Publications by authors named "Tom Liu"

33 Publications

Left Ventricular Diastolic Dysfunction and Pulmonary Hypertension: Outcomes in SAVR.

Thorac Cardiovasc Surg 2021 Apr 16. Epub 2021 Apr 16.

Department of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey, United States.

Background:  Severe pulmonary hypertension (PH) and left ventricular diastolic dysfunction (LVDD) are independently associated with poor outcomes in cardiac surgery. We evaluated the relationship of several measures of LVDD, PH, and hemodynamic subtypes of PH including precapillary pulmonary hypertension(pcPH) and isolated post-capillary pulmonary hypertension(ipcPH) and combined pre and post capillary pulmonary hypertension(cpcPH) capillary PH to postoperative outcomes in a cohort of patients who underwent elective isolated-AVR.

Methods:  We evaluated ( = 206) patients in our local STS database who underwent elective isolated-AVR between 2014 and 2018, with transthoracic echocardiogram ( = 177) or right heart catheterization ( = 183) within 1 year of operation (or both,  = 161). The primary outcome was a composite end point of death, prolonged ventilation, ICU readmission, and hospital stay >14 days.

Results:  Severe PH was associated with worse outcomes (moderate: OR, 1.1,  = 0.09; severe: OR, 1.28,  = 0.01), but degree of LVDD was not associated with worse outcomes. Across hemodynamic subtypes of PH, odds of composite outcome were similar ( = 0.89), however, patients with cpcPH had more postoperative complications (67 vs. 36%,  = 0.06) and patients with ipcPH had greater all-cause mortality at 1 (8 vs. 1%,  = 0.03) and 3 years (27 vs. 4%,  = 0.008).

Conclusion:  Severe PH conferred modestly greater risk of adverse events, and both LVDD grade and the combination of severe PH and LVDD were not associated with worse outcomes. However, hemodynamic stratification of PH revealed higher postoperative complications and worse long-term outcomes for those with cpcPH and ipcPH. Preoperative stratification of PH by hemodynamic subtype in valve replacement surgery may improve our risk stratification in this heterogenous condition. Further evaluation of the significance of LVDD and PH in other cardiac operations is warranted.
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http://dx.doi.org/10.1055/s-0041-1727138DOI Listing
April 2021

Retrospective analysis of ophthalmology referrals to a tertiary academic centre during the COVID-19 pandemic in comparison to the pre-COVID-19 era.

Can J Ophthalmol 2021 Mar 5. Epub 2021 Mar 5.

Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC.

Objective: This study was conducted to analyse emergency ophthalmology referrals to a Canadian tertiary academic centre during the current coronavirus disease 2019 (COVID-19) pandemic in comparison to prepandemic referrals.

Design: This was a retrospective chart review looking at emergency referrals seen by the ophthalmology service between March 18 to April 17, 2020 (representing the COVID-19 period), and March 18 to April 17, 2019 (representing the pre-COVID-19 period).

Methods: Data gathered from referral records included patient demographics, timing and site of referral, and ophthalmic diagnosis. Referrals were categorized as urgent or nonurgent, with urgent indicating the need for ophthalmic assessment within 24 hours.

Results: The total number of referrals decreased by 54.2% in the COVID-19 period versus the pre-COVID-19 period. There was a similar bimodal age distribution in both periods, with fewer patients over 65 years of age presenting during the pandemic. Tertiary hospital referrals decreased by 62% in the pandemic period, while nontertiary emergency department referral trends varied and outpatient clinic referrals increased by 16%. Overall, there was a significant shift in the distribution of referral sites (p = 0.04). The proportion of urgent referrals increased by 14% during the pandemic; this was not statistically significant. There was no significant change in the timing of referrals or in the distribution of diagnostic segments.

Conclusions: This study offers insight into the impact of the COVID-19 pandemic on ophthalmology referral patterns in a Canadian context. Moving forward, it helps to guide resource allocation and public education on the importance of seeking necessary eye care.
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http://dx.doi.org/10.1016/j.jcjo.2021.02.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934690PMC
March 2021

A Neutrophil Subset Defined by Intracellular Olfactomedin 4 is Associated with Mortality in Sepsis.

Am J Physiol Lung Cell Mol Physiol 2020 Dec 23. Epub 2020 Dec 23.

Departments of Medicine and Anesthesiology and the Cardiovascular Research Institute, University of California, San Francisco, California.

Sepsis is a heterogeneous syndrome clinically and biologically but biomarkers of distinct host response pathways for early prognostic information and testing targeted treatments are lacking. We hypothesized that Olfactomedin 4 (OLFM4), a matrix glycoprotein of neutrophil specific granules defines a distinct neutrophil subset that may be an independent risk factor for poor outcomes in sepsis. In a single-center, prospective cohort study, we enrolled adults admitted to an academic medical center from the Emergency Department (ED) with suspected sepsis (identified by 2 or greater Systemic Inflammatory Response Syndrome [SIRS] criteria and antibiotic receipt) from March 2016 through December 2017, followed by sepsis adjudication according to Sepsis-3. We collected 200mL of whole blood within 24 hours of admission and stained for the neutrophil surface marker CD66b followed by intracellular staining for OLFM4 quantitated by flow cytometry. The predictor for 60-day mortality was the percentage of OLFM4+ neutrophils and at a cut-point of OLFM4+ ≥37.6% determined by the Youden Index. Of 120 enrolled patients with suspected sepsis, 97 had sepsis and 23 had non-sepsis SIRS. The mean percentage of OLFM4+ neutrophils was significantly increased in both sepsis and non-sepsis SIRS patients who died (P ≤ 0.01). Among sepsis patients with elevated OLFM4+(≥37.6%), 56% died compared to 18% with OLFM4+ <37.6% (P=0.001).The association between OLFM4+ and mortality withstood adjustment for demographics, co-morbidities and measures of severity of illness (P<0.03). In sepsis, OLFM4+ neutrophil percentage is independently associated with 60-day mortality and may represent a novel measure of the heterogeneity of host response to sepsis.
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http://dx.doi.org/10.1152/ajplung.00090.2020DOI Listing
December 2020

Alternative Tobacco Product Use in Critically Ill Patients.

