIA invasive lobular carcinoma;
all were node-negative. CONCLUSIONS: DCIS upstaging rates in
women eligible for active surveillance trials are low
(6-10%), and in this series, all those with invasive disease
were early-stage, node-negative. The careful patient
selection for DCIS active surveillance trials has a low risk
of missing occult invasive cancer and additional studies
will determine clinical outcomes.},
Doi = {10.1245/s10434-017-6018-9},
Key = {fds339499}
}
@article{fds339500,
Author = {Cao, Y and Feng, Y and Ryser, MD and Zhu, K and Herschlag, G and Cao, C and Marusak, K and Zauscher, S and You, L},
Title = {Programmable assembly of pressure sensors using
pattern-forming bacteria.},
Journal = {Nat Biotechnol},
Volume = {35},
Number = {11},
Pages = {1087-1093},
Year = {2017},
Month = {November},
url = {http://dx.doi.org/10.1038/nbt.3978},
Abstract = {Biological systems can generate microstructured materials
that combine organic and inorganic components and possess
diverse physical and chemical properties. However, these
natural processes in materials fabrication are not readily
programmable. Here, we use a synthetic-biology approach to
assemble patterned materials. We demonstrate programmable
fabrication of three-dimensional (3D) materials by printing
engineered self-patterning bacteria on permeable membranes
that serve as a structural scaffold. Application of gold
nanoparticles to the colonies creates hybrid
organic-inorganic dome structures. The dynamics of the dome
structures' response to pressure is determined by their
geometry (colony size, dome height, and pattern), which is
easily modified by varying the properties of the membrane
(e.g., pore size and hydrophobicity). We generate resettable
pressure sensors that process signals in response to varying
pressure intensity and duration.},
Doi = {10.1038/nbt.3978},
Key = {fds339500}
}
@article{fds339501,
Author = {Ryser, MD and Rositch, A and Gravitt, PE},
Title = {Modeling of US Human Papillomavirus (HPV) Seroprevalence by
Age and Sexual Behavior Indicates an Increasing Trend of HPV
Infection Following the Sexual Revolution.},
Journal = {J Infect Dis},
Volume = {216},
Number = {5},
Pages = {604-611},
Year = {2017},
Month = {September},
url = {http://dx.doi.org/10.1093/infdis/jix333},
Abstract = {BACKGROUND: The United States has experienced an increase in
the incidence of human papillomavirus (HPV)-related cancers
that are not screen-detectable. It has been hypothesized,
but not directly demonstrated, that this is due to
increasing HPV prevalence in the unvaccinated population.
METHODS: Female self-reported numbers of lifetime sex
partners and HPV serology from the National Health and
Nutrition Examination Survey (NHANES) were used to develop
mathematical models of sexual partner acquisition and
antibody dynamics. Modeled trends in sexual behaviors were
compared to incidence data for cervical adenocarcinoma,
oropharyngeal cancer, and anal cancer. RESULTS: The
age-specific HPV seroprevalence data were best explained by
a partner acquisition model that explicitly accounted for
cohort-dependent changes in sexual behavior. Estimates of
the mean time to loss of natural antibodies varied by model,
ranging from 49 to 145 years. Inferred trends in sexual
behavior over the past decades paralleled the increasing
incidence of HPV-related cancers in the United States.
