Adedayo Onitilo
, Marshfield



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    ABSTRACT: Rationale and objectives: The discovery of germline genetic variants associated with breast cancer has engendered interest in risk stratification for improved, targeted detection and diagnosis. However, there has yet to be a comparison of the predictive ability of these genetic variants with mammography abnormality descriptors. Materials and methods: Our institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study utilized a personalized medicine registry in which participants consented to provide a DNA sample and to participate in longitudinal follow-up. In our retrospective, age-matched, case-controlled study of 373 cases and 395 controls who underwent breast biopsy, we collected risk factors selected a priori based on the literature, including demographic variables based on the Gail model, common germline genetic variants, and diagnostic mammography findings according to Breast Imaging Reporting and Data System (BI-RADS). We developed predictive models using logistic regression to determine the predictive ability of (1) demographic variables, (2) 10 selected genetic variants, or (3) mammography BI-RADS features. We evaluated each model in turn by calculating a risk score for each patient using 10-fold cross-validation, used this risk estimate to construct Receiver Operator Characteristic Curve (ROC) curves, and compared the area under the ROC curve (AUC) of each using the DeLong method. Results: The performance of the regression model using demographic risk factors was not statistically different from the model using genetic variants (P = 0.9). The model using mammography features (AUC = 0.689) was superior to both the demographic model (AUC = .598; P < 0.001) and the genetic model (AUC = .601; P < 0.001). Conclusions: BI-RADS features exceeded the ability of demographic and 10 selected germline genetic variants to predict breast cancer in women recommended for biopsy.
    Academic radiology 10/2015; DOI:10.1016/j.acra.2015.09.007 · 1.75 Impact Factor
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    ABSTRACT: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype for which there is a need to identify new therapeutic targets. Full-length estrogen receptor beta (ERβ1) may be a possible target given its antiproliferative effects on breast cancer cells. The prognostic significance of ERβ in breast cancer subtypes has remained elusive, and disparate results observed across previously published reports might be due to the detection of multiple ERβ isoforms, the lack of specific antibodies and the use of different cutoffs to define ERβpositivity. The objective of this retrospective study was to determine the association between ERβ1 expression and disease-free and overall survival, as well as Ki67 expression, in non-metastatic TNBC. Immunohistochemical protocols were optimized using xenograft tissues obtained from a breast cancer cell line with inducible ERβ1 expression. ERβ1 localization and expression were assessed in two cohorts of TNBC using the VECTRA(TM) platform. There was a close relationship between nuclear and cytoplasmic ERβ1 expression. ERβ1 was expressed in a subset of TNBCs, but its expression was significantly associated with Ki67 in only one of the cohorts. There was no significant association between ERβ1 expression and disease-free and overall survival in either cohort. Although these results suggest that ERβ1 expression alone may not be informative in TNBCs, this study provides a new strategy for optimizing and objectively measuring ERβ1 expression in tissues, which may provide a standard for ERβ1 immunohistochemistry in future large-scale clinical studies aimed at better understanding the role of ERβ1 in breast cancer.
    American Journal of Translational Research 09/2015; 7(7):1246-59. · 3.40 Impact Factor

  • 08/2015; DOI:10.2217/bmt.15.10
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    ABSTRACT: Recent large-scale genome-wide association studies (GWAS) have identified a number of genetic variants associated with breast cancer which showed great potential for clinical translation, especially in breast cancer diagnosis via mammograms. However, the amount of interaction between these genetic variants and mammographic features that can be leveraged for personalized diagnosis remains unknown. Our study utilizes germline genetic variants and mammographic features that we collected in a breast cancer case-control study. By computing the conditional mutual information between the genetic variants and mammographic features given the breast cancer status, we identified six interaction pairs which elevate breast cancer risk and five interaction pairs which reduce breast cancer risk.
    08/2015; 2015:107-11.

  • 08/2015; 2(4):041005. DOI:10.1117/1.JMI.2.4.041005
  • Suhail A R Doi · Sherry A Salzman-Scott · Adedayo A Onitilo ·
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    ABSTRACT: If a peer review instrument asks concrete questions (defined as items that can only generate disagreement if reviewers have different degrees of expertise), then questionnaires could become more meaningful in terms of resolving subjectivity thus leading to more reviewer agreement. A concrete item questionnaire with well chosen questions can also help resolve disagreement when reviewers have the same level of expertise. We have recently created the core-item reviewer evaluation (CoRE) questionnaire for which decision-threshold score levels have been created, but which have not been validated. This prospective validation of these thresholds for the CoRE questionnaire demonstrated strong agreement between reviewer recommendations and their reported score levels when tested prospectively at Clinical Medicine and Research. We conclude that using the CoRE questionnaire will help reduce peer reviewer disagreement. More importantly, when reviewer expertise varies, editors can more easily detect this and decide which opinion reflects the greater expertise.
