Preliminary Study on Open Labelled Randomized Controlled Trial of the Safety and Efficacy of Hydroxychloroquine and Chloroquine Phosphate for the Treatment of Persons Infected with 2019 Coronavirus Disease in Nigeria.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of COVID-19 is a leading cause of ill-health and deaths worldwide. Currently, COVID-19 has no known widely approved therapeutics. Thus, the need for effective treatment. OBJECTIVES: We investigated the safety and efficacy of two (2) therapeutic agents; chloroquine phosphate (CQ), 2- hydroxychloroquine (HCQ) and a control (standard supportive therapy) among hospitalized adults with COVID-19. METHODS: The clinical trial was done in accordance to the World Health Organization master protocol for investigational therapeutics for COVID-19. Atotal of 40 participants with laboratory-confirmed positive COVID-19 were enrolled. Blood samples and oropharyngeal (OP) swabs were obtained on days 1,3,15 and 29 for safety and efficacy assessments. RESULTS: The baseline demographics showed that the median ages in years (range) were 45 (31-57) in CQ, 45 (36.5-60.5) in HCQ, 43 (39.5-67.0) and 44.5 (25.3-51.3) in the control (P<0.042).At randomization, seven (7) participants were asymptomatic, thirty-three (33) had mild symptoms, eight (8) had moderate symptoms while three (3) had severe symptoms. The average day of conversion to negative COVID-19 was 15.5 days for CQ, 16 days for HCQ and 18 days for the control(P=0.036). CONCLUSION: The safety assessment revealed no adverse effect of the drugs in COVID-19 patients after treatment. These findings proved that chloroquine and hydroxychloroquine are effective for the treatment of COVID-19 among hospitalized adults. It also confirmed that they are safe.

CONTEXTE: Le coronavirus du syndrome respiratoire aigu sévère 2 (SARS-CoV-2),agentcausaldelaCOVID-19, est l'unedes principales causes demaladie et de décès dans le monde. À l'heure actuelle, il n'existe aucun traitement largement approuvé pour la COVID-19. Ainsi, ilya un besoin de traitement efficace. OBJECTIFS: Nous avons étudié l'innocuité et l'efficacité de deux (2) agents thérapeutiques, le phosphate de chloroquine (CQ) et l'hydroxychloroquine (HCQ), ainsi qu'un groupe témoin (traitement de soutien standard) chez des adultes hospitalisés atteints de la COVID-19.MÉTHODES: L'essai clinique a été mené conformément au protocole maître de l'Organisation mondiale de la santé pour les thérapeutiques à l'étude de la COVID-19. Au total, 40 participants atteints de la COVID-19, confirmée en laboratoire, ont été in scrits. Des échantillons de sang et des prélèvements oropharyngés (PO) ont été effectuésauxjours1,3,15et29pourévaluerl'innocuitéetl'efficacité. RÉSULTATS: Les données démographiques initiales ont révélé que l'âge médian en années (plage) était de 45 (31-57) pour le groupe CQ, de 45 (36,5-60,5) pour le groupe HCQ, de 43 (39,5-67,0) et de 44,5 (25,3-51,3) pour le groupe témoin (P<0,042). À la randomisation, sept (7) participants étaient asymptomatiques, trente-trois (33) présentaient des symptômes bénins, huit(8) avaient des symptômes modérés, tandis que trois(3) avaient des symptômes graves. Le jour moyende conversionentest COVID-19 négatif était de 15,5 jours pour le groupe CQ, de 16 jours pour le groupe HCQ et de 18 jours pourle groupe témoin (P=0,036). CONCLUSION: L'évaluation de la sécurité n'a révélé aucun effet indésirable des médicaments chez les patients atteints de la COVID-19 après le traitement. Ces conclusions ont prouvé que la chloroquine et l'hydroxychloroquine sont efficaces pour le traitement de la COVID-19 chez les adultes hospitalisés. Cela a également confirmé qu' ilssont sûrs. Mots-clés: COVID-19, SARS-CoV-2, essai clinique, innocuité, efficacité, thérapeutiques.

