BRCA1 and BRCA2 mutations and their clinical relevance in selected women diagnosed with triple-negative breast cancer in Kenya: a descriptive cross-sectional study.

Introduction: triple-negative breast cancer (TNBC) is a heterogeneous breast cancer type with a poor prognosis. About 25% of TNBC patients carry breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) mutations. Screening for BRCA mutations would facilitate early detection and initiation of personalized therapy, thus improving prognosis. However, this has not been explored in our population. We aimed at identifying BRCA1 and BRCA2 gene mutations and their clinical relevance among selected women with TNBC in Kenya. Methods: six participants enrolled in a larger descriptive cross-sectional study who met the inclusion criteria were selected. Structured questionnaires were used to obtain qualitative data. Deoxyribonucleic acid (DNA) was extracted from saliva. Whole exome sequencing of BRCA1 and BRCA2 genes using a next-generation sequencer was done. Results: overall, 83.3% of BRCA1 and BRCA2 gene mutations with clinical relevance were detected. Most of the variants (63%) were found in BRCA1 whereas 37% were found in BRCA2. Pathogenic mutations in BRCA1 gene included c.5513T>A, c.5291T>C, c.5297T>G, c.110C>A, c.5212G>C, c.122A>C, c.5117G>A, c.5095C>T, c.5054C>T, c.5053A>G, c.115T>A, c.5143A>G, and c.130T>G. Those in BRCA2 gene were c.7878G>A, c.9154C>T, c.8243G>A, c.7976G>A, c.8165C>G, c.8167G>C, and c.8168A>T. One variant (c.5352delG: p. Leu1785Terfs) not matching any in the BRCA Exchange and ClinVar databases was detected. Conclusion: our study revealed BRCA mutations that could be common among our population. Further, it has shown that BRCA1 and BRCA2 genetic mutations identified are of clinical relevance and there is a need to screen for these mutations in breast cancer patients to understand their implication in patient management outcomes.

Cytomorphological patterns of breast lesions among women with palpable breast lumps attending select teaching and referral hospitals in Kenya: a descriptive cross-sectional study.

Introduction: breast lumps account for a greater number of lesions in women attending surgical clinics in the developing world. Breast cancer which mostly presents as a breast lump is the leading cancer in Kenya, with an incidence of 12.5%. The study aims to describe the patterns of breast lesions in women presenting with palpable breast lumps in two major referral hospitals in Kenya. Methods: seven hundred and sixty-eight study participants with palpable lumps underwent fine needle aspiration cytology (FNAC). Sociodemographic data were captured using structured questionnaires. The FNAC materials were evaluated using the International Academy of Cytology Yokohama System (IACYS) and the lesions were classified into five-tier categories. Frequencies and percentages were used to summarize qualitative variables. Results: of 768 smears, 84.8% (n=651) were adequate for evaluation while 15.2% (n=117) were inadequate. Neoplastic lesions comprised 84.5% (n=550) and non-neoplastic 15.5% (n=101). Benign lesions accounted for 83.6% of the lesions followed by breast carcinoma (10.4%). Ductal carcinoma comprised 98.5% of cancerous lesions. The age group most affected with ductal carcinoma and suspicious lesions was 20-34 years (37.3% and 55.6% respectively). Fibroadenoma formed the bulk of the benign lesions identified (44.1%). Suspicious of malignancy was 4.1% (n=27). The age group with the most lesions (47.5%) was 20-34 years. Conclusion: a wide spectrum of breast lesions was established. Such include inflammatory, atypical, benign, suspicious of malignancy, and malignant lesions. Fibroadenoma was a common lesion diagnosed. The age group most affected by malignant lesions was 16-49 years, necessitating enhanced screening of women with breast lumps in our setups.

Acceptability and feasibility of inter-related activities to improve agency among African district health managers: A four-country study.

District health managers (DHMs) lead and manage Ministry of Health programmes and system performance. We report on the acceptability and feasibility of inter-related activities to increase the agency of DHMs in Kenya, Nigeria, South Africa and Uganda using a cross-sectional rapid appraisal with 372 DHMs employing structured questionnaires. We found differences and similarities between the countries, in particular, who becomes a DHM. The opportunity to provide leadership and effect change and being part of a team were reported as rewarding aspects of DHMs' work. Demotivating factors included limited resources, bureaucracy, staff shortages, lack of support from leadership and inadequate delegation of authority. District managers ranked the acceptability of the inter-related activities similarly despite differences between contexts. Activities highly ranked by DHMs were to employ someone to support primary care staff to compile and analyse district-level data; to undertake study tours to well-functioning districts; and joining an African Regional DHM Association. DHMs rated these activities as feasible to implement. This study confirms that DHMs are in support of a process to promote bottom-up, data-driven, context-specific actions that can promote self-actualisation, recognises the roles DHMs play, provides opportunities for peer learning and can potentially improve quality of care.