    Accountability in Research Policies and Quality Assurance 07/2015; 23(1). DOI:10.1080/08989621.2014.1002835 · 0.83 Impact Factor
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    ABSTRACT: Proteasome inhibitors and mammalian target of rapamycin inhibitors each have activity in various B-cell malignancies and affect distinct cellular pathways. Their combination has demonstrated synergy in vitro and in mouse models. The authors conducted a single-arm, phase 2 trial of combined temsirolimus and bortezomib in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (NHL) using a dosing scheme that was previously tested in multiple myeloma. The patients received bortezomib and temsirolimus weekly on days 1, 8, 15, and 22 of a 35-day cycle. Of 39 patients who received treatment, 3 achieved a complete response (7.7%; 95% confidence interval [CI], 1.6%-21%), and 9 had a partial response (PR) (23%; 95% CI, 11%-39%). Thus, the overall response rate (12 of 39 patients) was 31% (95% CI, 17%-48%), and the median progression-free survival was 4.7 months (95% CI, 2.1-7.8 months; 2 months for patients with diffuse large B-cell lymphoma [n = 18], 7.5 months for those with mantle cell lymphoma [n = 7], and 16.5 months for those with follicular lymphoma [n = 9]). Two extensively treated patients with diffuse large B-cell lymphoma achieved a complete response. There were no unexpected toxicities from the combination. The current results demonstrate that the combination of a mammalian target of rapamycin inhibitor and a proteasome inhibitor is safe and has activity in patients with heavily pretreated B-cell NHL. Further studies with this combination are warranted in specific subtypes of NHL. Cancer 2015. © 2015 American Cancer Society. © 2015 American Cancer Society.
    Cancer 06/2015; 121(19). DOI:10.1002/cncr.29502 · 4.89 Impact Factor
  • Jill L Depke · Amanda Boreen · Adedayo A Onitilo ·
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    ABSTRACT: We describe the development and establishment of a breast care program (BCP) with service for rural breast cancer patients. Our program is a comprehensive program serving rural communities in Wisconsin. Our BCP is committed to breast health throughout the continuum from breast cancer risk assessment and prevention, advanced diagnostics, and screening tools to genetic testing and state-of-the-art surgical techniques. To provide the highest level of care, we coordinate a breast care team involving collaboration of multidisciplinary healthcare professionals. Experts from various departments, including radiologists, pathologists, breast surgeons, medical and radiation oncologists, genetic counselors, clinical trial specialists, and our breast care navigator, all work together to provide cutting edge cancer treatment and management. Our distinctive BCP allows patients to see multiple providers without having to make multiple appointments and promotes discussion of treatment recommendations and creation of a personalized treatment plan for each patient by a team of specialists. © 2015 Marshfield Clinic.
    Clinical Medicine &amp Research 06/2015; DOI:10.3121/cmr.2015.1260
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    ABSTRACT: Women who live in rural and urban settings have different outcomes for breast cancer. A 21-gene assay predicts 10- year distant recurrence risk and potential benefit of chemotherapy for women with hormone receptor-positive (HR+) breast cancer. To assess differences in scores and cancer therapies received by rural versus urban residence. We conducted a multi-institutional retrospective chart review of breast cancer patients diagnosed 2005-2010 with score results. Comparisons by rural versus urban residence (determined by rural-urban commuting area (RUCA) codes derived from zip codes) were made using the Fisher exact test for discrete data such as recurrence score results (<18 vs >18; score range, 0-100, with lower results correlated with less risk of distant recurrence), stage, and receptor status. The Wilcoxon rank sum test was used for continuous data (score results 0-100 and age.) All tests were at a 2-sided significance level of .05. 504 patients had RUCA codes (92% white, 62% postmenopausal). For rural (n = 135) compared with urban (n = 369) patients, the median scores were 16 and 18, respectively, 𝑃 = .18. Most of the patients received endocrine therapy, 123 of 135 (91%) rural, compared with 339 of 369 (92%) urban (𝑃 = .19). For scores 18-30, 20 of 56 (36%) rural patients, compared with 82 of 159 (52%) urban patients received chemotherapy (𝑃 = .03). Limitations include lack of randomization to receipt of the assay. Recurrence score results did not significantly differ between women based on residence, although women living in a rural area received significantly less chemotherapy for scores >18. This suggests that for HR-positive breast cancer, discrepancies between rural and urban residence are driven by treatment factors rather than differences in biology. ©2015 Frontline Medical Communications.