Clinical predictors of Covid-19 mortality in a tertiary hospital in Lagos, Nigeria: A retrospective cohort study.

Background: The predictors of mortality among patients presenting with severe to critical disease in Nigeria are presently unknown. Aim: The aim of this study was to identify the predictors of mortality among patients with COVID-19 presenting for admission in a tertiary referral hospital in Lagos, Nigeria. Patients and Methods: The study was a retrospective study. Patients' sociodemographics, clinical characteristics, comorbidities, complications, treatment outcomes, and hospital duration were documented. Pearson's Chi-square, Fischer's Exact test, or Student's t-test were used to assess the relationship between the variables and mortality. To compare the survival experience across medical comorbidities, Kaplan Meir plots and life tables were used. Univariable and multivariable Cox-proportional hazard analyses were conducted. Results: A total of 734 patients were recruited. Participants' age ranged from five months to 92 years, with a mean ± SD of 47.4 ± 17.2 years, and a male preponderance (58.5% vs. 41.5%). The mortality rate was 9.07 per thousand person-days. About 73.9% (n = 51/69) of the deceased had one or more co-morbidities, compared to 41.6% (252/606) of those discharged. Patients who were older than 50 years, with diabetes mellitus, hypertension, chronic renal illness, and cancer had a statistically significant relationship with mortality. Conclusion: These findings call for a more comprehensive approach to the control of non-communicable diseases, the allocation of sufficient resources for ICU care during outbreaks, an improvement in the quality of health care available to Nigerians, and further research into the relationship between obesity and COVID-19 in Nigerians.

Outcome of Patients with Common Endocrine Diseases Who Had COVID-19 in two Centers in Lagos, Nigeria: A Cross-Sectional Study.

BACKGROUND: Endocrine diseases are ubiquitous. In our environment, diabetes mellitus (DM), obesity and thyroid disorders represent the most common examples. Diabetes mellitus is a global health problem with a myriad of complications. We sought to evaluate outcome in terms of fatality in those with common endocrine diseases who were infected with COVID-19. AIMS AND OBJECTIVES: To determine outcome in terms of mortality in patients with common endocrine diseases who contracted COVID-19. MATERIALS AND METHODS: We conducted an observational, descriptive, cross-sectional study with 120 participants drawn from the endocrinology/DM clinic at the Lagos University Teaching Hospital and Serenity Hospital, Surulere (a private medical clinic). Data collected included age, gender, type of endocrine disease, comorbid diseases, and COVID-19 status. Through charts from the medical records department, outcome of participants in terms of mortality was determined. RESULTS: Data of 120 subjects were analyzed. There were 61males and 59 females, yielding a male:female ratio of 1:1. Mean age was 58 years and the mode was 46 years. Over half (88) of the patients had diabetes mellitus, 22 had obesity, and 17 had thyroid disorders. The case fatality rate of patients with endocrine diseases who had COVID-19 was 11%, with about 85% of these deaths occurring in the elderly (those aged above 60 years). Ninety-two percent of the patients who died had type 2 DM. Approximately 80% of patients who were infected with COVID-19 had at least one co-morbid disease. CONCLUSION: Older age, type 2 diabetes mellitus, and the presence of at least one comorbidity were associated with increased mortality in patients with endocrine diseases who were infected with COVID-19 in our study.