Int J Environ Res Public Health 2020 11 24;17(23). Epub 2020 Nov 24.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA 94143, USA.

Alternative tobacco product (ATP) use has bee linked to critical illness, however, few studies have examined the use of these substances in critically ill populations. We sought to examine ATP use within critically ill patients and to define barriers in accurately assessing use within this population. We prospectively studied 533 consecutive patients from the Early Assessment of Renal and Lung Injury study, enrolled between 2013 and 2016 at a tertiary referral center and a safety-net hospital. ATP use information (electronic cigarettes, cigars, pipes, hookahs/waterpipes, and snus/chewing tobacco) was obtained from the patient or surrogate using a detailed survey. Reasons for non-completion of the survey were recorded, and differences between survey responders vs. non-responders, self- vs. surrogate responders, and ATP users vs. non-users were explored. Overall, 80% ( = 425) of subjects (56% male) completed a tobacco product use survey. Of these, 12.2% ( = 52) reported current ATP use, while 5.6% reported using multiple ATP products. When restricted to subjects who were self-responders, 17% reported ATP use, while 10% reported current cigarette smoking alone. The mean age of ATP users was 57 ± 17 years. Those who did not complete a survey were sicker and more likely to have died during admission. Subjects who completed the survey as self-responders reported higher levels of ATP use than ones with surrogate responders ( < 0.0001). ATP use is common among critically ill patients despite them being generally older than traditional users. Survey self-responders were more likely than surrogate responders to report use. These findings highlight the importance of improving our current methods of surveillance of ATP use in older adults in the outpatient setting.
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http://dx.doi.org/10.3390/ijerph17238707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727672PMC
November 2020

Acute respiratory distress syndrome-attributable mortality in critically ill patients with sepsis.

Intensive Care Med 2020 06 23;46(6):1222-1231. Epub 2020 Mar 23.

Cardiovascular Research Institute, University of California, San Francisco, CA, USA.

Purpose: Previous studies assessing impact of acute respiratory distress syndrome (ARDS) on mortality have shown conflicting results. We sought to assess the independent association of ARDS with in-hospital mortality among intensive care unit (ICU) patients with sepsis.

Methods: We studied two prospective sepsis cohorts drawn from the Early Assessment of Renal and Lung Injury (EARLI; n = 474) and Validating Acute Lung Injury markers for Diagnosis (VALID; n = 337) cohorts. ARDS was defined by Berlin criteria. We used logistic regression to compare in-hospital mortality in patients with and without ARDS, controlling for baseline severity of illness. We also estimated attributable mortality, adjusted for illness severity by stratification.

Results: ARDS occurred in 195 EARLI patients (41%) and 99 VALID patients (29%). ARDS was independently associated with risk of hospital death in multivariate analysis, even after controlling for severity of illness, as measured by APACHE II (odds ratio [OR] 1.65 (95% confidence interval [CI] 1.02, 2.67), p = 0.04 in EARLI; OR 2.12 (CI 1.16, 3.92), p = 0.02 in VALID). Patients with severe ARDS (P/F < 100) primarily drove this relationship. The attributable mortality of ARDS was 27% (CI 14%, 37%) in EARLI and 37% (CI 10%, 51%) in VALID. ARDS was independently associated with ICU mortality, hospital length of stay (LOS), ICU LOS, and ventilator-free days.

Conclusions: Development of ARDS among ICU patients with sepsis confers increased risk of ICU and in-hospital mortality in addition to other important outcomes. Clinical trials targeting patients with severe ARDS will be best poised to detect measurable differences in these outcomes.
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http://dx.doi.org/10.1007/s00134-020-06010-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224051PMC
June 2020

Homologous recombination and DNA repair mutations in patients treated with carboplatin and nab-paclitaxel for metastatic non-small cell lung cancer.

Lung Cancer 2019 08 17;134:167-173. Epub 2019 Jun 17.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

Objectives: Chemotherapy remains a cornerstone treatment in non-small cell lung cancer either in combination with checkpoint inhibitors or as subsequent therapy. Identifying molecular predictors of response allows for optimal treatment selection. We performed genomic analysis on tumor samples of patients treated with carboplatin and nab-paclitaxel as part of a phase II trial to evaluate the prognostic and predictive value of mutations in DNA repair pathway in patients treated with this regimen.

Materials And Methods: Next-generation sequencing libraries were produced using a capture-based targeted panel covering the coding exons of 278 genes on patients treated on clinical trial NCT00729612. Overall survival (OS) and progression-free survival (PFS) were assessed as part of the clinical outcomes and correlated with mutation analysis.

Results: Of 63 patients enrolled, 25 patients had sufficient and acceptable DNA isolated from archival tumor samples for targeted sequencing. The most commonly altered pathways included DNA repair (DR) including Fanconi anemia and homologous recombination, JAK-STAT signaling, IGF-1, mTOR, and MAPK-ERK. Four patients with mutations in homologous recombination mutations had a shorter PFS (hazard ratio [HR] = 4.54, 95% CI 1.2, 17.1, p = 0.026) and OS (HR = 6.3, 95% CI 1.8, 21.3, p = 0.003).