    05/2015; 13(5):195-201. DOI:10.12788/jcso.0135
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    ABSTRACT: The value of annual mammography remains an area of debate because of concerns regarding risk versus benefit. The potential for harm due to overdiagnosis and treatment of clinically insignificant cancers may not be captured by breast cancer-specific mortality. Instead, we examined all-cause mortality as a function of missed annual mammography examinations before breast cancer diagnosis. Primary breast cancer cases diagnosed in the Marsh-field Clinic Health System from 2002 through 2008 were identified for retrospective review, and whether annual mammography examinations had been performed in the 5 years before diagnosis was assessed. Analyses were performed on 1421 women with breast cancer. After adjustment of data for age, comorbidity status, a family history of breast cancer, insurance status, medical encounter frequency, and the calendar year, women who had missed any of the previous five annual mammography examinations had a 2.3-fold increased risk of all-cause mortality compared with subjects with no missed mammography examinations (hazard ratio = 2.28; 95% CI, 1.58-3.30; p < 0.0001). Additionally, an analysis by the number of missed annual mammography examinations showed a progressive increase in hazard as the number of missed mammography studies increased. These results suggest that annual mammography before breast cancer diagnosis is predictive of increased overall survival. A stepwise decline in overall survival was noted for each additional missed mammography examination. These results are similar to findings in the literature for breast cancer-specific mortality and illustrate the importance of recommending annual mammography to all eligible women.
    American Journal of Roentgenology 04/2015; 204(4):898-902. DOI:10.2214/AJR.14.12666 · 2.73 Impact Factor
  • Adedayo A Onitilo · Jessica M Engel · Rachel V Stankowski · Suhail A R Doi ·
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    ABSTRACT: Evidence suggests superiority of breast conserving surgery (BCS) plus radiation over mastectomy alone for treatment of early stage breast cancer. Whether the superiority of BCS plus radiation is related to the surgical approach itself or to the addition of adjuvant radiation therapy following BCS remains unclear. We conducted a retrospective cohort study of women with breast cancer diagnosed from 1994-2012. Data regarding patient and tumor characteristics and treatment specifics were captured electronically. Kaplan-Meier survival analyses were performed with inverse probability of treatment weighting to reduce selection bias effects in surgical assignment. Data from 5335 women were included, of which two-thirds had BCS and one-third had mastectomy. Surgical decision trends changed over time with more women undergoing mastectomy in recent years. Women who underwent BCS versus mastectomy differed significantly regarding age, cancer stage/grade, adjuvant radiation, chemotherapy, and endocrine treatment. Overall survival was similar for BCS and mastectomy. When BCS plus radiation was compared to mastectomy alone, 3-, 5-, and 10-year overall survival was 96.5 vs 93.4%, 92.9 vs 88.3% and 80.9 vs 67.2%, respectively. These analyses suggest that survival benefit is not related only to the surgery itself, but that the prognostic advantage of BCS plus radiation over mastectomy may also be related to the addition of adjuvant radiation therapy. This conclusion requires prospective confirmation in randomized trials. © 2014 Marshfield Clinic.
    Clinical Medicine &amp Research 12/2014; 13(2). DOI:10.3121/cmr.2014.1245
  • Mahender R. Yellu · Jessica M. Engel · Abhimanyu Ghose · Adedayo A. Onitilo ·
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    ABSTRACT: Neurological complications related to multiple myeloma (MM) are not uncommon; however, direct involvement of the central nervous system (CNS) is extremely rare and represents a diagnostic and therapeutic challenge. Significant survival difference has been noted with the introduction of novel therapy in patients with MM, but their effect on the incidence and their use for management of leptomeningeal myeloma (LMM) is uncertain. Analysis of published data demonstrates its recent increased incidence, median time to CNS presentation, and slight improvement in median survival after diagnosis of LMM. Less common MM isotypes have been overrepresented in LMM. CNS relapse occurred mostly in patients with Durie–Salmon stage III MM. Despite treatments, standard or experimental, the survival rates of LMM remain dismal. Monitoring high risk patients closely, even after achieving complete remission, may be useful in early detection of LMM. As we gain better understanding of LMM, we recommend that future research and clinical care focus on earlier diagnosis and development of more efficient CNS-directed therapy to improve survival in this patient population. Copyright © 2014 John Wiley & Sons, Ltd.