CONTEXTE: Les maladies endocriniennes sont omniprésentes. Dans notre environnement, le diabète sucré, l'obésité et les troubles thyroïdiens en sont les exemples les plus courants. Le diabète est un problème de santé mondial qui s'accompagne d'une myriade de complications. Nous avons cherché à évaluer l'issue en termes de mortalité chez les personnes atteintes de maladies endocriniennes courantes qui ont été infectées par COVID-19. BUTS ET OBJECTIFS: Déterminer l'issue en termes de mortalité chez les patients atteints de maladies endocriniennes courantes qui ont contracté COVID 19. MATÉRIEL ET MÉTHODOLOGIES: Nous avons mené une étude observationnelle, descriptive et transversale auprès de 120 participants provenant de la clinique d'endocrinologie/DM de l'hôpital universitaire de Lagos et de l'hôpital Serenity, Surulere (clinique médicale privée). Les données recueillies comprenaient l'âge, le sexe, le type de maladie endocrinienne, les maladies concomitantes et le statut COVID-19. Les résultats des participants en termes de mortalité ont été déterminés à partir des dossiers médicaux. RÉSULTATS: Les données de 120 sujets ont été analysées. Il y avait 61 hommes et 59 femmes, avec un ratio homme/femme de 1:1. L'âge moyen était de 58 ans, le mode de 46 ans. Plus de la moitié [88] des patients souffraient de diabète sucré. 22 patients souffraient d'obésité et 17 de troubles thyroïdiens. Le taux de létalité des patients souffrant de maladiesendocriniennes et atteints de COVID-19 était de 11 %, 85 % de ces décès survenant chez des personnes âgées, c'est-à-dire de plus de 60 ans. 92 % des patients décédés souffraient de diabète de type 2. Environ 80 % des patients infectés par COVID-19 présentaient au moins une maladie concomitante. CONCLUSION: L'âge avancé, le diabète de type 2, la présence d'au moins une comorbidité sont associés à une mortalité accrue chez les patients atteints de maladies endocriniennes et infectés par COVID-19 dans notre étude. Mots-clés: Maladies endocriniennes, COVID-19, comorbidités, syndrome métabolique.

Immunohistochemical Study and Clinicopathologic Correlation of Cox-2 and Her-2 Expression in Colorectal Carcinoma: A 5-Year Retrospective Study.

BACKGROUND: Colorectal cancer (CRC) is the fourth most common cancer in Nigeria, and it affects mostly persons in their middle age. In a bid to gain some insight into the molecular characteristics of CRC in our environment, we set out to investigate the expression of COX-2 and HER-2 among Nigerian subjects. OBJECTIVES: To evaluate the expression of COX-2 and HER-2 and determine their correlation with clinicopathologic parameters in surgically resected histologically diagnosed cases of colorectal cancer. METHODS: Fifty-three paraffin-embedded tissue blocks of colorectal resections and corresponding patient information were retrieved from the archives of the Anatomic and Molecular Pathology Department of Lagos University Teaching Hospital. A 4-micron slide section was obtained from each specimen and immunohistochemistry for COX-2 and HER-2 expression was performed. RESULTS: Mean age of cases was 53.9years with an almost equal M:F ratio of 1.12:1. Half of the cases were moderately differentiated adenocarcinoma and 17% were high grade tumors. Eighty three percent of the tumours showed positive cytoplasmic COX-2 expression and extremely low membranous HER-2 positivity was observed in 2%. There was no significant correlation between COX-2 expression and age, gender, tumour location, tumour size, depth of invasion or lymph node status. However, COX-2 expression revealed a significant correlation with tumour grade (p= 0.013). CONCLUSION: This study detects a high COX-2 and low HER- 2 expression in colorectal cancer using immunohistochemistry, suggesting a possible role for COX-2 in CRC pathogenesis. This report should trigger further investigations of both markers vis-à-vis the management of CRC in our environment.