Conclusion: In this analysis of patients with predominantly squamous cell non-small cell lung cancer treated with carboplatin and nab-paclitaxel in a phase II trial, patients with mutations in homologous recombination pathways had shorter overall and progression-free survival. Validation on additional datasets of patients treated with platinum-based chemotherapy and immunotherapy combinations is warranted.
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http://dx.doi.org/10.1016/j.lungcan.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194132PMC
August 2019

Two Distinct E2F Transcriptional Modules Drive Cell Cycles and Differentiation.

Cell Rep 2019 06 23;27(12):3547-3560.e5. Epub 2019 May 23.

Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address:

Orchestrating cell-cycle-dependent mRNA oscillations is critical to cell proliferation in multicellular organisms. Even though our understanding of cell-cycle-regulated transcription has improved significantly over the last three decades, the mechanisms remain untested in vivo. Unbiased transcriptomic profiling of G, G-S, and S-G-M sorted cells from FUCCI mouse embryos suggested a central role for E2Fs in the control of cell-cycle-dependent gene expression. The analysis of gene expression and E2F-tagged knockin mice with tissue imaging and deep-learning tools suggested that post-transcriptional mechanisms universally coordinate the nuclear accumulation of E2F activators (E2F3A) and canonical (E2F4) and atypical (E2F8) repressors during the cell cycle in vivo. In summary, we mapped the spatiotemporal expression of sentinel E2F activators and canonical and atypical repressors at the single-cell level in vivo and propose that two distinct E2F modules relay the control of gene expression in cells actively cycling (E2F3A-8-4) and exiting the cycle (E2F3A-4) during mammalian development.
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http://dx.doi.org/10.1016/j.celrep.2019.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673649PMC
June 2019

KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid Cancer.

J Natl Compr Canc Netw 2019 05;17(5):409-413

Division of Medical Oncology.

BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS. This case report describes a patient with radioactive iodine-refractory metastatic PTC treated in a clinical trial with combination BRAF and MEK inhibition who achieved a durable PR. At time of progression, biopsy revealed an acquired KRAS G12V-activating mutation. The patient subsequently went on to have a PR to cabozantinib therapy in the clinical trial. This is the first reported case of an acquired KRAS-activating mutation that developed during treatment with BRAF and MEK inhibition in a patient with BRAF-mutated PTC. The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.ClinicalTrials.gov identifier: NCT01723202.
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http://dx.doi.org/10.6004/jnccn.2019.7292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673655PMC
May 2019

Predisposing factors of necrotizing fasciitis with comparison to cellulitis in Taiwan: A nationwide population-based case-control study.

J Formos Med Assoc 2020 Jan 6;119(1 Pt 1):18-25. Epub 2019 Feb 6.

Division of Plastic Surgery, Department of Surgery, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan. Electronic address:

Background: Necrotizing fasciitis (NF) is a life-threatening soft tissue infection with low incidence that requires prompt surgery. In the initial stage, it is difficult to distinguish NF and cellulitis, and limited population-based reports are available.

Methods: We queried inpatient data sets of National Health Institute Research Database in Taiwan from 2002 to 2011 for all patients with diagnoses of NF. Of them, only patients who underwent surgeries and had been admitted to intensive care units were included as the study group. Age and gender-matched patients with admission diagnoses of cellulitis were enrolled in a ratio of 1:4 as the control group. We calculated annual incidence, mortality rate, risk factors and predictors of mortality of NF.

Results: The study group consisted of 7391 NF patients. Among them, 4715 patients (64%) were man and 2676 (36%) were women. The overall annual incidence of NF was 3.26 hospitalizations per 100,000 person-years, which rose with age with male predominance. The in-hospital mortality rate, which also rose with age, was 32.2%. Diabetes mellitus (adjusted odds ratio, 2.93; 95% confidence interval, 2.77-3.11; P value < 0.0001), alcoholism (2.64; 2.27-3.08; P < .0001), and chronic kidney disease (1.98; 1.84-2.14; P < .001) were identified as risk factors. Chronic kidney disease (1.86; 1.64-2.10; P < .001) and liver cirrhosis (1.68; 1.50-1.88; P < .001) were identified as predictors of in-hospital mortality.

Conclusion: Age and the presence of chronic diseases are major risk factors as well as prognostic factors of NF in Taiwan. Diabetes mellitus increases the risk of NF, but does not adversely affect the outcome.
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http://dx.doi.org/10.1016/j.jfma.2019.01.014DOI Listing
January 2020

Nodular fasciitis: A rapidly enlarging destructive periorbital mass in an infant.

Am J Ophthalmol Case Rep 2019 Mar 19;13:119-121. Epub 2018 Apr 19.

Department of Ophthalmology and Visual Sciences, The University of British Columbia, Vancouver, Canada.

Purpose: To review the clinical and histopathological features of nodular fasciitis, a rare benign periorbital tumor that mimics orbital malignancy, by presenting a case involving an infant with marked orbital wall erosion requiring repair.

Observations: A 9-month-old boy developed a rapidly growing periorbital mass concerning for a soft tissue malignancy. Computerized tomography (CT) scans showed bony erosion of the lateral orbital wall. Incisional biopsy revealed nodular fasciitis. gene rearrangement was negative. The tumor was completely excised and the underlying orbital wall defect was repaired with polydioxanone (PDS) plate.

Conclusions And Importance: Nodular fasciitis is a benign periorbital tumor that presents like malignancies and warrants prompt investigations, especially in children. Orbital wall erosion is rare and can be repaired to yield good functional and cosmetic outcome.
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http://dx.doi.org/10.1016/j.ajoc.2018.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312801PMC
March 2019

Response of a local hospital to a burn disaster: Contributory factors leading to zero mortality outcomes.

Burns 2018 08 9;44(5):1083-1090. Epub 2018 May 9.

Department of Surgery, National Taiwan University Hospital, No. 7, Chung Shan South Road, Taipei, Taiwan. Electronic address:

Objective: To investigate the outcomes of a local healthcare system in managing a burn mass casualty incident (BMCI).

