Reliability and Variability of Ki-67 Digital Image Analysis Methods for Clinical Diagnostics in Breast Cancer.

Ki-67 is a nuclear protein associated with proliferation, and a strong potential biomarker in breast cancer, but is not routinely measured in current clinical management owing to a lack of standardization. Digital image analysis (DIA) is a promising technology that could allow high-throughput analysis and standardization. There is a dearth of data on the clinical reliability as well as intra- and interalgorithmic variability of different DIA methods. In this study, we scored and compared a set of breast cancer cases in which manually counted Ki-67 has already been demonstrated to have prognostic value (n = 278) to 5 DIA methods, namely Aperio ePathology (Lieca Biosystems), Definiens Tissue Studio (Definiens AG), Qupath, an unsupervised immunohistochemical color histogram algorithm, and a deep-learning pipeline piNET. The piNET system achieved high agreement (interclass correlation coefficient: 0.850) and correlation (R = 0.85) with the reference score. The Qupath algorithm exhibited a high degree of reproducibility among all rater instances (interclass correlation coefficient: 0.889). Although piNET performed well against absolute manual counts, none of the tested DIA methods classified common Ki-67 cutoffs with high agreement or reached the clinically relevant Cohen's κ of at least 0.8. The highest agreement achieved was a Cohen's κ statistic of 0.73 for cutoffs 20% and 25% by the piNET system. The main contributors to interalgorithmic variation and poor cutoff characterization included heterogeneous tumor biology, varying algorithm implementation, and setting assignments. It appears that image segmentation is the primary explanation for semiautomated intra-algorithmic variation, which involves significant manual intervention to correct. Automated pipelines, such as piNET, may be crucial in developing robust and reproducible unbiased DIA approaches to accurately quantify Ki-67 for clinical diagnosis in the future.

Epithelial Lacrimal Gland Tumours in Nigeria: Clinicopathological Features and Treatment.

Background: Epithelial lacrimal gland tumours are uncommon orbital tumours and are not widely reported among African populations. Objective: This study aimed to describe the clinicopathological features, treatment, and outcomes of epithelial lacrimal gland tumours in Nigeria. Design: Retrospective case series. Setting: Ocular Oncology Unit, Ophthalmology Department and Pathology Department of University College Hospital, Ibadan, Nigeria. Materials and Methods: A review of the medical records of all patients with histopathological diagnoses of epithelial lacrimal gland tumours managed at a tertiary health facility, southwestern Nigeria over 11.5 years was carried out. Results: Eighteen patients with equal numbers of men and women, and mean age at presentation of 42.2 ± 15.7 years (median 42 years, range 17-70 years) were managed. All patients presented with orbital swelling and had nonaxial proptosis with palpable firm to hard mass in the superotemporal quadrant of the orbit. The mean duration of symptoms was 42.2 ± 38.6 months (median 24 months, range 3-120 months). Visual acuity was <3/60 at presentation in eight (44.4%) of the affected eyes. Thirteen (72.2%) patients underwent orbitotomy and tumour excision, while five (27.8%) patients had orbital exenteration, and two of whom (11.1%) had combined orbital exenteration and craniotomy. Histopathological examination of the specimens revealed pleomorphic adenoma in nine (50.0%) patients, low-grade mucoepidermoid carcinoma in three (16.7%) patients, high-grade mucoepidermoid carcinoma in two (11.1%) patients, adenoid cystic carcinoma in three (16.7%) patients, and adenocarcinoma "not otherwise specified" in one (5.6%) patient. Mortality was reported in four (44.4%) of nine patients with malignant tumours, while no mortality was noted in the patients with benign pleomorphic adenoma. The mean follow-up period for the patients was 28.9 months (median, 4.5 months; range, 2-140 months). Conclusion: The main presenting symptom of epithelial lacrimal gland tumours in our patients was an orbital mass and the most common clinical finding, in addition to the orbital mass, was nonaxial proptosis. The tumours were equally divided into benign and malignant lesions in our studied population. Pleomorphic adenoma was the only benign tumour while mucoepidermoid carcinoma was the commonest malignant lesion. Orbital exenteration was performed in a high proportion of our patients and high mortality was noted among patients with malignant tumours.