CONCLUSIONS: The findings suggest that lower HPV
seroprevalence in older US women primarily reflects
cohort-specific differences in sexual behaviors, and is only
marginally attributable to immune waning with age. Our
results emphasize the importance of continuing surveillance
of sexual behaviors, alongside vaccine status, to predict
future disease burden.},
Doi = {10.1093/infdis/jix333},
Key = {fds339501}
}
@article{fds339502,
Author = {Ryser, MD and Gravitt, PE and Myers, ER},
Title = {Mechanistic mathematical models: An underused platform for
HPV research.},
Journal = {Papillomavirus Research (Amsterdam, Netherlands)},
Volume = {3},
Pages = {46-49},
Year = {2017},
Month = {June},
url = {http://dx.doi.org/10.1016/j.pvr.2017.01.004},
Abstract = {Health economic modeling has become an invaluable
methodology for the design and evaluation of clinical and
public health interventions against the human papillomavirus
(HPV) and associated diseases. At the same time, relatively
little attention has been paid to a different yet
complementary class of models, namely that of mechanistic
mathematical models. The primary focus of mechanistic
mathematical models is to better understand the intricate
biologic mechanisms and dynamics of disease. Inspired by a
long and successful history of mechanistic modeling in other
biomedical fields, we highlight several areas of HPV
research where mechanistic models have the potential to
advance the field. We argue that by building quantitative
bridges between biologic mechanism and population level
data, mechanistic mathematical models provide a unique
platform to enable collaborations between experimentalists
who collect data at different physical scales of the HPV
infection process. Through such collaborations, mechanistic
mathematical models can accelerate and enhance the
investigation of HPV and related diseases.},
Doi = {10.1016/j.pvr.2017.01.004},
Key = {fds339502}
}
@article{fds354109,
Author = {Ryser, MD and Murgas, KA},
Title = {Bone remodeling as a spatial evolutionary
game.},
Journal = {Journal of Theoretical Biology},
Volume = {418},
Pages = {16-26},
Year = {2017},
Month = {April},
url = {http://dx.doi.org/10.1016/j.jtbi.2017.01.021},
Abstract = {Bone remodeling is a complex process involving cell-cell
interactions, biochemical signaling and mechanical stimuli.
Early models of the biological aspects of remodeling were
non-spatial and focused on the local dynamics at a fixed
location in the bone. Several spatial extensions of these
models have been proposed, but they generally suffer from
two limitations: first, they are not amenable to analysis
and are computationally expensive, and second, they neglect
the role played by bone-embedded osteocytes. To address
these issues, we developed a novel model of spatial
remodeling based on the principles of evolutionary game
theory. The analytically tractable framework describes the
spatial interactions between zones of bone resorption, bone
formation and quiescent bone, and explicitly accounts for
regulation of remodeling by bone-embedded,
mechanotransducing osteocytes. Using tools from the theory
of interacting particle systems we systematically classified
the different dynamic regimes of the spatial model and
identified regions of parameter space that allow for global
coexistence of resorption, formation and quiescence, as
observed in physiological remodeling. In coexistence
scenarios, three-dimensional simulations revealed the
emergence of sponge-like bone clusters. Comparison between
spatial and non-spatial dynamics revealed substantial
differences and suggested a stabilizing role of space. Our
findings emphasize the importance of accounting for spatial
structure and bone-embedded osteocytes when modeling the
process of bone remodeling. Thanks to the lattice-based
framework, the proposed model can easily be coupled to a
mechanical model of bone loading.},
Doi = {10.1016/j.jtbi.2017.01.021},
Key = {fds354109}
}
@article{fds339503,
Author = {Storey, K and Ryser, MD and Leder, K and Foo, J},
Title = {Spatial Measures of Genetic Heterogeneity During
Carcinogenesis.},
Journal = {Bull Math Biol},
Volume = {79},
Number = {2},
Pages = {237-276},
Year = {2017},
Month = {February},
url = {http://dx.doi.org/10.1007/s11538-016-0234-5},
Abstract = {In this work we explore the temporal dynamics of spatial
heterogeneity during the process of tumorigenesis from
healthy tissue. We utilize a spatial stochastic model of