Methods: Thirty-three victims admitted to the National Taiwan University Hospital within 96h of the explosion were included in the study. Data were recorded on: patient demographics, Baux score, laboratory data, management response, treatment strategies, and outcomes. Case notes from June 27, 2015 to November 2015 were reviewed with a focus on fluid resuscitation, ventilation support, nutrition, infection control, sepsis treatment, and wound closure plan.

Results: Female predominance (mean age: 21.7 years) and lower extremity circumferential flame burns were the characteristics of the burn injury. The mean Baux score was 70±18. The mean burn area was 42% of the total body surface area (TBSA). A total of 79% patients arrived at the hospital within 24h of sustaining injuries. Intensive care unit (ICU) admission criteria were modified to accommodate patients with 40% TBSA of burns, facilities were expanded from 4 ICU beds to 18 beds, and new staff was recruited. A total of 36% patients (n=12/33, 62±13 TBSA of burns) required fluid resuscitation. The mean volume of Lactate Ringer administered in the first 24h of burns was 3.34±2.18ml/kg/%TBSA, while the mean volume of fresh frozen plasma administered was 0.60±0.63ml/kg/h. Forty-two percent patients were intubated on the day of admission, and 71% of the intubated patients had inhalation injuries that were confirmed by diagnostic bronchoscopy. The mean intubation period was 17±9 days. The incidence of pulmonary edema was 58% (n=7/12), possibly due to sub-optimal monitoring. Of these, 57% (n=4/7) patients progressed to adult respiratory distress syndrome, but were successfully treated with early strict fluid restriction, systemic antibiotics, ventilation support, and bronchial lavage. A total of 94% patients received grafting. The mean grafted area was 4432.3±3891cm. Tube feeding was provided to patients with burns >40% TBSA. All patients tolerated gastric tube feeding without conversion to duodenal switch. On admission, all patients received prophylactic antibiotics. Septic shock was noted in 12 patients, but no mortality occurred. The mean hospital stay was 1.5 days per percent burn.

Conclusions: This article highlights the value of precise triage, traffic control, and effective resource allocation in treating a BMCI. Effective supporting systems for facility expansion, staff recruitment, medical supplies and clear-cut treatment strategies for severely burned patients are contributory factors leading to zero mortalities in our series, in addition to young age and minimal inhalation injuries. The need for reevaluation of the safety of cornstarch powder in festival activities is clear.
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http://dx.doi.org/10.1016/j.burns.2018.03.019DOI Listing
August 2018

Sexual response of male Drosophila to honey bee queen mandibular pheromone: implications for genetic studies of social insects.

J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2017 Feb 1;203(2):143-149. Epub 2017 Feb 1.

Biology Department, Western University, 1151 Richmond Street, London, ON, N6A 5B7, Canada.

Honey bees secrete a queen mandibular pheromone that renders workers reproductively altruistic and drones sexually attentive. This sex-specific function of QMP may have evolved from a sexually dimorphic signaling mechanism derived from pre-social ancestors. If so, there is potential for pre-social insects to respond to QMP, and in a manner that is comparable to its normal effect on workers and drones. Remarkably, QMP applied to female Drosophila does induce worker-like qualities [Camiletti et al. (Entomol Exp Appl 147:262, 2013)], and we here extend this comparison to examine the effects of bee pheromone on male fruit flies. We find that male Drosophila melanogaster consistently orient towards a source of queen pheromone in a T-maze, suggesting a recruitment response comparable to the pheromone's normal effect on drones. Moreover, exposure to QMP renders male flies more sexually attentive; they display intensified pre-copulatory behavior towards conspecific females. We can inhibit this sexual effect through a loss-of-olfactory-function mutation, which suggests that the pheromone-responsive behavioral mechanism is olfactory-driven. These pheromone-induced changes to male Drosophila behavior suggest that aspects of sexual signaling are conserved between these two distantly related taxa. Our results highlight a role for Drosophila as a genetically tractable pre-social model for studies of social insect biology.
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http://dx.doi.org/10.1007/s00359-017-1147-yDOI Listing
February 2017

Case of Actinomyces lacrimal sac abscess mimicking malignancy.

Can J Ophthalmol 2016 Oct 25;51(5):e147-e149. Epub 2016 Aug 25.

Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, B.C. Electronic address:

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http://dx.doi.org/10.1016/j.jcjo.2016.06.016DOI Listing
October 2016

Impact of Pre-Analytical Variables on Cancer Targeted Gene Sequencing Efficiency.

PLoS One 2015 25;10(11):e0143092. Epub 2015 Nov 25.

James Thoracic Center, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, 43210, United States of America.

Tumor specimens are often preserved as formalin-fixed paraffin-embedded (FFPE) tissue blocks, the most common clinical source for DNA sequencing. Herein, we evaluated the effect of pre-sequencing parameters to guide proper sample selection for targeted gene sequencing. Data from 113 FFPE lung tumor specimens were collected, and targeted gene sequencing was performed. Libraries were constructed using custom probes and were paired-end sequenced on a next generation sequencing platform. A PCR-based quality control (QC) assay was utilized to determine DNA quality, and a ratio was generated in comparison to control DNA. We observed that FFPE storage time, PCR/QC ratio, and DNA input in the library preparation were significantly correlated to most parameters of sequencing efficiency including depth of coverage, alignment rate, insert size, and read quality. A combined score using the three parameters was generated and proved highly accurate to predict sequencing metrics. We also showed wide read count variability within the genome, with worse coverage in regions of low GC content like in KRAS. Sample quality and GC content had independent effects on sequencing depth, and the worst results were observed in regions of low GC content in samples with poor quality. Our data confirm that FFPE samples are a reliable source for targeted gene sequencing in cancer, provided adequate sample quality controls are exercised. Tissue quality should be routinely assessed for pre-analytical factors, and sequencing depth may be limited in genomic regions of low GC content if suboptimal samples are utilized.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143092PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659597PMC
June 2016

Somatic Mutation Spectrum of Non-Small-Cell Lung Cancer in African Americans: A Pooled Analysis.

