Publications by authors named "Adam J Kole"

10 Publications

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Predictors of In-Hospital Death in Patients with Lung Cancer Admitted for Acute Radiation Pneumonitis: A Healthcare Cost and Utilization Project (HCUP) Analysis.

Clin Lung Cancer 2021 Feb 3. Epub 2021 Feb 3.

Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, AL. Electronic address:

Background: Radiation pneumonitis (RP) is a dose-limiting and potentially fatal toxicity of thoracic radiotherapy most often seen in patients treated for primary lung cancer. The purpose of this study was to identify predictors of in-hospital death among lung cancer patients admitted for acute RP in the Healthcare Cost and Utilization Project (HCUP) database.

Materials And Methods: The HCUP National Inpatient Sample database was queried from 2012 through 2016 to capture adult lung cancer patients admitted to the hospital with a principal diagnosis of acute RP. Multivariate logistic regression modeling and χ tests were used to determine predictors of in-hospital death.

Results: Of the 882 patients with lung cancer admitted for RP, 67 patients (7.6%) died during the hospitalization and 90 patients (10.2%) required mechanical ventilation. Of those requiring mechanical ventilation, 38 patients (42.2%) died. The average age at hospitalization was 70.4 years (range, 35-90). Of those factors associated with death on univariate analysis, interstitial lung disease (odds ratio [OR] = 6.14; 95% confidence interval [CI], 1.9-19.4; P = .002), pulmonary hypertension (OR = 3.1; 95% CI, 1.6-6.2; P = .001), diabetes mellitus (OR = 2.0; 95% CI, 1.1-3.3; P = .013), and more affluent Zip Code (OR = 1.9; 95% CI, 1.1-3.2; P = .021) remained statistically significant on multivariate logistic regression.

Conclusion: In the largest reported cohort of patients with lung cancer hospitalized with a principal diagnosis of acute RP, the presence of interstitial lung disease, pulmonary hypertension, diabetes mellitus, and more affluent Zip Code were associated with in-hospital death. Comorbid diagnoses may be useful for risk-stratified management of inpatients with RP.
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http://dx.doi.org/10.1016/j.cllc.2021.01.016DOI Listing
February 2021

Overall survival is improved when DCIS accompanies invasive breast cancer.

Sci Rep 2019 07 9;9(1):9934. Epub 2019 Jul 9.

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.

Invasive ductal carcinoma (IDC) often presents alone or with a co-existing ductal carcinoma in situ component (IDC + DCIS). Studies have suggested that pure IDC may exhibit different biological behavior than IDC + DCIS, but whether this translates to a difference in outcomes is unclear. Here, utilizing the National Cancer Database we identified 494,801 stage I-III breast cancer patients diagnosed with either IDC alone or IDC + DCIS. We found that IDC + DCIS was associated with significantly better overall survival (OS) compared to IDC alone (5-year OS, 89.3% vs. 85.5%, p < 0.001), and this finding persisted on multivariable Cox modeling adjusting for demographic, clinical, and treatment-related variables. The significantly superior OS observed for IDC + DCIS was limited to patients with invasive tumor size < 4 cm or with node negative disease. A greater improvement in OS was observed for tumors containing ≥25% DCIS component. We also found IDC + DCIS to be associated with lower T/N stage, low/intermediate grade, ER/PR positivity, and receipt of mastectomy. Thus, the presence of a DCIS component in patients with IDC is associated with favorable clinical characteristics and independently predicts improved OS. IDC + DCIS could be a useful prognostic factor for patients with breast cancer, particularly if treatment de-escalation is being considered for small or node negative tumors.
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http://dx.doi.org/10.1038/s41598-019-46309-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616329PMC
July 2019

Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA.

Clin Cancer Res 2018 04 12;24(8):1872-1880. Epub 2018 Jan 12.

Department of Therapeutic Radiology, Yale School of Medicine, Yale University, New Haven, Connecticut.

Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses are uniquely challenging to interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation. We hypothesized that monitoring tumor cell death in real time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy. We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 patients with metastatic non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitor therapy. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multigene next-generation sequencing assay. We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement. Strong agreement was observed between ctDNA response and radiographic response (Cohen's kappa, 0.753). Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA versus 72.5 days by imaging. Time on treatment was significantly longer for ctDNA responders versus nonresponders (median, 205.5 vs. 69 days; < 0.001). A ctDNA response was associated with superior progression-free survival [hazard ratio (HR), 0.29; 95% CI, 0.09-0.89; = 0.03], and superior overall survival (HR, 0.17; 95% CI, 0.05-0.62; = 0.007). A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for NSCLC. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899677PMC
April 2018

Acute radiation dermatitis in breast cancer patients: challenges and solutions.

Breast Cancer (Dove Med Press) 2017 5;9:313-323. Epub 2017 May 5.

Department of Therapeutic Radiology.