mutation accumulation and clonal expansion in a structured
tissue to describe this process. Under a two-step
tumorigenesis model, we first derive estimates of a
non-spatial measure of diversity: Simpson's Index, which is
the probability that two individuals sampled at random from
the population are identical, in the premalignant
population. We next analyze two new measures of spatial
population heterogeneity. In particular we study the typical
length scale of genetic heterogeneity during the
carcinogenesis process and estimate the extent of a
surrounding premalignant clone given a clinical observation
of a premalignant point biopsy. This evolutionary framework
contributes to a growing literature focused on developing a
better understanding of the spatial population dynamics of
cancer initiation and progression.},
Doi = {10.1007/s11538-016-0234-5},
Key = {fds339503}
}
@article{fds354110,
Author = {Ryser, MD and Lee, WT and Ready, NE and Leder, KZ and Foo,
J},
Title = {Quantifying the Dynamics of Field Cancerization in
Tobacco-Related Head and Neck Cancer: A Multiscale Modeling
Approach.},
Journal = {Cancer Res},
Volume = {76},
Number = {24},
Pages = {7078-7088},
Year = {2016},
Month = {December},
url = {http://dx.doi.org/10.1158/0008-5472.CAN-16-1054},
Abstract = {High rates of local recurrence in tobacco-related head and
neck squamous cell carcinoma (HNSCC) are commonly attributed
to unresected fields of precancerous tissue. Because they
are not easily detectable at the time of surgery without
additional biopsies, there is a need for noninvasive methods
to predict the extent and dynamics of these fields. Here, we
developed a spatial stochastic model of tobacco-related
HNSCC at the tissue level and calibrated the model using a
Bayesian framework and population-level incidence data from
the Surveillance, Epidemiology, and End Results (SEER)
registry. Probabilistic model analyses were performed to
predict the field geometry at time of diagnosis, and model
predictions of age-specific recurrence risks were tested
against outcome data from SEER. The calibrated models
predicted a strong dependence of the local field size on age
at diagnosis, with a doubling of the expected field diameter
between ages at diagnosis of 50 and 90 years, respectively.
Similarly, the probability of harboring multiple, clonally
unrelated fields at the time of diagnosis was found to
increase substantially with patient age. On the basis of
these findings, we hypothesized a higher recurrence risk in
older than in younger patients when treated by surgery
alone; we successfully tested this hypothesis using
age-stratified outcome data. Further clinical studies are
needed to validate the model predictions in a
patient-specific setting. This work highlights the
importance of spatial structure in models of epithelial
carcinogenesis and suggests that patient age at diagnosis
may be a critical predictor of the size and multiplicity of
precancerous lesions. Cancer Res; 76(24); 7078-88. ©2016
AACR.},
Doi = {10.1158/0008-5472.CAN-16-1054},
Key = {fds354110}
}
@article{fds339504,
Author = {Ryser, MD and Worni, M and Turner, EL and Marks, JR and Durrett, R and Hwang, ES},
Title = {Outcomes of Active Surveillance for Ductal Carcinoma in
Situ: A Computational Risk Analysis.},
Journal = {J Natl Cancer Inst},
Volume = {108},
Number = {5},
Pages = {djv372},
Year = {2016},
Month = {May},
url = {http://dx.doi.org/10.1093/jnci/djv372},
Abstract = {BACKGROUND: Ductal carcinoma in situ (DCIS) is a noninvasive
breast lesion with uncertain risk for invasive progression.
Usual care (UC) for DCIS consists of treatment upon
diagnosis, thus potentially overtreating patients with low
propensity for progression. One strategy to reduce
overtreatment is active surveillance (AS), whereby DCIS is
treated only upon detection of invasive disease. Our goal
was to perform a quantitative evaluation of outcomes
following an AS strategy for DCIS. METHODS: Age-stratified,
10-year disease-specific cumulative mortality (DSCM) for AS
was calculated using a computational risk projection model
based upon published estimates for natural history
parameters, and Surveillance, Epidemiology, and End Results
data for outcomes. AS projections were compared with the
DSCM for patients who received UC. To quantify the
propagation of parameter uncertainty, a 95% projection range
(PR) was computed, and sensitivity analyses were performed.