Contexte: Les tumeurs épithéliales des glandes lacrymales sont des tumeurs orbitales rares et ne sont pas largement rapportées parmi les populations africaines. Objectif: Cette étude visait à décrire les caractéristiques clinico-pathologiques, le traitement et le résultat des tumeurs épithéliales des glandes lacrymales au Nigeria. Conception: Série de cas rétrospectifs. Cadre: Unité d'oncologie oculaire, département d'ophtalmologie et département de pathologie du Collège Hospitalier Universitaire, Ibadan, Nigéria. Méthode: Un examen des dossiers médicaux de tous les patients présentant des diagnostics histopathologiques de tumeurs épithéliales des glandes lacrymales gérées dans un établissement de santé tertiaire du sud-ouest du Nigéria pendant 11,5 ans a été effectué. Résultats: Dix - huit patients avec un nombre égal d'hommes et de femmes et un âge moyen à la présentation de 42,2 ± 15,7 ans (médian de 42 ans, intervalle de 17 à 70 ans) ont été pris en charge. Tous les patients présentaient un gonflement orbital et avait l'exophtalmie non-axiale avec ferme à dur masse palpable dans le quadrant temporel supérieur de l'orbite. La durée moyenne des symptômes était de 42,2 ± 38,6 mois (médiane de 24 mois, intervalle de 3 à 120 mois). L'acuité visuelle était <3/60 à la présentation dans huit (44,4%) des yeux atteints. Treize (72,2%) patients ont subi une orbitotomie et une excision de la tumeur, tandis que cinq (27,8%) patients avaient une exentération orbitaire, dont deux (11,1%) avaient l'exentération orbitale et la craniotomie combinées. L'examen histopathologique des échantillons a révélé un adénome pléomorphe chez neuf (50,0%) patients, un carcinome muco-épidermoïde de bas grade chez trois (16,7%) patients, un carcinome muco-épidermoïde de haut grade chez deux (11,1%) patients, un carcinome adénoïde kystique chez trois (16,7%) patients et adénocarcinome "non autrement spécifié" (NOS) chez un patient (5,6%). La mortalité a été rapportée chez quatre (44,4%) des neuf patients atteints de tumeurs malignes, alors qu'aucune mortalité n'a été notée chez les patients présentant un adénome pléomorphe bénin. La période moyenne de suivi des patients était de 28,9 mois (médiane de 4,5 mois; intervalle de 2 à 140 mois). Conclusion: Le principal symptôme de présentation des tumeurs épithéliales des glandes lacrymales chez nos patients était une masse orbitale et le résultat clinique le plus courant, en plus de la masse orbitale, était une exophtalmie non axiale. Les tumeurs étaient également divisées entre les lésions bénignes et malignes dans notre population étudiée. L'adénome pléomorphe était la seule tumeur bénigne tandis que le carcinome muco-épidermoïde était la lésion maligne la plus courante. Une exentération orbitale a été réalisée chez une forte proportion de nos patients et une mortalité élevée a été notée chez les patients atteints de tumeurs malignes.

Testicular ischemia secondary to epididymo-orchitis: A case report.

Testicular infarction is a common urological emergency in clinical practice, it is still underreported when it results from other than spermatic cord torsion. It rarely arises from other pathological processes like vasculitis and infectious disease. We report a case of 18-year-old with epididymo-orchitis complicated by testicular ischemia. This case accentuates the need for a high index of suspicion to rule out concomitant testicular ischemia secondary to epididymo-orchitis that might be salvaged in the future with immediate surgical intervention. Testicular infarction is a devastating complication from epididymo-orchitis that is difficult to predict and distinguish from more common presentations of acute scrotum.

Author Correction: Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

The original version of this Article contained an error in the author affiliations. The affiliation of Kevin P. White with Tempus Labs, Inc. Chicago, IL, USA was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.

Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

Racial/ethnic disparities in breast cancer mortality continue to widen but genomic studies rarely interrogate breast cancer in diverse populations. Through genome, exome, and RNA sequencing, we examined the molecular features of breast cancers using 194 patients from Nigeria and 1037 patients from The Cancer Genome Atlas (TCGA). Relative to Black and White cohorts in TCGA, Nigerian HR + /HER2 - tumors are characterized by increased homologous recombination deficiency signature, pervasive TP53 mutations, and greater structural variation-indicating aggressive biology. GATA3 mutations are also more frequent in Nigerians regardless of subtype. Higher proportions of APOBEC-mediated substitutions strongly associate with PIK3CA and CDH1 mutations, which are underrepresented in Nigerians and Blacks. PLK2, KDM6A, and B2M are also identified as previously unreported significantly mutated genes in breast cancer. This dataset provides novel insights into potential molecular mechanisms underlying outcome disparities and lay a foundation for deployment of precision therapeutics in underserved populations.

Development of a Breast Cancer Risk Prediction Model for Women in Nigeria.