Utility of p16INK4a expression for the interpretation of uterine cervical biopsies in Kenya.

INTRODUCTION: histologic interpretation of hematoxylin and eosin-stained cervical biopsies is subject to substantial discordance among pathologists. Immunohistochemical staining for p16INK4a can reduce inter-observer disagreement. We did a cross-sectional study to evaluate the utility of p16INK4a staining in the assessment of cervical biopsies in Nairobi, Kenya. METHODS: hematoxylin and eosin-stained sections from 91 colposcopic biopsies diagnosed as negative for dysplasia or as cervical intraepithelial neoplasia (CIN) grade 1-3 from 2011-2013 in Nairobi, Kenya, were reviewed and immunostained for p16INK4a. Agreement in interpretation of cervical biopsies was compared between primary and consensus review results. RESULTS: on primary evaluation, 16 cases were negative for squamous dysplasia; 23 were CIN 1; 37 CIN 2; and 15 CIN 3. On consensus review, 32 cases were negative for dysplasia; 19 were CIN 1; 16 CIN 2 and 24 CIN 3. Agreement was moderate between primary and consensus histology review results for the diagnosis of low-grade versus high-grade squamous intraepithelial lesions (Kappa = 0.568). None of the cases negative for dysplasia were positive for p16INK4a expression, but in primary and consensus review results, 17% and 5% cases of CIN 1; 49% and 69% of CIN 2, and 80% and 96% of CIN 3 were p16INK4a positive, respectively. CONCLUSION: there was significant variability in the interpretation of cervical biopsies on hematoxylin and eosin between primary and consensus review assessments. 75% of CIN 1 cases that were upgraded to CIN 2 during consensus review expressed p16INK4a. These findings demonstrate the role of p16INK4a in increasing diagnostic accuracy and as a marker of high-grade CIN 2/3.

Task Sharing and Shifting to Provide Pathology Diagnostic Services: The Kenya Fine-Needle Aspiration Biopsy Cytology and Bone Marrow Aspiration and Trephine Biopsy Training Program.

PURPOSE: Fine-needle aspiration biopsy (FNAB) cytology is a simple, inexpensive, and accurate diagnostic test for benign, infectious, and malignant lesions of the breast, thyroid, lymph nodes, and other organs. Similarly, bone marrow aspiration and trephine (BMAT) biopsy procedures are relatively simple and inexpensive techniques that are important for diagnosing and monitoring many hematologic diseases including leukemias and lymphomas. However, the scarcity of pathologists in Kenya limits patient access to these simple diagnostic tests. We describe a task sharing and shifting program that sought to improve the provision of FNABs and BMAT biopsies in tertiary public hospitals in Kenya. METHODS: Between January 2016 and February 2017, we trained pathologists, pathology residents, and technologists from the University of Nairobi and Aga Khan University Hospital, Nairobi, in FNAB and BMAT biopsies, who in turn trained pathologists, medical officers (MO), clinical officers (CO), and technologists at five tertiary public hospitals. The program involved curriculum development, training workshops, the establishment of new and strengthening existing FNAB and BMAT biopsy clinics, interim site visits, audits, and stakeholder workshops. RESULTS: Fifty-one medical personnel at the tertiary hospitals were trained. The FNAB numbers increased by 41% to 1,681, with 139 malignant diagnoses (7.1%). BMAT biopsy numbers increased by 268% to 140, with 34 malignant cases. Between 60% and 100% of the FNAB and BMAT biopsy procedures were performed by MO and CO over the project period. One new FNAB and two new BMAT biopsy clinics were established. CONCLUSION: This project demonstrates a successful model of task sharing and shifting from specialist pathologists to MO and CO that improved access to important FNAB and BMAT biopsy services in a low-resource setting.

Curriculum and training needs of mid-level health workers in Africa: a situational review from Kenya, Nigeria, South Africa and Uganda.