J Thorac Oncol 2015 Oct;10(10):1430-6

*Department of Internal Medicine, James Thoracic Center, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; †Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee; ‡Department of Internal Medicine, Baptist Center for Cancer Care, Columbus, Mississippi; §Department of Pathology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; ‖Pathology Associates of Saint Thomas, Nashville, Tennessee; ¶Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; #GenomOncology, Cleveland, Ohio; ††Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio; and ‡‡Department of Biomedical Informatics, Biomedical Informatics Shared Resource, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Introduction: The mutational profile of non-small-cell lung cancer (NSCLC) has become an important tool in tailoring therapy to patients, with clear differences according to the population of origin. African Americans (AAs) have higher lung cancer incidence and mortality than Caucasians, yet discrepant results have been reported regarding the frequency of somatic driver mutations. We hypothesized that NSCLC has a distinct mutational profile in this group.

Methods: We collected NSCLC samples resected from self-reported AAs in five sites from Tennessee, Michigan, and Ohio. Gene mutations were assessed by either SNaPshot or next generation sequencing, and ALK translocations were evaluated by fluorescence in situ hybridization.

Results: Two hundred sixty patients were included, mostly males (62.3%) and smokers (86.6%). Eighty-one samples (31.2%) were squamous cell carcinomas. The most frequently mutated genes were KRAS (15.4%), epidermal growth factor receptor (EGFR, 5.0%), PIK3CA (0.8%), BRAF, NRAS, ERBB2, and AKT1 (0.4% each). ALK translocations were detected in two nonsquamous tumors (1.7%), totaling 61 cases (23.5%) with driver oncogenic alterations. Among 179 nonsquamous samples, 54 (30.2%) presented a driver alteration. The frequency of driver alterations altogether was lower than that reported in Caucasians, whereas no difference was detected in either EGFR or KRAS mutations. Overall survival was longer among patients with EGFR mutations.

Conclusions: We demonstrated that NSCLC from AAs has a different pattern of somatic driver mutations than from Caucasians. The majority of driver alterations in this group are yet to be described, which will require more comprehensive panels and assessment of noncanonical alterations.
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http://dx.doi.org/10.1097/JTO.0000000000000650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618391PMC
October 2015

Genomic Characterization of Non-Small-Cell Lung Cancer in African Americans by Targeted Massively Parallel Sequencing.

J Clin Oncol 2015 Jun 27;33(17):1966-73. Epub 2015 Apr 27.

Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.

Purpose: Technologic advances have enabled the comprehensive analysis of genetic perturbations in non-small-cell lung cancer (NSCLC); however, African Americans have often been underrepresented in these studies. This ethnic group has higher lung cancer incidence and mortality rates, and some studies have suggested a lower incidence of epidermal growth factor receptor mutations. Herein, we report the most in-depth molecular profile of NSCLC in African Americans to date.

Methods: A custom panel was designed to cover the coding regions of 81 NSCLC-related genes and 40 ancestry-informative markers. Clinical samples were sequenced on a massively parallel sequencing instrument, and anaplastic lymphoma kinase translocation was evaluated by fluorescent in situ hybridization.

Results: The study cohort included 99 patients (61% males, 94% smokers) comprising 31 squamous and 68 nonsquamous cell carcinomas. We detected 227 nonsilent variants in the coding sequence, including 24 samples with nonoverlapping, classic driver alterations. The frequency of driver mutations was not significantly different from that of whites, and no association was found between genetic ancestry and the presence of somatic mutations. Copy number alteration analysis disclosed distinguishable amplifications in the 3q chromosome arm in squamous cell carcinomas and pointed toward a handful of targetable alterations. We also found frequent SMARCA4 mutations and protein loss, mostly in driver-negative tumors.

Conclusion: Our data suggest that African American ancestry may not be significantly different from European/white background for the presence of somatic driver mutations in NSCLC. Furthermore, we demonstrated that using a comprehensive genotyping approach could identify numerous targetable alterations, with potential impact on therapeutic decisions.
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http://dx.doi.org/10.1200/JCO.2014.59.2444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451177PMC
June 2015

Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS.

Am J Physiol Lung Cell Mol Physiol 2015 Jun 20;308(11):L1102-13. Epub 2015 Mar 20.

Departments of Medicine and Anesthesia, University of California-San Francisco, San Francisco, California; Cardiovascular Research Institute, University of California-San Francisco, San Francisco, California; Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California-San Francisco, San Francisco, California; and.

The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission at a tertiary care center. Whole genome expression was compared in patients with sepsis and ARDS to patients with sepsis alone. We selected genes with >1 log2 fold change and false discovery rate <0.25, determined their significance in the literature, and performed pathway analysis. Several genes were upregulated in 29 patients with sepsis with ARDS compared with 28 patients with sepsis alone. The most differentially expressed genes included key mediators of the initial neutrophil response to infection: olfactomedin 4, lipocalin 2, CD24, and bactericidal/permeability-increasing protein. These gene expression differences withstood adjustment for age, sex, study batch, white blood cell count, and presence of pneumonia or aspiration. Pathway analysis demonstrated overrepresentation of genes involved in known respiratory and infection pathways. These data indicate that several neutrophil-related pathways may be involved in the early pathogenesis of sepsis-related ARDS. In addition, identifiable gene expression differences occurring early in the course of sepsis-related ARDS may further elucidate understanding of the neutrophil-related mechanisms in progression to ARDS.
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http://dx.doi.org/10.1152/ajplung.00380.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451399PMC
June 2015

The Epstein-Barr Virus Lytic Protein BZLF1 as a Candidate Target Antigen for Vaccine Development.