    Hematological Oncology 12/2014; DOI:10.1002/hon.2185 · 3.08 Impact Factor
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    ABSTRACT: Aim: To evaluate the ability of the McGill Brisbane Symptom Score (MBSS) to predict survival in resectable pancreatic head adenocarcinoma (PHA) patients. Methods: All PHA patients (n = 83) undergoing pancreaticoduodenectomy at the McGill University Health Center, Quebec between 1/2001-1/2010 were evaluated. Data related to patient and cancer characteristics, MBSS variables, and treatment were collected; univariable and multivariable survival analyses were performed. We obtained complete follow-up until February 2011 in all patients through the database of the provincial health insurance plan of Quebec. The unique health insurance numbers of these patients were used to retrieve information from this database which captures all billable clinical encounters, and ensures 100% actual survival data. Results: Median survival was 23 mo overall: 45 mo for patients with low MBSS, 17 mo for high MBSS (P = 0.005). At twelve months survival was 83.3% (95%CI: 66.6-92.1) vs 58.1% (95%CI: 42.1-71.2) in those with low vs high MBSS, and 24 mo survival was 63.8% (95%CI: 45.9-77.1) and 34.0% (95%CI: 20.2-48.2) respectively. In the multivariate Cox model (stratified by chemotherapy), after addition of clinically meaningful covariates, MBSS was the variable with the strongest association with survival (HR = 2.63; P = 0.001). Adjuvant chemotherapy interacted with MBSS category such that only high MBSS patients accrued a benefit. In univariate analysis we found a lower mortality in high MBSS but not low MBSS patients receiving adjuvant chemotherapy. This interaction variable, on Cox model, resulted in an adjusted mortality HR for the high MBSS (compared to low MBSS) of 4.14 (95%CI: 1.48-11.64) without chemotherapy and 2.11 (95%CI: 1.06-4.17) with chemotherapy. Conclusion: The MBSS is a simple prognostic tool for resectable PHA. Preoperative categorization of patients according to the MBSS allows effective stratification of patients to guide therapy.
    World Journal of Gastroenterology 09/2014; 20(34):12226-32. DOI:10.3748/wjg.v20.i34.12226 · 2.37 Impact Factor

  • Adedayo A Onitilo · Jessica M Engel · Rachel V Stankowski ·
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    ABSTRACT: Before the advent of the human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody trastuzumab, HER2-positive breast cancers were difficult to treat and had a poor prognosis. Adjuvant trastuzumab is now an important part of the treatment regimen for many women with HER2-positive breast cancer and has undoubtedly resulted in a significant improvement in prognosis, but it is associated with a risk for cardiotoxicity. In this review, we describe the prevalence, patient characteristics, and risk factors for cardiotoxicity associated with use of adjuvant trastuzumab. Understanding risk factors for trastuzumab-induced cardiotoxicity and appropriate patient monitoring during trastuzumab treatment allows for safe and effective use of this important adjuvant therapy.
    Therapeutic Advances in Drug Safety 08/2014; 5(4):154-66. DOI:10.1177/2042098614529603
  • Rafiullah · Sabo Tanimu · Adedayo A Onitilo ·
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    ABSTRACT: Gangliocytic paragangliomas are rare neuroendocrine tumours residing in the gastrointestinal tract, most commonly the periampullary region. Most are benign tumours with a low malignancy rate. We report a 50-year-old man who presented with acute onset of left-upper quadrant abdominal pain with radiation to the back. An intraluminal mass at the junction of the duodenum with normal pancreatic/hepatic parenchyma was discovered on abdominal CT. Following upper endoscopy and MRI revealing a periampullary lesion, fine-needle aspiration and biopsies were. Immunohistochemistry was positive for synaptophysin and S100HU, consistent with gangliocytic paraganglioma. The benign nature of this tumour and unique anatomy of a separate opening of the pancreatic and common bile ducts led to transduodenal excision with sphincteroplasty, thereby avoiding extensive surgery. Surveillance CT every 6 months and upper endoscopy initially every 6 months (now yearly) revealed no evidence of endoscopic or histological recurrence at 3 years follow-up.