BACKGROUND: Africa's health systems rely on services provided by mid-level health workers (MLWs). Investment in their training is worthwhile since they are more likely to be retained in underserved areas, require shorter training courses and are less dependent on technology and investigations in their clinical practice than physicians. Their training programs and curricula need up-dating to be relevant to their practice and to reflect advances in health professional education. This study was conducted to review the training and curricula of MLWs in Kenya, Nigeria, South Africa and Uganda, to ascertain areas for improvement. METHODS: Key informants from professional associations, regulatory bodies, training institutions, labour organisations and government ministries were interviewed in each country. Policy documents and training curricula were reviewed for relevant content. Feedback was provided through stakeholder and participant meetings and comments recorded. 421 District managers and 975 MLWs from urban and rural government district health facilities completed self-administered questionnaires regarding MLW training and performance. RESULTS: Qualitative data indicated commonalities in scope of practice and in training programs across the four countries, with a focus on basic diagnosis and medical treatment. Older programs tended to be more didactic in their training approach and were often lacking in resources. Significant concerns regarding skills gaps and quality of training were raised. Nevertheless, quantitative data showed that most MLWs felt their basic training was adequate for the work they do. MLWs and district managers indicated that training methods needed updating with additional skills offered. MLWs wanted their training to include more problem-solving approaches and practical procedures that could be life-saving. CONCLUSIONS: MLWs are essential frontline workers in health services, not just a stop-gap. In Kenya, Nigeria and Uganda, their important role is appreciated by health service managers. At the same time, significant deficiencies in training program content and educational methodologies exist in these countries, whereas programs in South Africa appear to have benefited from their more recent origin. Improvements to training and curricula, based on international educational developments as well as the local burden of disease, will enable them to function with greater effectiveness and contribute to better quality care and outcomes.

The potential of RNA as a target for national screening of pre-cancer.

Whole national screening of pre-cancer is done only in some few countries, dominated by The Netherlands, Denmark, UK, Norway and Finland. These national screenings are done combining national cancer registry, national public health and national medical bodies or hospitals. Until some few years ago national screening was only done using morphological or visual methods or technology. Today a number of molecular methods have been implemented to serve these national screening programs. Based on all the discussions within this review, it is clear that the main driving engine and the cause of cervical pre-cancer and the main cause of invasive cervical cancer is the expression of E6 and E7 oncoproteins from HPV 16, 18, 31, 33 and 45. However, the main challenge is the role of morphology or imaging-based diagnosis in the original definition of pre-cancer disease. This definition is not based on the cause of cervical precancer but based on a complex, subjective, morphological observations. The difference between these two definitions are discussed in this review. The unique discovery done while validating the first standardized detection technology used against mRNA, confirmed that the presence of both abnormal E6 and/or E7 mRNA and protein is the cause of cervical pre-cancer or severe neoplasia and the main cause of invasive cervical cancer. This confirmation was evident even though all these studies were disturbed by the above defined biases from morphology or imaging-based diagnosis. The use of the screening target that cause stable and high expression of the most carcinogenic compounds ever discovered, must cause a more accurate screening program. A number of studies have proved that the detection of E6/E7 mRNA followed-up by indirect or direct treatment in a well-organized national screening program, would reduce the incidence of cervical cancer. This review discusses the main studies involved in the scientific, clinical evaluation and how this unique technology could be used as a new medical gold standard for national screening of cervical pre-cancer.

Esophageal cytology sponge diagnostic test results in kenyatta national referral hospital, kenya.

OBJECTIVE: To describe the cytological findings of the esophagus using sponge cytology as a triage test in patients referred for esophageal endoscopy at Kenyatta National Hospital. STUDY DESIGN: A cross-sectional descriptive study was undertaken to obtain specimens from the esophagus for cytological evaluation using a sponge. The cellular yield and pattern of esophageal cytological findings was described by cytopathologists using the Bethesda system. The cytological findings were compared with endoscopy findings and whenever possible with biopsy results. RESULTS: All the participants (100%) swallowed the encapsulated sponge successfully and had smears with satisfactory material for evaluation. Negative smears for intraepithelial lesion or malignancy were the most common (86.6%), with intestinal metaplasia reported in 10% of all patients, high-grade squamous intraepithelial lesions in 1.7% and squamous cell carcinoma in 1.7%. There was good agreement between endoscopic and cytological findings. CONCLUSION: Sponge cytology is a simple and inexpensive technique which seems to have promising results as a primary test as well as a triage test whenever there is any suspicion of an esophageal lesion, especially in clinical settings where endoscopic facilities and medical professionals are not available. Hence, further evaluation using a larger sample size is recommended.

The prevalence of human papillomavirus infection in Mombasa, Kenya.

OBJECTIVES: A human papillomavirus (HPV) prevalence survey was done in Mombasa, Kenya, to improve the knowledge of HPV prevalence and genotype distribution in sub-Saharan African countries overall, and in women of different ages. METHODS: HPV prevalence was assessed using PCR in women older than 15 years attending family planning and mother-child care services. RESULTS: Among 496 women, HPV prevalence was high (42.3%; 95% CI: 37.9-46.8; world age-standardized). Moreover, 46% of HPV-positive women harbored multiple-type infections. The most common types were HPV58 (10.5% of women), HPV16 (7.7%), HPV53 (6.7%), HPV18 (4.6%), and HPV6 (4.4%), and the prevalence of any high-risk HPV type was 28.8%. HPV prevalence was elevated among all age-groups (range 36.4-45.7%). Independent associations with HPV positivity were found for being in a polygamous marriage (OR = 1.7) and lifetime number of sexual partners (OR for ≥ 3 vs. 1 = 1.5), although they were of only borderline statistical significance. CONCLUSIONS: These findings differ from other world regions, showing a high HPV burden in all age-groups with a high proportion of multiple-type infections. Our data strengthen the urgency of HPV vaccination in Kenya but also highlight the elevated number of women who would have positive results in an HPV-based screening program in the country.