RESULTS: Under the assumption that AS cannot outperform UC,
the projected median differences in 10-year DSCM between AS
and UC when diagnosed at ages 40, 55, and 70 years were 2.6%
(PR = 1.4%-5.1%), 1.5% (PR = 0.5%-3.5%), and 0.6% (PR =
0.0%-2.4), respectively. Corresponding median numbers of
patients needed to treat to avert one breast cancer death
were 38.3 (PR = 19.7-69.9), 67.3 (PR = 28.7-211.4), and
157.2 (PR = 41.1-3872.8), respectively. Sensitivity analyses
showed that the parameter with greatest impact on DSCM was
the probability of understaging invasive cancer at
diagnosis. CONCLUSION: AS could be a viable management
strategy for carefully selected DCIS patients, particularly
among older age groups and those with substantial competing
mortality risks. The effectiveness of AS could be markedly
improved by reducing the rate of understaging.},
Doi = {10.1093/jnci/djv372},
Key = {fds339504}
}
@article{fds339505,
Author = {Cao, Y and Ryser, MD and Payne, S and Li, B and Rao, CV and You,
L},
Title = {Collective Space-Sensing Coordinates Pattern Scaling in
Engineered Bacteria.},
Journal = {Cell},
Volume = {165},
Number = {3},
Pages = {620-630},
Year = {2016},
Month = {April},
url = {http://dx.doi.org/10.1016/j.cell.2016.03.006},
Abstract = {Scale invariance refers to the maintenance of a constant
ratio of developing organ size to body size. Although
common, its underlying mechanisms remain poorly understood.
Here, we examined scaling in engineered Escherichia coli
that can form self-organized core-ring patterns in colonies.
We found that the ring width exhibits perfect scale
invariance to the colony size. Our analysis revealed a
collective space-sensing mechanism, which entails sequential
actions of an integral feedback loop and an incoherent
feedforward loop. The integral feedback is implemented by
the accumulation of a diffusive chemical produced by a
colony. This accumulation, combined with nutrient
consumption, sets the timing for ring initiation. The
incoherent feedforward is implemented by the opposing
effects of the domain size on the rate and duration of ring
maturation. This mechanism emphasizes a role of timing
control in achieving robust pattern scaling and provides a
new perspective in examining the phenomenon in natural
systems.},
Doi = {10.1016/j.cell.2016.03.006},
Key = {fds339505}
}
@article{fds339506,
Author = {Worni, M and Akushevich, I and Greenup, R and Sarma, D and Ryser, MD and Myers, ER and Hwang, ES},
Title = {Trends in Treatment Patterns and Outcomes for Ductal
Carcinoma In Situ.},
Journal = {J Natl Cancer Inst},
Volume = {107},
Number = {12},
Pages = {djv263},
Year = {2015},
Month = {December},
url = {http://dx.doi.org/10.1093/jnci/djv263},
Abstract = {BACKGROUND: Impact of contemporary treatment of pre-invasive
breast cancer (ductal carcinoma in situ [DCIS]) on long-term
outcomes remains poorly defined. We aimed to evaluate
national treatment trends for DCIS and to determine their
impact on disease-specific (DSS) and overall survival (OS).
METHODS: The Surveillance, Epidemiology, and End Results
(SEER) registry was queried for patients diagnosed with DCIS
from 1991 to 2010. Treatment pattern trends were analyzed
using Cochran-Armitage trend test. Survival analyses were
performed using inverse probability weights (IPW)-adjusted
competing risk analyses for DSS and Cox proportional hazard
regression for OS. All tests performed were two-sided.
RESULTS: One hundred twenty-one thousand and eighty DCIS
patients were identified. The greatest proportion of
patients was treated with lumpectomy and radiation therapy
(43.0%), followed by lumpectomy alone (26.5%) and unilateral
(23.8%) or bilateral mastectomy (4.5%) with significant
shifts over time. The rate of sentinel lymph node biopsy
increased from 9.7% to 67.1% for mastectomy and from 1.4% to
17.8% for lumpectomy. Compared with mastectomy, OS was
higher for lumpectomy with radiation (hazard ratio [HR] =
0.79, 95% confidence interval [CI] = 0.76 to 0.83, P < .001)
and lower for lumpectomy alone (HR = 1.17, 95% CI = 1.13 to
1.23, P < .001). IPW-adjusted ten-year DSS was highest in
lumpectomy with XRT (98.9%), followed by mastectomy (98.5%),
and lumpectomy alone (98.4%). CONCLUSIONS: We identified
substantial shifts in treatment patterns for DCIS from 1991
to 2010. When outcomes between locoregional treatment
options were compared, we observed greater differences in OS
than DSS, likely reflecting both a prevailing patient
selection bias as well as clinically negligible differences
in breast cancer outcomes between groups.},
Doi = {10.1093/jnci/djv263},
Key = {fds339506}
}
@article{fds244097,
Author = {Ryser, MD and McGoff, K and Herzog, DP and Sivakoff, DJ and Myers,
ER},
Title = {Impact of coverage-dependent marginal costs on optimal HPV
vaccination strategies.},
Journal = {Epidemics},
Volume = {11},
Pages = {32-47},
Year = {2015},
Month = {June},
ISSN = {1755-4365},
url = {http://hdl.handle.net/10161/9500 Duke open
access},
Abstract = {The effectiveness of vaccinating males against the human
papillomavirus (HPV) remains a controversial subject. Many
existing studies conclude that increasing female coverage is
more effective than diverting resources into male
vaccination. Recently, several empirical studies on HPV
immunization have been published, providing evidence of the
fact that marginal vaccination costs increase with coverage.