    Case Reports 07/2014; 2014(jul02 1). DOI:10.1136/bcr-2013-202941
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    ABSTRACT: Introduction: Routine mammography screening and early detection are important prognostic indicators for breast cancer. Geographical and seasonal barriers to mammography services and relationship to breast cancer stage at diagnosis were examined. Methods: Travel time to mammography center, seasonal distribution of mammogram use, mammography frequency, and stage of cancer were retrospectively examined in 1428 female patients diagnosed with primary breast cancer at a tertiary care clinic system in Wisconsin, USA, from 2002 to 2008. Results: Women with no missed mammograms before diagnosis lived a median of 15 minutes from the nearest facility, while those who missed five of their past five annual mammograms lived nearly twice as far, with a median travel time of 27 minutes (p<0.0001). There was a direct relationship between travel time to nearest mammogram facility and stage of breast cancer at diagnosis, with travel time increasing from 17 to 24 minutes for stage 0 and stage 4 breast cancers, respectively (p=0.0586). Women were less likely to undergo mammography screening during the winter months (p<0.0001), especially women with greater than 30 mi (48.3 km) to travel to the nearest mammogram facility (p=0.0448). Conclusions: In the studied service area, travel time to nearest mammogram center appears inversely related to regular mammography screening and breast cancer stage at diagnosis. Mammograms are less common in the winter, especially in women with further to travel. This is the first study to demonstrate that inclement winter weather may impact on screening behaviors in rural areas and demonstrates the importance of considering climate as part of geographical access to preventative care.
    Rural and remote health 07/2014; 14(3):2738. · 0.88 Impact Factor
  • Michael J Sanfelippo · Jessica M Engel · Adedayo A Onitilo ·
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    ABSTRACT: Context.-The results of studies among patients with antithrombin deficiency have suggested that the use of warfarin will increase the level of antithrombin. Objective.-To reevaluate the effect of warfarin on antithrombin levels using an automated amidolytic method in current use. Design.-Antithrombin levels were measured in patients who were receiving warfarin for atrial fibrillation and were compared with antithrombin levels in preoperative patients who had not received warfarin. Results.-Patients receiving warfarin had a mean antithrombin level of 100.40% (range, 81%-153%). Patients not receiving warfarin had a mean antithrombin level of 99.97% (range, 79%-120%). The Student t test was not significant for a difference between the mean antithrombin levels of the 2 populations. Conclusions.-The use of warfarin does not increase the level of antithrombin in patients receiving the drug.
    Archives of pathology & laboratory medicine 07/2014; 138(7):967-968. DOI:10.5858/arpa.2013-0065-OA · 2.84 Impact Factor
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    ABSTRACT: Background We developed an algorithm for the identification of patients with type 2 diabetes and ascertainment of the date of diabetes onset for examination of the temporal relationship between diabetes and cancer using data in the electronic medical record (EMR). Methods The Marshfield Clinic EMR was searched for patients who developed type 2 diabetes between January 1, 1995 and December 31, 2009 using a combination of diagnostic codes and laboratory data. Subjects without diabetes were also identified and matched to subjects with diabetes by age, gender, smoking history, residence, and date of diabetes onset/reference date. Results The final cohort consisted of 11,236 subjects with and 54,365 subjects without diabetes. Stringent requirements for laboratory values resulted in a decrease in the number of potential subjects by nearly 70%. Mean observation time in the EMR was similar for both groups with 13—14 years before and 5–7 years after the reference date. The two cohorts were largely similar except that BMI and frequency of healthcare encounters were greater in subjects with diabetes. Conclusion The cohort described here will be useful for the examination of the temporal relationship between diabetes and cancer and is unique in that it allows for determination of the date of diabetes onset with reasonable accuracy.
    BMC Medical Informatics and Decision Making 05/2014; 14(1):38. DOI:10.1186/1472-6947-14-38 · 1.83 Impact Factor
  • Sabo Tanimu · Rafiullah · Jeffrey Resnick · Adedayo A Onitilo ·
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    ABSTRACT: Oesophageal papillomatosis is a very rare entity, with only 10 cases (including ours) reported in the literature. We report a 51-year-old man with a 25-year history of dysphagia with solids and liquids who failed a trial of proton pump inhibitors and fluticasone. His initial endoscopy revealed a viliform mass with dense eosinophilic infiltrate without neoplasia. Endoscopic ultrasound examination revealed a 4×1.6×0.7 cm mucosal hemicircumferential lesion without regional adenopathy. Pathological findings from the oesophagectomy specimen confirmed oesophageal papillomatosis with no malignancy. Surveillance endoscopy 4 months later revealed the lesion had increased in size. Additional ablative therapies failed, and the patient underwent oesophagectomy. Surveillance CT of the chest and abdomen at 3 months and oesophagogastroduodenoscopy at 6 months were negative. This case illustrates that oesophageal squamous papillomatosis not amenable to medical therapy requires surgical treatment.
    Case Reports 05/2014; 2014(apr30_2). DOI:10.1136/bcr-2013-200195

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