Cancer Immunol Res 2015 Jul 3;3(7):787-94. Epub 2015 Mar 3.

The Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio. Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.

The Epstein-Barr virus (EBV) is an oncogenic, γ-herpesvirus associated with a broad spectrum of disease. Although most immune-competent individuals can effectivley develop efficient adaptive immune responses to EBV, immunocompromised individuals are at serious risk for developing life-threatening diseases, such as Hodgkin lymphoma and posttransplant lymphoproliferative disorder (PTLD). Given the significant morbidity associated with EBV infection in high-risk populations, there is a need to develop vaccine strategies that restore or enhance EBV-specific immune responses. Here, we identify the EBV immediate-early protein BZLF1 as a potential target antigen for vaccine development. Primary tumors from patients with PTLD and a chimeric human-murine model of EBV-driven lymphoproliferative disorder (EBV-LPD) express BZLF1 protein. Pulsing human dendritic cells (DC) with recombinant BZLF1 followed by incubation with autologous mononuclear cells led to expansion of BZLF1-specific CD8(+) T cells in vitro and primed BZLF1-specific T-cell responses in vivo. In addition, vaccination of hu-PBL-SCID mice with BZLF1-transduced DCs induced specific cellular immunity and significantly prolonged survival from fatal EBV-LPD. These findings identify BZLF1 as a candidate target protein in the immunosurveillance of EBV and provide a rationale for considering BZLF1 in vaccine strategies to enhance primary and recall immune responses and potentially prevent EBV-associated diseases.
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http://dx.doi.org/10.1158/2326-6066.CIR-14-0242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491000PMC
July 2015

Clinical Application of Different Surgical Navigation Systems in Complex Craniomaxillofacial Surgery: The Use of Multisurface 3-Dimensional Images and a 2-Plane Reference System.

Ann Plast Surg 2016 Apr;76(4):411-9

From the Department of Surgery, National Taiwan University College of Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Background: Intraoperative navigation is a tool that provides surgeons with real-time guidance based on patients' preoperative imaging studies. The application of intraoperative navigation to neurosurgery and otolaryngology has been well documented; however, only isolated reports have analyzed its potential in the field of craniomaxillofacial surgery.

Methods: From November 2010 to July 2014, 15 patients were operated on for complex craniomaxillofacial surgery with assistance by 3 different navigation systems, which used either infrared or electromagnetic technologies. We imported fine-cut (0.625-mm) computed tomographic scan images of the patients to the navigation systems whose software processed them into multisurface 3-dimentional models used as guiding material for the surgical navigation. We also developed a simple "2-plane reference system" to ensure that the final results were symmetric to the normal half of the face. Appearance outcome was evaluated by questionnaire.

Results: Of these 15 cases, 3 cases were performed with infrared-based navigation, and the remaining 12 cases were accomplished by electromagnetic technology. Most of these cases resulted in satisfactory outcomes after tumor resection, posttraumatic reconstruction, and postablative reconstruction.

Conclusion: Navigation systems offer highly valuable intraoperative assistance in complex craniomaxillofacial surgery. Not only can these systems pinpoint deep-seated lesions as neurosurgeons or otolaryngologists do, but they can also use a simple 2-plane reference system for accurate bone alignment. Moreover, advancements in multisurface 3-D models provide us more reliable intuitive image guidance. The application of electromagnetic technology, with its smaller reference obviation of the line-of-sight problem, makes the manipulation of craniomaxillofacial surgery more comfortable.
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http://dx.doi.org/10.1097/SAP.0000000000000429DOI Listing
April 2016

Video-assisted thoracoscopic surgical thymectomy to treat early thymoma: a comparison with the conventional transsternal approach.

Ann Surg Oncol 2014 Jan 28;21(1):322-8. Epub 2013 Aug 28.

Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan, ROC.

Background: For thymoma, the feasibility of resection via video-assisted thoracoscopic surgery (VATS) remains controversial. The objective of our study was to compare the outcomes of VATS and transsternal thymectomy in order to evaluate the efficacy of the VATS method for treatment of early stage thymoma.

Methods: This study is a retrospective study of 120 patients who underwent thymectomy of early stage thymoma (Masaoka stage I and II) in a single medical center from 1991 to 2010. Of these patients, 76 patients underwent VATS thymectomy (VATS group) and 44 patients underwent the conventional transsternal approach (sternotomy group). We applied the Kaplan-Meier method to estimate overall survival (OS), recurrence-free survival (RFS), and time to tumor recurrence (TTR) of these two groups.

Results: The mean follow-up time was 61.9 months in the VATS group and 69.7 months in the sternotomy group. There was no surgery-related mortality or major complication. The VATS group had smaller specimen size (p < 0.05) and tumor size (p < 0.01), shorter length of stay (LOS) in the hospital (p < 0.01), and shorter duration of chest tube drainage (p < 0.05) than the sternotomy group. There were no significant differences between the two groups for OS, RFS, and TTR.

Conclusions: In early stage thymoma, VATS thymectomy associated with shorter hospital LOS and shorter duration of pleural drainage compared with the conventional transsternal approach. Otherwise, the two approaches had similar oncologic outcomes during the mean 60-month follow-up period.
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http://dx.doi.org/10.1245/s10434-013-3228-7DOI Listing
January 2014

Effects of radiation therapy for breast cancer based on type of free flap reconstruction.

Plast Reconstr Surg 2013 Jan;131(1):1e-8e

Los Angeles, Calif. From the Department of Surgery, Division of Plastic and Reconstructive Surgery, University of California, Los Angeles Medical Center.