CONTEXTE: Le cancer colorectal (CCR) est le quatrième cancer le plus fréquent au Nigeria et il touche surtout les personnes d'âge moyen. Dans le but de mieux comprendre les caractéristiques moléculaires du CCR dans notre environnement, nous avons entrepris d'étudier l'expression de COX-2 et de HER-2 chez les sujets nigérians. OBJECTIFS: Évaluer l'expression de COX-2 et HER-2 et déterminer leur corrélation avec les paramètres clinicopathologiques dans les cas de cancer colorectal diagnostiqués histologiquement et réséqués chirurgicalement. MÉTHODES: Cinquante-trois blocs de tissus inclus en paraffine provenant de résections colorectales et les informations correspondantes sur les patients ont été récupérés dans les archives du département de pathologie anatomique et moléculaire du Lagos University Teaching Hospital. Une section de lame de 4 microns a été obtenue de chaque spécimen et une immunohistochimie pour l'expression de COX-2 et HER-2 a été réalisée. RÉSULTATS: L'âge moyen des cas était de 53,9 ans avec un rapport M:F presque égal de 1,12:1. La moitié des cas étaient des adénocarcinomes modérément différenciés et 17% des tumeurs de haut grade. Quatre-vingt-trois pour cent des tumeurs présentaient une expression cytoplasmique positive de la COX-2 et une positivité HER-2 membranaire extrêmement faible a été observée dans 2 % des cas. Il n'y avait pas de corrélation significative entre l'expression de la COX-2 et l'âge, le sexe, la localisation de la tumeur, la taille de la tumeur, la profondeur de l'invasion ou le statut des ganglions lymphatiques. Cependant, l'expression du COX-2 a révélé une corrélation significative avec le grade de la tumeur (p= 0,013). CONCLUSION: Cette étude détecte une forte expression de COX- 2 et une faible expression de HER-2 dans le cancer colorectal en utilisant l'immunohistochimie, suggérant un rôle possible de COX-2 dans la pathogenèse du CCR. Ce rapport devrait déclencher des investigations plus poussées des deux marqueurs vis-à-vis de la gestion du CRC dans notre environnement.

Clinical Presentation and Intensity of Infection with Intestinal Helminths among School Children in Ile-Ife, Osun State, Nigeria.

BACKGROUND: Intestinal helminthiases are public health problems of children in developing countries of the world and account for significant morbidity as it results in stunted growth, intestinal obstruction, anaemia, cognitive impairment, acute pancreatitis, acute cholecystitis and rectal prolapse. This study assessed intestinal helminths, infection intensity and symptoms in primary school children in Ile-Ife. METHODS: It was a cross sectional study. Three hundred and eighty-four pupils randomly selected from six public primary schools in Ife Central Local Government were enrolled for the study. Ethical approval was obtained. Stool samples were collected and processed using the Formol-ether concentration method. Questionnaires were administered to obtain relevant information. Data entry and processing were done using Microsoft excel and IBM SPSS Statistics for windows, version 17. Statistical analysis included frequency, proportion and percentages. RESULTS: Helminthic parasites were recovered from the stool of the schoolchildren and the overall prevalence of helminthic infection was 24%. Ascaris lumbricoides was the most prevalent (22.1%) with moderate and light intensities of infection, Hookworm (3.4%) with light intensity infection and Hymenolepis nana 0.3%. Symptoms were present in 48.2% of the participants and 31.5% presented with abdominal pain, nausea 22.1%, diarrhoea 21.1%, anorexia 7%. Weight loss, nausea and vomiting were found to be significantly associated with infection with intestinal helminths. CONCLUSION: Light to moderate intestinal helminthic infections are still prevalent among school children with weight loss, nausea and vomiting being the most significant symptoms. Continuous studies among school children are needed including those in private schools to better understand the epidemiology of these infections.