Nearly all women who receive radiotherapy (RT) for breast cancer experience some degree of radiation dermatitis. However, evidence describing the appropriate management of radiation dermatitis is often lacking or contradictory. Here, we summarize the available literature regarding radiation dermatitis causes, the presentation and timing of symptoms, methods for dermatitis assessment and prevention, and review evidence-based management strategies.
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http://dx.doi.org/10.2147/BCTT.S109763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426474PMC
May 2017

Predictors of Nonadherence to NCCN Guideline Recommendations for the Management of Stage I Anal Canal Cancer.

J Natl Compr Canc Netw 2017 03;15(3):355-362

Department of Therapeutic Radiology, Surgical Oncology Section, Yale School of Medicine, New Haven, Connecticut

Definitive chemoradiotherapy (CRT) is recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Anal Carcinoma for all patients with stage I anal canal cancer. Because these patients were not well represented in clinical trials establishing CRT as standard therapy, it is unclear whether NCCN recommendations are being closely followed for stage I disease. This study identified factors that predict for NCCN Guideline-concordant versus NCCN Guideline-discordant care. Using the National Cancer Data Base, we identified patients diagnosed with anal canal carcinoma from 2004 to 2012 who received concurrent CRT (radiotherapy [RT] 45.0-59.4 Gy with multiagent chemotherapy), RT alone (45.0-59.4 Gy), or surgical procedure alone (local tumor destruction, tumor excision, or abdominoperineal resection). Demographic and clinicopathologic factors were analyzed using the chi-square test and logistic regression modeling. A total of 1,082 patients with histologically confirmed stage I anal cancer were identified, among whom 665 (61.5%) received CRT, 52 (4.8%) received RT alone, and 365 (33.7%) received only a surgical procedure. Primary analyses were restricted to patients receiving CRT or excision alone, as these were most common. Multivariable analysis identified factors independently associated with reduced odds of CRT receipt: low versus intermediate/high tumor grade (adjusted odds ratio [AOR], 0.21; 95% CI, 0.14-0.29; <.001), tumor size <1 cm vs 1 to 2 cm (AOR, 0.24; 95% CI, 0.17-0.35; <.001), age ≥70 versus 50 to 69 years (AOR, 0.36; 95% CI, 0.24-0.54; <.001), male sex (AOR, 0.63; 95% CI, 0.45-0.90; =.009), and treatment at an academic versus a non-academic facility (AOR, 0.58; 95% CI, 0.41-0.81; =.002). Despite the NCCN recommendation of CRT for stage I anal cancer, at least one-third of patients appear to be receiving guideline-discordant management. Excision alone is more common for patients who are elderly, are male, have small or low-grade tumors, or were evaluated at academic facilities.
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http://dx.doi.org/10.6004/jnccn.2017.0035DOI Listing
March 2017

Concurrent chemoradiotherapy versus radiotherapy alone for "biopsy-only" glioblastoma multiforme.

Cancer 2016 08 12;122(15):2364-70. Epub 2016 May 12.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut.

Background: Combined temozolomide and radiotherapy (RT) is the standard postoperative therapy for glioblastoma multiforme (GBM). However, the clearest benefit of concurrent chemoradiotherapy (CRT) observed in clinical trials has been among patients who undergo surgical resection. Whether the improved survival with CRT extends to patients who undergo "biopsy only" is less certain. The authors compared overall survival (OS) in a national cohort of patients with GBM who underwent biopsy and received either RT alone or CRT during the temozolomide era.

Methods: The US National Cancer Data Base was used to identify patients with histologically confirmed, biopsy-only GBM who received either RT alone or CRT from 2006 through 2011. Demographic and clinicopathologic predictors of treatment were analyzed using the chi-square test, the t test, and multivariable logistic regression. OS was evaluated using the log-rank test, multivariable Cox proportional hazard regression, and propensity score-matched analysis.

Results: In total, 1479 patients with biopsy-only GBM were included, among whom 154 (10.4%) received RT alone and 1325 (89.6%) received CRT. The median age at diagnosis was 61 years. CRT was associated with a significant OS benefit compared with RT alone (median, 9.2 vs 5.6 months; hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.54-0.76; P < .001). CRT was independently associated with improved OS compared with RT alone on multivariable analysis (HR, 0.71; 95% CI, 0.60-0.85; P < .001). A significant OS benefit for CRT persisted in a propensity score-matched analysis (HR, 0.72; 95% CI, 0.56-0.93; P = .009).

Conclusions: The current data suggest that CRT significantly improves OS in patients with GBM who undergo biopsy only compared with RT alone and should remain the standard of care for patients who can tolerate therapy. Cancer 2016;122:2364-2370. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30063DOI Listing
August 2016

The E3 ligase PARC mediates the degradation of cytosolic cytochrome c to promote survival in neurons and cancer cells.

Sci Signal 2014 Jul 15;7(334):ra67. Epub 2014 Jul 15.

Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA. Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.