In this study, we use a stochastic agent-based modeling
framework to revisit the male vaccination debate in light of
these new findings. Within this framework, we assess the
impact of coverage-dependent marginal costs of vaccine
distribution on optimal immunization strategies against HPV.
Focusing on the two scenarios of ongoing and new vaccination
programs, we analyze different resource allocation policies
and their effects on overall disease burden. Our results
suggest that if the costs associated with vaccinating males
are relatively close to those associated with vaccinating
females, then coverage-dependent, increasing marginal costs
may favor vaccination strategies that entail immunization of
both genders. In particular, this study emphasizes the
necessity for further empirical research on the nature of
coverage-dependent vaccination costs.},
Doi = {10.1016/j.epidem.2015.01.003},
Key = {fds244097}
}
@article{fds339507,
Author = {Ryser, MD and Myers, ER and Durrett, R},
Title = {HPV clearance and the neglected role of stochasticity.},
Journal = {Plos Computational Biology},
Volume = {11},
Number = {3},
Pages = {e1004113},
Year = {2015},
Month = {March},
url = {http://dx.doi.org/10.1371/journal.pcbi.1004113},
Abstract = {Clearance of anogenital and oropharyngeal HPV infections is
attributed primarily to a successful adaptive immune
response. To date, little attention has been paid to the
potential role of stochastic cell dynamics in the time it
takes to clear an HPV infection. In this study, we combine
mechanistic mathematical models at the cellular level with
epidemiological data at the population level to disentangle
the respective roles of immune capacity and cell dynamics in
the clearing mechanism. Our results suggest that chance-in
form of the stochastic dynamics of basal stem cells-plays a
critical role in the elimination of HPV-infected cell
clones. In particular, we find that in immunocompetent
adolescents with cervical HPV infections, the immune
response may contribute less than 20% to virus clearance-the
rest is taken care of by the stochastic proliferation
dynamics in the basal layer. In HIV-negative individuals,
the contribution of the immune response may be
negligible.},
Doi = {10.1371/journal.pcbi.1004113},
Key = {fds339507}
}
@article{fds367152,
Author = {Ryser, MD and Komarova, SV},
Title = {Mathematical Modeling of Cancer Metastases},
Pages = {211-230},
Booktitle = {Computational Bioengineering},
Publisher = {CRC},
Year = {2015},
Month = {January},
ISBN = {9781466517561},
url = {http://dx.doi.org/10.1201/b18320-13},
Abstract = {Most cancer types develop the ability to leave their site of
origin and spread to distant organs to form metastases, also
called secondary cancers. Metastases are the most common
cause of death among cancer patients, and hence there is an
immense clinical interest to understand the underlying
biological mechanisms and to develop preventive and
therapeutic measures. Over the past decades, an increasing
number of applied mathematicians and biomedical engineers
have taken on the challenge to design models and devise in
silico tools for the study of cancer and cancer metastases.
The goals of this chapter are to introduce to the reader the
important challenges in the field of metastases and to give
an overview of the existing modeling tools. Guided by
pertinent biological questions, we review a number of
deterministic and stochastic approaches and discuss their
potential and limitations.},
Doi = {10.1201/b18320-13},
Key = {fds367152}
}
@article{fds339510,
Author = {Foo, J and Leder, K and Ryser, MD},
Title = {Multifocality and recurrence risk: a quantitative model of
field cancerization.},
Journal = {J Theor Biol},
Volume = {355},
Pages = {170-184},
Year = {2014},
Month = {August},
url = {http://dx.doi.org/10.1016/j.jtbi.2014.02.042},
Abstract = {Primary tumors often emerge within genetically altered
fields of premalignant cells that appear histologically
normal but have a high chance of progression to malignancy.