BACKGROUND: Les helminthiases intestinales sont des problèmes de santé publique, des enfants dans les pays en voie de développement du monde et représentent une morbidité importante, car elles entraînent un retard de croissance, l'obstruction intestinale, l'anémie, les troubles cognitifs, la pancréatite aiguë, la cholécystite aiguë et prolapsus rectal. Cette étude a évalué les helminthes intestinaux, l'intensité de l'infection et les symptômes chez les enfants des écoles primaires d'Ile-Ife. MÉTHODES: Il s'agissait d'une étude transversale. Trois cent quatre-vingt-quatre élèves choisis au hasard dans six écoles primaires publiques de Ife Central Local Government ont été recrutés pour l'étude. L'approbation éthique a été obtenue. Les échantillons de selles ont été collectés et traités en utilisant la méthode de concentration Formol-Ether. Des questionnaires ont été administrés pour obtenir des informations pertinentes. La saisie et le traitement des données ont été effectués à l'aide de Microsoft Excel et IBM SPSS. Statistique pour wndows, version 17. L'analyse statistique comprenait fréquence, proportion et pourcentages. RÉSULTATS: Les parasites helminthiques ont été récupérés dans les selles des écoliers et la prévalence globale de l'infection helminthique était de 24%. Ascaris lumbricoides était le plus répandu (22,1%) avec une intensités d'infection modérée et légère, l'ankylostome (3,4%) avec une intensités d'infection légère et Hymenolepis nana 0,3 %. Les symptômes étaient présents chez 48,2% des participants et 31,5% présentaient des douleurs abdominales, nausées 22,1%, diarrhées 21,1%, anorexie 7%. La perte de poids, les nausées et les vomissements ont été associés de manière significative à l'infection par des helminthes intestinaux. CONCLUSION: Les infections légères à modérées par les helminthes intestinaux sont encore répandues chez les écoliers, la perte de poids, les nausées et les vomissements étant les symptômes les plus significatifs. Des études continues parmi les enfants scolarisés, y compris dans les écoles privées, sont nécessaires pour mieux comprendre l'épidémiologie de ces infections. Mots-clés: Helminthes, Intensité, Enfants scolarisés, Symptômes.

Immunohistochemical Study and Clinicopathologic Correlation of Cox-2 and Her-2 Expression in Colorectal Carcinoma: A 5-Year Retrospective Study

BACKGROUND: Colorectal cancer (CRC) is the fourth most common cancer in Nigeria, and it affects mostly persons in their middle age. In a bid to gain some insight into the molecular characteristics of CRC in our environment, we set out to investigate the expression of COX-2 and HER-2 among Nigerian subjects. OBJECTIVES: To evaluate the expression of COX-2 and HER2 and determine their correlation with clinicopathologic parameters in surgically resected histologically diagnosed cases of colorectal cancer. METHODS: Fifty-three paraffin-embedded tissue blocks of colorectal resections and corresponding patient information were retrieved from the archives of the Anatomic and Molecular Pathology Department of Lagos University Teaching Hospital.A 4-micron slide section was obtained from each specimen and immunohistochemistry for COX-2 and HER-2 expression was performed. RESULTS: Mean age of cases was 53.9years with an almost equal M:F ratio of 1.12:1. Half of the cases were moderately differentiated adenocarcinoma and 17% were high grade tumors.Eighty three percent of the tumours showed positive cytoplasmic COX-2 expression and extremely low membranous HER-2 positivity was observed in 2%. There was no significant correlation between COX-2 expression and age, gender, tumour location, tumour size, depth of invasion or lymph node status.However, COX-2 expression revealed a significant correlation with tumour grade (p= 0.013). CONCLUSION: This study detects a high COX-2 and low HER2 expression in colorectal cancer using immunohistochemistry,suggesting a possible role for COX-2 in CRC pathogenesis.This report should trigger further investigations of both markers vis-à-vis the management of CRC in our environment. WAJM 2022; 39(11): 1134­1140.

Medical mortality in an emergency department in Nigeria: the transition is obvious!

INTRODUCTION: The emergency department (ED), a major entry point into the hospital, provides an insight to the type of cases seen, the quality of care and mortality spectrum in a health institution. We aim to identify the spectrum of medical causes of mortality in our ED, the demographic pattern and duration of stay before death. METHOD: This is a retrospective study that looked at medical mortality in the ED from January 2004 to December 2009. We obtained data on the demographics and causes of death from the medical records and case notes of the deceased. RESULTS: A total of 16587 patients were admitted during the period under review, of these 1262 (7.61%) died in the ED. The male to female ratio was 1.58:1.0 [772 males (61.2%), and 489 females (38.8%)]. Mortality was highest among the 20-45 years age range, followed by 46-65 years, >65 years and < 20 years in decreasing frequency [589(46.7%), 421(33.4%), 186 (14.8%) and 66(5.2%) respectively]. The three most common causes of death were stroke 315(25%), HIV related illnesses 126(10.0%), and heart failure 123(9.7%). Most deaths occurred less than 24hours of admission, 550(43.6%), followed by one day (36.0%) and two days (10.8%) post admissions respectively. CONCLUSION: The commonest cause of death in the ED was stroke. The burden of death was highest in the younger age group, with most occurring less than 24 hours of admission.