The ability to withstand mitochondrial damage is especially critical for the survival of postmitotic cells, such as neurons. Likewise, cancer cells can also survive mitochondrial stress. We found that cytochrome c (Cyt c), which induces apoptosis upon its release from damaged mitochondria, is targeted for proteasome-mediated degradation in mouse neurons, cardiomyocytes, and myotubes and in human glioma and neuroblastoma cells, but not in proliferating human fibroblasts. In mouse neurons, apoptotic protease-activating factor 1 (Apaf-1) prevented the proteasome-dependent degradation of Cyt c in response to induced mitochondrial stress. An RNA interference screen in U-87 MG glioma cells identified p53-associated Parkin-like cytoplasmic protein (PARC, also known as CUL9) as an E3 ligase that targets Cyt c for degradation. The abundance of PARC positively correlated with differentiation in mouse neurons, and overexpression of PARC reduced the abundance of mitochondrially-released cytosolic Cyt c in various cancer cell lines and in mouse embryonic fibroblasts. Conversely, neurons from Parc-deficient mice had increased sensitivity to mitochondrial damage, and neuroblastoma or glioma cells in which PARC or ubiquitin was knocked down had increased abundance of mitochondrially-released cytosolic Cyt c and decreased viability in response to stress. These findings suggest that PARC-mediated ubiquitination and degradation of Cyt c is a strategy engaged by both neurons and cancer cells to prevent apoptosis during conditions of mitochondrial stress.
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http://dx.doi.org/10.1126/scisignal.2005309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182917PMC
July 2014

Activation of apoptosis by cytoplasmic microinjection of cytochrome c.

J Vis Exp 2011 Jun 29(52). Epub 2011 Jun 29.

Department of Cell and Developmental Biology, Neuroscience Center, University of North Carolina.

Apoptosis, or programmed cell death, is a conserved and highly regulated pathway by which cells die¹. Apoptosis can be triggered when cells encounter a wide range of cytotoxic stresses. These insults initiate signaling cascades that ultimately cause the release of cytochrome c from the mitochondrial intermembrane space to the cytoplasm². The release of cytochrome c from mitochondria is a key event that triggers the rapid activation of caspases, the key cellular proteases which ultimately execute cell death³⁻⁴. The pathway of apoptosis is regulated at points upstream and downstream of cytochrome c release from mitochondria⁵. In order to study the post-mitochondrial regulation of caspase activation, many investigators have turned to direct cytoplasmic microinjection of holocytochrome c (heme-attached) protein into cells⁶⁻⁹. Cytochrome c is normally localized to the mitochondria where attachment of a heme group is necessary to enable it to activate apoptosis¹⁰⁻¹¹. Therefore, to directly activate caspases, it is necessary to inject the holocytochrome c protein instead of its cDNA, because while the expression of cytochrome c from cDNA constructs will result in mitochondrial targeting and heme attachment, it will be sequestered from cytosolic caspases. Thus, the direct cytosolic microinjection of purified heme-attached cytochrome c protein is a useful tool to mimic mitochondrial cytochrome c release and apoptosis without the use of toxic insults which cause cellular and mitochondrial damage. In this article, we describe a method for the microinjection of cytochrome c protein into cells, using mouse embryonic fibroblasts (MEFs) and primary sympathetic neurons as examples. While this protocol focuses on the injection of cytochrome c for investigations of apoptosis, the techniques shown here can also be easily adapted for microinjection of other proteins of interest.
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http://dx.doi.org/10.3791/2773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197050PMC
June 2011

miR-29b is activated during neuronal maturation and targets BH3-only genes to restrict apoptosis.

Genes Dev 2011 Jan;25(2):125-30

Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

The execution of apoptosis is critical for proper development of the nervous system. However, it is equally important that neurons strictly inhibit apoptosis after development to ensure their survival throughout the lifetime of the organism. Here we show that a microRNA, miR-29b, is markedly induced with neuronal maturation and functions as a novel inhibitor of neuronal apoptosis. The prosurvival function of miR-29b is mediated by targeting genes in the proapoptotic BH3-only family. Our results identify a unique strategy evolved by maturing neurons that uses a single microRNA to inhibit the multiple, redundant BH3-only proteins that are key initiators of apoptosis.
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http://dx.doi.org/10.1101/gad.1975411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022258PMC
January 2011

Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance.

Mol Cell 2004 Nov;16(3):425-38

Laboratories for Reproductive Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

The androgen receptor (AR) is required for male sex development and contributes to prostate cancer cell survival. In contrast to other nuclear receptors that bind the LXXLL motifs of coactivators, the AR ligand binding domain is preferentially engaged in an interdomain interaction with the AR FXXLF motif. Reported here are crystal structures of the ligand-activated AR ligand binding domain with and without bound FXXLF and LXXLL peptides. Key residues that establish motif binding specificity are identified through comparative structure-function and mutagenesis studies. A mechanism in prostate cancer is suggested by a functional AR mutation at a specificity-determining residue that recovers coactivator LXXLL motif binding. An activation function transition hypothesis is proposed in which an evolutionary decline in LXXLL motif binding parallels expansion and functional dominance of the NH(2)-terminal transactivation domain in the steroid receptor subfamily.
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http://dx.doi.org/10.1016/j.molcel.2004.09.036DOI Listing
November 2004