Clinical observations have suggested that these premalignant
fields pose high risks for emergence of recurrent tumors if
left behind after surgical removal of the primary tumor. In
this work, we develop a spatio-temporal stochastic model of
epithelial carcinogenesis, combining cellular dynamics with
a general framework for multi-stage genetic progression to
cancer. Using the model, we investigate how various
properties of the premalignant fields depend on microscopic
cellular properties of the tissue. In particular, we provide
analytic results for the size-distribution of the
histologically undetectable premalignant fields at the time
of diagnosis, and investigate how the extent and the
geometry of these fields depend upon key groups of
parameters associated with the tissue and genetic pathways.
We also derive analytical results for the relative risks of
local vs. distant secondary tumors for different parameter
regimes, a critical aspect for the optimal choice of
post-operative therapy in carcinoma patients. This study
contributes to a growing literature seeking to obtain a
quantitative understanding of the spatial dynamics in cancer
initiation.},
Doi = {10.1016/j.jtbi.2014.02.042},
Key = {fds339510}
}
@article{fds339511,
Author = {Payne, S and Li, B and Cao, Y and Schaeffer, D and Ryser, MD and You,
L},
Title = {Temporal control of self-organized pattern formation without
morphogen gradients in bacteria.},
Journal = {Molecular Systems Biology},
Volume = {9},
Number = {697},
Pages = {697},
Year = {2013},
Month = {October},
url = {http://dx.doi.org/10.1038/msb.2013.55},
Abstract = {Diverse mechanisms have been proposed to explain biological
pattern formation. Regardless of their specific molecular
interactions, the majority of these mechanisms require
morphogen gradients as the spatial cue, which are either
predefined or generated as a part of the patterning process.
However, using Escherichia coli programmed by a synthetic
gene circuit, we demonstrate here the generation of robust,
self-organized ring patterns of gene expression in the
absence of an apparent morphogen gradient. Instead of being
a spatial cue, the morphogen serves as a timing cue to
trigger the formation and maintenance of the ring patterns.
The timing mechanism enables the system to sense the domain
size of the environment and generate patterns that scale
accordingly. Our work defines a novel mechanism of pattern
formation that has implications for understanding natural
developmental processes.},
Doi = {10.1038/msb.2013.55},
Key = {fds339511}
}
@article{fds303560,
Author = {Ryser, MD and Nigam, N and Tupper, PF},
Title = {On the well-posedness of the stochastic Allen-Cahn equation
in two dimensions},
Journal = {Journal of Computational Physics},
Volume = {231},
Number = {6},
Pages = {2537-2550},
Year = {2012},
Month = {March},
url = {http://arxiv.org/abs/1104.0720v4},
Abstract = {White noise-driven nonlinear stochastic partial differential
equations (SPDEs) of parabolic type are frequently used to
model physical systems in space dimensions d= 1, 2, 3.