Pharmacogenomics-Based Point-of-Care Clinical Decision Support Significantly Alters Drug Prescribing.

Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green = genomically favorable, yellow = genomic caution, red = high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint. In all, 2,279 outpatient encounters were analyzed. Independent of other potential prescribing mediators, medications with high pharmacogenomic risk were changed significantly more often than prescription drugs lacking pharmacogenomic information (odds ratio (OR) = 26.2 (9.0-75.3), P < 0.0001). Medications with cautionary pharmacogenomic information were also changed more frequently (OR = 2.4 (1.7-3.5), P < 0.0001). No pharmacogenomically high-risk medications were prescribed during the entire study when physicians consulted the CDS tool. Pharmacogenomic information improved prescribing in patterns aimed at reducing patient risk, demonstrating that enhanced prescription decision-making is achievable through clinical integration of genomic medicine.

SNP discovery, expression and cis-regulatory variation in the UGT2B genes.

UGT2B enzymes metabolize multiple endogenous and exogenous molecules, including steroid hormones and clinical drugs. However, little is known about the inter-individual variation in gene expression and its determinants. We re-sequenced candidate regulatory regions and the partial coding regions (41.1 kb) of UGT2B genes and identified 332 genetic variants. We measured gene expression in normal breast and liver samples and observed different patterns. The expression levels varied greatly across individuals in both tissues and were significantly correlated with each other in liver. Genotyping of tagging single-nucleotide polymorphisms (SNPs) in the same samples and association tests between genotype and transcript levels identified 62 variants that were associated with at least one UGT2B mRNA levels in either tissue. Most of these cis-regulatory SNPs were not shared between tissues, suggesting that this gene family is regulated in a tissue-specific manner. Our results provide insight into studying the role of UGT2B variation in hormone-dependent cancers and drug response.

Atopy is associated with asthma in adults living in rural and urban southwestern Nigeria.

RATIONALE: Factors affecting the course of asthma are not clearly understood in rural and urban communities within low-resource countries. Furthermore, the interactions between atopy, environmental exposure, and helminthic infections in modulating asthma have not been well investigated. OBJECTIVES: To conduct a feasibility study to examine the relationship between atopy and asthma in adults at two rural Health Centers and urban university college hospital in southwestern Nigeria. METHODS: A convenient sample of 55 consecutive patients with stable physician-diagnosed asthma and 55 age-matched nonasthmatic controls seen at the outpatient clinics in two rural Health Centers and an urban university hospital were enrolled. All subjects underwent blood test, allergy skin test, and stool examination for ova and parasites. Wilcoxon sign-rank tests were used to compare serum eosinophilia and allergy skin test between the two groups. RESULTS: Asthmatics in both urban and rural settings had significantly more positive skin reactions to house dust mite, cockroach, mold, and mouse epithelium than nonasthmatic controls (p < .05). Mean total serum IgE was also significantly higher in asthmatics than in nonasthmatic controls (360 vs. 90 IU/L, p <.001). Stool parasitemia was infrequent in both groups and not statistically significant. CONCLUSION: Atopy is associated with adult asthma in southwest Nigeria. Larger studies to confirm the nature of this association and to examine the role of helminthic infection and other environmental factors on the expression of asthma are needed.

Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.