Background: Adjuvant radiation therapy for locally advanced breast cancer decreases local recurrence and improves survival. Immediate autologous breast reconstruction before postmastectomy irradiation is highly controversial. However, it is presently unknown whether there exist differences in the durability of various autologous flaps (myocutaneous or fasciocutaneous) to the effects of radiation.

Methods: All patients who underwent autologous breast reconstruction at the authors' institution between July of 2002 and July of 2005 were evaluated retrospectively. Patients who did not complete all stages of their reconstruction at the authors' institution were excluded. Free flap types were analyzed based on postoperative radiation exposure versus no radiation exposure. The authors also analyzed patients who underwent reconstruction in a delayed fashion with prior radiation exposure and assessed overall outcomes for early and late complications and secondary breast procedures.

Results: Three hundred sixty-three of 446 flaps (81 percent) were included in the analysis, with the three most common flaps being the free transverse rectus abdominis myocutaneous (TRAM) flap (7.4 percent), the muscle-sparing free TRAM flap (44 percent), and the deep inferior epigastric perforator flap (41 percent). There were no significant differences in early or late complications among the different flap types or radiation categories. Flaps with prior radiation exposure were associated with higher percentages of contralateral symmetry procedures, whereas flaps with postoperative radiation exposure had a lower incidence of ipsilateral revisions.

Conclusions: Autologous breast reconstruction can be performed safely regardless of preoperative or postoperative radiation therapy. There are no significant differences in complication rates or number of revisions based on the type of free flap.

Clinical Question/level Of Evidence: Therapeutic, III.
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http://dx.doi.org/10.1097/PRS.0b013e3182729d33DOI Listing
January 2013

Long-term results of face lift surgery: patient photographs compared with patient satisfaction ratings.

Plast Reconstr Surg 2012 Jan;129(1):253-262

San Francisco, Calif. From the Aesthetic Surgery Institute, California Pacific Medical Center-Davies Campus.

Background: Surgical facial rejuvenation (face lift) remains the aesthetic standard for correction of the anatomical changes of the aging face and for long-lasting results. However, younger patients (younger than 50 years) with early facial aging are often fearful of or discouraged from face-lift surgery in favor of simpler yet short-lived nonsurgical and surgical options. The superficial musculoaponeurotic system-platysma face lift is associated with a high degree of patient satisfaction at 1 year (97.8 percent) and at 12.6 years (68.5 percent). When the satisfaction scores were subdivided into three age groups (younger than 50, 50 to 60, and older than 60 years), the authors found greater satisfaction among the younger age group at the early and long-term intervals. To illustrate these observations, the authors analyzed the photographic results of their survey patients and compared them with their survey results.

Methods: The photographic results of the patients from our Owsley Facelift Satisfaction Survey were analyzed and stratified into the three age groups. Six patients (two per age group) were included for analysis and are presented for review.

Results: Patient-rated survey results show that the younger age group consistently scored higher positive ratings, longer lasting aesthetic improvement of their five main anatomical areas of correction, and greater overall satisfaction at long-term follow-up.

Conclusions: Younger patients with early or minimal signs of facial aging should be considered candidates for surgical facial rejuvenation ("maintenance face lifts") and are the preferred candidates. This age group of patients has consistently positive overall satisfaction with longer lasting facial aesthetic correction.

Clinical Question/level Of Evidence: Therapeutic, III.
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http://dx.doi.org/10.1097/PRS.0b013e3182362b55DOI Listing
January 2012

Staged wise-pattern skin excision for reconstruction of the large and ptotic breast.

Plast Reconstr Surg 2010 Dec;126(6):1831-1839

Los Angeles, Calif. From the Division of Plastic and Reconstructive Surgery, Department of Surgery, University of California, Los Angeles Medical Center.

Background: The postmastectomy reconstruction of large and/or ptotic breasts poses a more difficult aesthetic challenge than the reconstruction of small or moderately sized breasts because of an excessively large skin envelope in both horizontal and vertical dimensions. The Wise-pattern skin excision best addresses this excess skin but is associated with a high incidence of tissue necrosis with subsequent wound breakdown, primarily at the T point. To optimize the aesthetic potential and minimize complications in the setting of these large skin envelopes, the authors have deconstructed the single-stage Wise-pattern skin excision into a two-stage procedure, eliminating the need for a primary simultaneous T-point closure.

Methods: In the first stage, the mastectomy and reconstruction are performed using a vertical excision, which tightens the breast skin envelope horizontally. In the second stage, the redundant skin at the inframammary fold is excised horizontally, tightening the breast skin envelope vertically. The summation of the two staged excisions recreates the Wise pattern, breaking up the T point into two straightforward primary closures.

Results: Twelve patients (21 breasts) underwent successful reconstruction using the staged Wise-pattern skin excision. The breast size, shape, and projection of the patients were greatly improved without any wound complications.

Conclusions: The staged Wise-pattern skin excision for breast reconstruction is a simple technique that delivers superior results for the challenging reconstruction of large and/or ptotic breasts. This method offers an aesthetically pleasing breast shape, allows for the correction of ptosis, eliminates wound complications, and results in a standard Wise-pattern scar.
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http://dx.doi.org/10.1097/PRS.0b013e3181f5278fDOI Listing
December 2010

The diamond double-opposing V-Y flap: a reliable, simple, and versatile technique for nipple reconstruction.

Plast Reconstr Surg 2010 Jun;125(6):1643-1648

Los Angeles and Encino, Calif. From the Department of Surgery, Division of Plastic and Reconstructive Surgery, University of California, Los Angeles Medical Center, and Lesavoy Plastic Surgery.

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http://dx.doi.org/10.1097/PRS.0b013e3181ccda8bDOI Listing
June 2010

Resolution of EEG artifact during continuous renal replacement therapy: case report.