Whereas existence and uniqueness of weak solutions to these
equations are well established in one dimension, the
situation is different for d≥ 2. Despite their popularity
in the applied sciences, higher dimensional versions of
these SPDE models are generally assumed to be ill-posed by
the mathematics community. We study this discrepancy on the
specific example of the two dimensional Allen-Cahn equation
driven by additive white noise. Since it is unclear how to
define the notion of a weak solution to this equation, we
regularize the noise and introduce a family of
approximations. Based on heuristic arguments and numerical
experiments, we conjecture that these approximations exhibit
divergent behavior in the continuum limit. The results
strongly suggest that shrinking the mesh size in simulations
of the two-dimensional white noise-driven Allen-Cahn
equation does not lead to the recovery of a physically
meaningful limit. © 2011 .},
Doi = {10.1016/j.jcp.2011.12.002},
Key = {fds303560}
}
@article{fds303558,
Author = {Hairer, M and Ryser, M and Weber, H},
Title = {Triviality of the 2D stochastic Allen-Cahn
equation},
Journal = {Electronic Journal of Probability},
Volume = {17},
Number = {none},
Publisher = {Institute of Mathematical Statistics},
Year = {2012},
Month = {January},
url = {http://arxiv.org/abs/1201.3089v1},
Abstract = {We consider the stochastic Allen-Cahn equation driven by
mollified space-time white noise. We show that, as the
mollifier is removed, the solutions converge weakly to 0,
independently of the initial condition. If the intensity of
the noise simultaneously converges to 0 at a sufficiently
fast rate, then the solutions converge to those of the
deterministic equation. At the critical rate, the limiting
solution is still deterministic, but it exhibits an
additional damping term.},
Doi = {10.1214/ejp.v17-1731},
Key = {fds303558}
}
@article{fds244098,
Author = {Ryser, MD and Qu, Y and Komarova, SV},
Title = {Osteoprotegerin in bone metastases: mathematical solution to
the puzzle.},
Journal = {Plos Computational Biology},
Volume = {8},
Number = {10},
Pages = {e1002703},
Year = {2012},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23093918},
Abstract = {Bone is a common site for cancer metastasis. To create space
for their growth, cancer cells stimulate bone resorbing
osteoclasts. Cytokine RANKL is a key osteoclast activator,
while osteoprotegerin (OPG) is a RANKL decoy receptor and an
inhibitor of osteoclastogenesis. Consistently, systemic
application of OPG decreases metastatic tumor burden in
bone. However, OPG produced locally by cancer cells was
shown to enhance osteolysis and tumor growth. We propose
that OPG produced by cancer cells causes a local reduction
in RANKL levels, inducing a steeper RANKL gradient away from
the tumor and towards the bone tissue, resulting in faster
resorption and tumor expansion. We tested this hypothesis
using a mathematical model of nonlinear partial differential
equations describing the spatial dynamics of OPG, RANKL,
PTHrP, osteoclasts, tumor and bone mass. We demonstrate that
at lower expression rates, tumor-derived OPG enhances the
chemotactic RANKL gradient and osteolysis, whereas at higher
expression rates OPG broadly inhibits RANKL and decreases
osteolysis and tumor burden. Moreover, tumor expression of a
soluble mediator inducing RANKL in the host tissue, such as
PTHrP, is important for correct orientation of the RANKL
gradient. A meta-analysis of OPG, RANKL and PTHrP expression
in normal prostate, carcinoma and metastatic tissues
demonstrated an increase in expression of OPG, but not
RANKL, in metastatic prostate cancer, and positive
correlation between OPG and PTHrP in metastatic prostate
cancer. The proposed mechanism highlights the importance of
the spatial distribution of receptors, decoys and ligands,
and can be applied to other systems involving regulation of
spatially anisotropic processes.},
Doi = {10.1371/journal.pcbi.1002703},
Key = {fds244098}
}
@article{fds303559,
Author = {Ryser, MD and Komarova, SV and Nigam, N},
Title = {The cellular dynamics of bone remodeling: A mathematical
model},
Journal = {Siam Journal on Applied Mathematics},
Volume = {70},
Number = {6},
Pages = {1899-1921},
Year = {2010},
Month = {April},
url = {http://arxiv.org/abs/1111.6916v1},
Abstract = {The mechanical properties of vertebrate bone are largely
determined by a process which involves the complex interplay
of three different cell types. This process is called bone
remodeling and occurs asynchronously at multiple sites in
the mature skeleton. The cells involved are bone resorbing
osteoclasts, bone matrix producing osteoblasts, and
mechanosensing osteocytes. These cells communicate with each
other by means of autocrine and paracrine signaling factors
and operate in complex entities, the so-called bone
multicellular units (BMUs). To investigate the BMU dynamics
in silico, we develop a novel mathematical model resulting
in a system of nonlinear partial differential equations
(PDEs) with time delays. The model describes the osteoblast
and osteoclast populations together with the dynamics of the
key messenger molecule RANKL and its decoy receptor OPG.
Scaling theory is used to address parameter sensitivity and
predict the emergence of pathological remodeling regimes.