PURPOSE: The objective of this study was to estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers; and measure the extent to which host, family history, and cancer treatment-related factors modify the risk. PATIENTS AND METHODS: Patients were 810 women, with stage I or II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up. RESULTS: Overall, 149 subjects (18.4%) developed a contralateral breast cancer. The 15-year actuarial risk of contralateral breast cancer was 36.1% for women with a BRCA1 mutation and was 28.5% for women with a BRCA2 mutation. Women younger than 50 years of age at the time of breast cancer diagnosis were significantly more likely to develop a contralateral breast cancer at 15 years, compared with those older than 50 years (37.6 vs 16.8%; P=0.003). Women aged <50 years with two or more first-degree relatives with early-onset breast cancer were at high risk of contralateral breast cancer, compared with women with fewer, or no first-degree relatives with breast cancer (50 vs 36%; P=0.005). The risk of contralateral breast cancer was reduced with oophorectomy (RR 0.47; 95% CI 0.30-0.76; P=0.002). CONCLUSION: The risk of contralateral breast cancer risk in BRCA mutation carriers declines with the age of diagnosis and increases with the number of first-degree relatives affected with breast cancer. Oophorectomy reduces the risk of contralateral breast cancer in young women with a BRCA mutation.

Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers.

BACKGROUND: Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. METHOD: To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. RESULTS: No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. CONCLUSION: Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.

Characterizing early contrast uptake of ductal carcinoma in situ with high temporal resolution dynamic contrast-enhanced MRI of the breast: a pilot study.

Improvements in the reliable diagnosis of preinvasive ductal carcinoma in situ (DCIS) by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are needed. In this study, we present a new characterization of early contrast kinetics of DCIS using high temporal resolution (HiT) DCE-MRI and compare it with other breast lesions and normal parenchyma. Forty patients with mammographic calcifications suspicious for DCIS were selected for HiT imaging using T(1)-weighted DCE-MRI with ∼7 s temporal resolution for 90 s post-contrast injection. Pixel-based and whole-lesion kinetic curves were fit to an empirical mathematical model (EMM) and several secondary kinetic parameters derived. Using the EMM parameterized and fitted concentration time curve for subsequent analysis allowed for calculation of kinetic parameters that were less susceptible to fluctuations due to noise. The parameters' initial area under the curve (iAUC) and contrast concentration at 1 min (C(1 min)) provided the highest diagnostic accuracy in the task of distinguishing pathologically proven DCIS from normal tissue. There was a trend for DCIS lesions with solid architectural pattern to exhibit a negative slope at 1 min (i.e. increased washout rate) compared to those with a cribriform pattern (p < 0.04). This pilot study demonstrates the feasibility of quantitative analysis of early contrast kinetics at high temporal resolution and points to the potential for such an analysis to improve the characterization of DCIS.

Rapid progression of prostate cancer in men with a BRCA2 mutation.

Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P<0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation.

Parity and breastfeeding are protective against breast cancer in Nigerian women.

As the relation between reproductive factors and breast cancer risk has not been systematically studied in indigenous women of sub-Saharan Africa, we examined this in a case-control study in Nigeria. In-person interviews were conducted using structured questionnaires to collect detailed reproductive history in 819 breast cancer cases and 569 community controls between 1998 and 2006. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI). Compared with women with menarcheal age<17 years, the adjusted OR for women with menarcheal age>or=17 years was 0.72 (95% CI: 0.54-0.95, P=0.02). Parity was negatively associated with risk (P-trend=0.02) but age at first live birth was not significant (P=0.16). Importantly, breast cancer risk decreased by 7% for every 12 months of breastfeeding (P-trend=0.005). It is worth noting that the distribution of reproductive risk factors changed significantly from early to late birth cohorts in the direction of increasing breast cancer incidence. Our findings also highlight the heterogeneity of breast cancer aetiology across populations, and indicate the need for further studies among indigenous sub-Saharan women.

An exploratory analysis of HER-2 amplification and overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group study.