Background: Risk prediction models have been widely used to identify women at higher risk of breast cancer. We aimed to develop a model for absolute breast cancer risk prediction for Nigerian women.Methods: A total of 1,811 breast cancer cases and 2,225 controls from the Nigerian Breast Cancer Study (NBCS, 1998-2015) were included. Subjects were randomly divided into the training and validation sets. Incorporating local incidence rates, multivariable logistic regressions were used to develop the model.Results: The NBCS model included age, age at menarche, parity, duration of breastfeeding, family history of breast cancer, height, body mass index, benign breast diseases, and alcohol consumption. The model developed in the training set performed well in the validation set. The discriminating accuracy of the NBCS model [area under ROC curve (AUC) = 0.703, 95% confidence interval (CI), 0.687-0.719] was better than the Black Women's Health Study (BWHS) model (AUC = 0.605; 95% CI, 0.586-0.624), Gail model for white population (AUC = 0.551; 95% CI, 0.531-0.571), and Gail model for black population (AUC = 0.545; 95% CI, 0.525-0.565). Compared with the BWHS and two Gail models, the net reclassification improvement of the NBCS model were 8.26%, 13.45%, and 14.19%, respectively.Conclusions: We have developed a breast cancer risk prediction model specific to women in Nigeria, which provides a promising and indispensable tool to identify women in need of breast cancer early detection in Sub-Saharan Africa populations.Impact: Our model is the first breast cancer risk prediction model in Africa. It can be used to identify women at high risk for breast cancer screening. Cancer Epidemiol Biomarkers Prev; 27(6); 636-43. ©2018 AACR.

Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression.

Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor's ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.

Bilateral breast cancer among three Yoruba women in a Nigerian teaching hospital.

Breast cancer is the most common cancer among females in Nigeria. Bilateral breast cancer can occur synchronously or metachronously. We report three different cases of bilateral breast cancer in three female patients managed by the Ibadan Multidisciplinary Breast Tumour Board, domiciled at the University College Hospital (UCH), over a 3-year period. Two of these patients had synchronous bilateral breast cancer and developed cancer in the second breast during the course of management. These case reports may therefore stimulate further research on the clinicopathological features and the progression of bilateral breast cancer among females, especially in our environment. Our patients were premenopausal and the immunochemistry of the tumours showed a triple-negative immunophenotype. The other features of presentation, investigation, diagnosis and follow-up care are the highlights of this presentation.

Orbital intravascular papillary endothelial hyperplasia in a Nigerian child: a case report and review of the literature.

INTRODUCTION: Intravascular papillary endothelial hyperplasia is a reactive proliferative lesion of endothelial cells in blood vessels. It typically presents as a painless, reddish purple lesion in the sites affected. The orbit remains an uncommon site of affectation of this relatively common disease. It is noteworthy that this is the first reported case, to the best of our knowledge, of orbital intravascular papillary endothelial hyperplasia in a Nigerian child. CASE PRESENTATION: The case reported here is an orbital intravascular papillary endothelial hyperplasia causing non-axial proptosis and loss of vision in a 14-year-old Nigerian boy. We describe the clinical and histological findings of intravascular papillary endothelial hyperplasia in the orbit of this 14-year-old boy. The key distinguishing features are discussed and relevant literature is reviewed. CONCLUSION: Although unusual in presentation, intravascular papillary endothelial proliferation should be considered in the list of differentials of proptosis due to mass lesion in young Nigerians and, possibly, Africans.

Sinonasal paraganglioma: a case report.

OBJECTIVE: To highlight the importance of a high index of suspicion and meticulous evaluation of a patient with bleeding sinonasal mass in the diagnosis of sinonasal paraganglioma. METHOD: Case report of a 39-year-old female who presented with a bleeding lobulated left nasal mass necessitating multiple blood transfusions is presented. RESULT: Diagnostic investigations revealed that the patient was HIV-positive (ELISA and Western blot) and a tumour histology of paraganglioma. She had a CD4+ count of 487 cells/mm3. The urinary vanillylmandelic acid assay and echocardiography were normal. Subsequently, she had complete tumour excision through a medial maxillectomy and has remained without a recurrence 12 months after. CONCLUSION: To our knowledge, this is the first report in the world literature of sinonasal paraganglioma in a HIV-positive patient and the first reported case of sinonasal paraganglioma in Africa. It is, however, not clear from this report if the patient's HIV status preceded her development of the paraganglioma or not.

Dermoid cyst of the urinary bladder as a differential diagnosis of bladder calculus: a case report.

Dermoid cysts are extremely rare in the urinary bladder and can pose a diagnostic dilemma to both the Urologist and the Histopathologist. Only a few cases were found documented and cited in PubMed. We present a case of dermoid cyst in the urinary bladder presenting as a bladder stone with a brief review of the literature.