Clin EEG Neurosci 2009 Jul;40(3):204-5

Grand River Hospital, Kitchener, Ontario, Canada.

We describe an electrical EEG artifact seen during continuous renal replacement therapy (CRRT). This artifact was spiky waves that disappeared with grounding of the CRRT device allowing accurate interpretation of the EEG tracing.
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http://dx.doi.org/10.1177/155005940904000315DOI Listing
July 2009

Documenting the density of innervation in a sensate radial forearm flap based on the lateral antebrachial cutaneous nerve.

Plast Reconstr Surg 2009 Jun;123(6):216e-217e

Division of Plastic and Reconstructive Surgery; Harbor-University of California, Los Angeles Medical Center; David Geffen School of Medicine at; University of California, Los Angeles; Los Angeles, Calif.

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http://dx.doi.org/10.1097/PRS.0b013e3181a65b46DOI Listing
June 2009

Economic analysis of the future growth of cosmetic surgery procedures.

Plast Reconstr Surg 2008 Jun;121(6):404e-412e

Los Angeles, Calif. From the Department of Surgery, Division of Plastic and Reconstructive Surgery, University of California, Los Angeles Medical Center.

Background: The economic growth of cosmetic surgical and nonsurgical procedures has been tremendous. Between 1992 and 2005, annual U.S. cosmetic surgery volume increased by 725 percent, with over $10 billion spent in 2005. It is unknown whether this growth will continue for the next decade and, if so, what impact it will it have on the plastic surgeon workforce.

Methods: The authors analyzed annual U.S. cosmetic surgery procedure volume reported by the American Society of Plastic Surgeons (ASPS) National Clearinghouse of Plastic Surgery Statistics between 1992 and 2005. Reconstructive plastic surgery volume was not included in the analysis. The authors analyzed the ability of economic and noneconomic variables to predict annual cosmetic surgery volume. The authors also used growth rate analyses to construct models with which to predict the future growth of cosmetic surgery.

Results: None of the economic and noneconomic variables were a significant predictor of annual cosmetic surgery volume. Instead, based on current compound annual growth rates, the authors predict that total cosmetic surgery volume (surgical and nonsurgical) will exceed 55 million annual procedures by 2015. ASPS members are projected to perform 299 surgical and 2165 nonsurgical annual procedures. Non-ASPS members are projected to perform 39 surgical and 1448 nonsurgical annual procedures.

Conclusions: If current growth rates continue into the next decade, the future demand in cosmetic surgery will be driven largely by nonsurgical procedures. The growth of surgical procedures will be met by ASPS members. However, meeting the projected growth in nonsurgical procedures could be a potential challenge and a potential area for increased competition.
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http://dx.doi.org/10.1097/PRS.0b013e318170818dDOI Listing
June 2008

Salvage of congested deep inferior epigastric perforator flap with a reverse flow venous anastomosis.

Ann Plast Surg 2007 Aug;59(2):214-7

UCLA Medical Center, Department of Surgery, Division of Plastic and Reconstructive Surgery, 200 UCLA Medical Plaza, Los Angeles, CA 90095, USA.

The deep inferior epigastric perforator flap (DIEP) is an increasingly popular method for autologous breast reconstruction because of less abdominal wall donor-site morbidity. However, disadvantages with the DIEP flap are its greater technical difficulties for flap harvest and a greater incidence of venous congestion. We report a case of salvage of a congested DIEP flap with a superficial inferior epigastric vein (SIEV) to deep inferior epigastric vein reverse flow anastomosis. Drainage of both the superficial and deep system resulted in complete reversal of venous congestion and flap salvage. Preservation and use of the SIEV for venous augmentation via a reverse flow anastomosis is a novel and simple method for DIEP flap salvage of venous congestion.
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http://dx.doi.org/10.1097/01.sap.0000250853.40099.49DOI Listing
August 2007

Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia.

Blood 2007 Sep 30;110(6):2075-83. Epub 2007 May 30.

Department of Pharmacology, The Ohio State University, Columbus, OH 43210, USA.

Entry into the cell cycle is mediated by cyclin-dependent kinase 4/6 (CDK4/6) activation, followed by CDK2 activation. We found that pharmacologic inhibition of the Flt3 internal tandem duplication (ITD), a mutated receptor tyrosine kinase commonly found in patients with acute myelogenous leukemia (AML), led to the down-regulation of cyclin D2 and D3 followed by retinoblastoma protein (pRb) dephosphorylation and G(1) cell-cycle arrest. This implicated the D-cyclin-CDK4/6 complex as a downstream effector of Flt3 ITD signaling. Indeed, single-agent PD0332991, a selective CDK4/6 inhibitor, caused sustained cell-cycle arrest in Flt3 ITD AML cell lines and prolonged survival in an in vivo model of Flt3 ITD AML. PD0332991 caused an initial cell-cycle arrest in well-established Flt3 wild-type (wt) AML cell lines, but this was overcome by down-regulation of p27(Kip) and reactivation of CDK2. This acquired resistance was not observed in a Flt3 ITD and a Flt3 wt sample from a patient with primary AML. In summary, the mechanism of cell-cycle arrest after treatment of Flt3 ITD AML with a Flt3 inhibitor involves down-regulation of cyclin D2 and D3. As such, CDK4/6 can be a therapeutic target in Flt3 ITD AML but also in primary Flt3 wt AML. Finally, acquired resistance to CDK4/6 inhibition can arise through activation CDK2.
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http://dx.doi.org/10.1182/blood-2007-02-071266DOI Listing
September 2007

Retained central venous haemodialysis access catheters.

Nephrol Dial Transplant 2007 Mar 27;22(3):960-1; author reply 961. Epub 2006 Dec 27.

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http://dx.doi.org/10.1093/ndt/gfl730DOI Listing
March 2007