OBJECTIVES: To investigate the frequency and potential prognostic or predictive value of HER-2 amplification or overexpression in advanced and recurrent endometrial cancers. METHODS: Immunohistochemical staining (IHC; DAKO Herceptest) and fluorescence in situ hybridization (FISH; Vysis Inc. PathVysion DNA Probe Kit) were performed on specimens collected on a randomized Gynecologic Oncology Group (GOG) protocol testing the addition of paclitaxel to doxorubicin/cisplatin. RESULTS: HER-2 overexpression (either 2+ (moderate) or 3+ (strong) immunostaining) and HER-2 gene amplification (a ratio of HER-2 copies to chromosome 17 (CEP17) copies > or = 2) were detected in 44% (104 of 234; 58 were 2+ and 46 were 3+) and 12% (21 of 182) of specimens, respectively. There was a significant increased frequency of overexpression in serous tumors vs. all others (23 of 38, 61% vs. 81 of 196, 41%, respectively, P=0.03). HER-2 amplification also appeared to be more common in serous tumors, but results were not significant (6 of 28, 21% vs. 15 of 141, 11%, P=0.12). There was a significant association between grade and HER-2 amplification among nonserous tumors, with grades 1, 2, and 3 cancers demonstrating 3%, 2%, and 21% amplification, respectively (P=0.003). Neither overexpression nor amplification predicted overall survival (OS) after adjusting for treatment and performance status. CONCLUSIONS: HER-2 amplification was more common in high grade tumors with a trend to being more common in serous tumors. There was no clear evidence for a survival difference or a difference in benefit from the addition of paclitaxel for women with HER-2 amplified or overexpressed tumors; however, power to detect clinically meaningful differences was low.

Phenotypic heterogeneity in multiple myeloma families.

PURPOSE: To describe a series of families with familial multiple myeloma (MM). Observations were used to generate hypotheses about the role of genetic factors, the mode of inheritance of these factors, and the association of other cancers with familial MM. PATIENTS AND METHODS: This observational study consisted of 39 families with multiple cases of MM or related disorders from four collaborating research centers. Each center followed its usual family study method. Probands were interviewed, and, when possible, cancers were verified by medical records and pathology review. A working pedigree was compiled on each family. RESULTS: Seventeen families had affected members in two or more generations, and eight families had two or more affected members in a single generation. Four families had two or more members with plasma cell dyscrasias, with or without a single case of MM. In the remaining 10 families, a single MM case occurred with a family history of other cancers. Other cancers observed in family members included hematologic malignancies and solid tumors. In families with MM in multiple generations, there was a decrease in the age at MM diagnosis in successive generations. CONCLUSION: The study of familial MM may provide insights into the pathogenesis and, ultimately, the control and prevention of MM and related disorders. Population-based epidemiologic studies are crucial, but because of the rarity of familial MM, a concerted case-finding approach may also be fruitful. Therefore, we propose an international consortium to study familial MM, and we invite all interested colleagues to participate.

Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives.

Oral contraceptives have been shown to be protective against hereditary ovarian cancer. The variant progesterone receptor allele named PROGINS is characterized by an Alu insertion into intron G and two additional mutations in exons 4 and 5. The PROGINS allele codes for a progesterone receptor with increased stability and increased hormone-induced transcriptional activity. We studied the role of the PROGINS allele as a modifying gene in hereditary breast and ovarian cancer. The study included 195 BRCA1 and BRCA2 carriers with a prior diagnosis of ovarian cancer, 392 carriers with a diagnosis of breast cancer and 249 carriers with neither cancer. Fifty-eight women had both forms of cancer. Five hundred and ninety-five women had a BRCA1 mutation and 183 women had a BRCA2 mutation. Overall, there was no association between disease status and the presence of the PROGINS allele. Information on oral contraception use was available for 663 of the 778 carriers of BRCA1 or BRCA2 mutations. Among the 449 subjects with a history of oral contraceptive use (74 cases and 365 controls), no modifying effect of PROGINS was observed [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.5-1.3]. Among the 214 carriers with no past exposure to oral contraceptives, the presence of one or more PROGINS alleles was associated with an OR of 2.4 for ovarian cancer, compared to women without ovarian cancer and with no PROGINS allele (P = 0.004; 95% CI 1.4-4.3). The association was present after adjustment for ethnic group and for year of birth.