The model is studied numerically in one and two space
dimensions using finite difference schemes in space and
explicit delay equation solvers in time. The computational
results are in agreement with in vivo observations and
provide new insights into the role of the RANKL/OPG pathway
in the spatial regulation of bone remodeling. © 2010
Society for Industrial and Applied Mathematics.},
Doi = {10.1137/090746094},
Key = {fds303559}
}
@article{fds244101,
Author = {Ryser, MD and Nigam, N and Komarova, SV},
Title = {Mathematical modeling of spatio-temporal dynamics of a
single bone multicellular unit.},
Journal = {J Bone Miner Res},
Volume = {24},
Number = {5},
Pages = {860-870},
Year = {2009},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19063683},
Abstract = {During bone remodeling, bone-resorbing osteoclasts and
bone-forming osteoblasts are organized in bone multicellular
units (BMUs), which travel at a rate of 20-40 mum/d for 6-12
mo, maintaining a cylindrical structure. However, the
interplay of local BMU geometry with biochemical regulation
is poorly understood. We developed a mathematical model of
BMU describing changes in time and space of the
concentrations of proresorptive cytokine RANKL and its
inhibitor osteoprotegerin (OPG), in osteoclast and
osteoblast numbers, and in bone mass. We assumed that
osteocytes surrounding a microfracture produce RANKL, which
attracted osteoclasts. OPG and RANKL were produced by
osteoblasts and diffused through bone, RANKL was eliminated
by binding to OPG and RANK. Osteoblasts were coupled to
osteoclasts through paracrine factors. The evolution of the
BMU arising from this model was studied using numerical
simulations. Our model recapitulated the spatio-temporal
dynamics observed in vivo in a cross-section of bone. In
response to a RANKL field, osteoclasts moved as a
well-confined cutting cone. The coupling of osteoclasts to
osteoblasts allowed for sufficient recruitment of
osteoblasts to the resorbed surfaces. The RANKL field was
the highest at the microfracture in front of the BMU,
whereas the OPG field peaked at the back of the BMU,
resulting in the formation of a RANKL/OPG gradient, which
strongly affected the rate of BMU progression and its size.
Thus, the spatial organization of a BMU provides important
constraints on the roles of RANKL and OPG as well as
possibly other regulators in determining the outcome of
remodeling in the BMU.},
Doi = {10.1359/jbmr.081229},
Key = {fds244101}
}
@article{fds244100,
Author = {Lehning, M and Loewe, H and Ryser, MD and Raderschall,
N},
Title = {Inhomogeneous precipitation distribution and snow transport
in steep terrain},
Journal = {Water Resour. Res.},
Year = {2008},
url = {http://www.agu.org/pubs/crossref/2008/2007WR006545.shtml},
Key = {fds244100}
}
@article{fds244099,
Author = {Buenzli, PR and Martin, PA and Ryser, MD},
Title = {Thermal quantum electrodynamics of nonrelativistic charged
fluids.},
Journal = {Physical Review. E, Statistical, Nonlinear, and Soft Matter
Physics},
Volume = {75},
Number = {4 Pt 1},
Pages = {041125},
Year = {2007},
Month = {April},
ISSN = {1539-3755},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17500883},
Abstract = {The theory relevant to the study of matter in equilibrium
with the radiation field is thermal quantum electrodynamics
(TQED). We present a formulation of the theory, suitable for
nonrelativistic fluids, based on a joint functional integral
representation of matter and field variables. In this
formalism cluster expansion techniques of classical
statistical mechanics become operative. They provide an
alternative to the usual Feynman diagrammatics in many-body
problems, which is not perturbative with respect to the
coupling constant. As an application we show that the
effective Coulomb interaction between quantum charges is
partially screened by thermalized photons at large
distances. More precisely one observes an exact cancellation
of the dipolar electric part of the interaction, so that the
asymptotic particle density correlation is now determined by
relativistic effects. It still has the r(-6) decay typical
for quantum charges, but with an amplitude strongly reduced
by a relativistic factor.},
Doi = {10.1103/PhysRevE.75.041125},
Key = {fds244099}
}
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Mathematics Department