Routine assessment of hormonal receptor and her-2/neu status underscores the need for more therapeutic targets in Kenyan women with breast cancer.

OBJECTIVE: To report the expression of estrogen receptors, progesterone receptors and human epidermal growth factor receptor (Her-2/neu) in 158 Kenyan women with breast cancer and correlation with other prognostic indicators in this high-risk group. This study stressed the importance of routine assessment of the steroid receptors and Her-2/neu as a mode of therapeutic selection of patients for antihormonal or targeting monoclonal antibody (Herceptin) therapy, directed at the juxtamembrane domain of Her-2/neu protein in the developing countries such as Kenya. STUDY DESIGN: The study population consisted of 158 female patients with histologically confirmed breast carcinoma seen at the pathology department of The Nairobi Hospital. An immunohistochemical (IHC) study of ER, PR and Her-2/neu was conducted, followed by fluorescent in situ hybridization (FISH) validation for Her-2/neu gene amplification in cases initially scored as positive 2+ with IHC. Mastectomy samples registered at the pathology department of The Nairobi Hospital were used for this study. The study was approved by the institution's ethical review committee and informed consent obtainedfrom the concerned patients. RESULTS: In the studied cohort, positivity for both hormonal receptors and Her-2/neu was noted in 10 (6.33%) cases and negativity in 44 (27.85%) cases. Conversely, Her-2/neu negativity was noted in 32 (20.25%) cases with both steroid receptors positive and Her-2/neu positivity with both steroid receptors negative in 20 (12.66%) cases. Overall, no predictive factor was found in the Her-2/neu amplified 31/153 (20.26%) cases completely assessed with IHC and FISH. Grade III invasive ductal carcinomas, however, had a high prevalence of Her-2/neu overexpression. Association of both menopausal status (p = 0.044) and progesterone receptor status (p = 0.004) with high grade tumors were found to be statistically significant at 95% CI (p < 0.5). Consistent with other studies, Her-2/neu overexpression in this cohort was 20.26%. CONCLUSION: Her-2/neu positivity may activate ER expression through signaling kinases, and the combined target of mitogenic estrogen plus the monoclonal antibody therapy against Her-2/neu-overexpressing tumors expand chances of survival for patients in developing countries such as Kenya. The cost factor for these tests, selection for appropriate combined therapies and lack of awareness were noted as limiting factors for access to basic health care service and resulted in advanced tumor grade at time of patient presentation.

Distribution of human papillomavirus in a family planning population in nairobi, kenya.

BACKGROUND: In sub-Saharan Africa, cervical cancer is the leading cancer among women. The causative role of different human papillomavirus (HPV) types in cervical cancer is established, but the distribution of HPV types within this region is largely unknown. GOAL: The goal was to study the distribution of HPV among family planning clinic attendees in Nairobi, Kenya. STUDY DESIGN: This was a cross-sectional study of persons attending a family planning center in Nairobi, Kenya. RESULTS: HPV data of 429 women were analyzed; 7.0% had low-grade intraepithelial lesions, 6.8% had high-grade intraepithelial lesions, and 0.23% had invasive cancer. One hundred ninety samples (44.3%) were HPV-positive (28.4% were positive for multiple types). The most common HPV types were HPV 52 (17.9% of positive samples), HPV 16 (14.7%), HPV 35 (11.6%), and HPV 66 (9.0%). The risk of high-grade squamous intraepithelial lesions (HSIL) was 88.5 times higher (95% CI, 8.5-1.4 x 10 ) in HPV 16-positive women than in HPV-negative women. Relative risks were 54.3 (95% CI, 4.0-1.4 x 10 ) for HPV 35, 49.2 (95% CI, 3.6-9.5 x 10 ) for HPV 52, and 21.7 (95% CI, 0.0-1.9 x 10 ) for HPV 18. The prevalence of HSIL was not increased in association with HIV-positivity, yet HIV-1 was significantly associated with high-risk HPV types ( P< 0.00001). CONCLUSION: The pattern of HPV distribution in this population was different from that in other regions in the world, which has important consequences for HPV vaccine development.

Progesterone, estradiol and their receptors in leiomyomata and the adjacent normal myometria of black Kenyan women.

The contents of progesterone and oestrogen, and their respective receptors in uterine leiomyomata and adjacent normal myometrial tissue in indigenous black women in Kenya were studied. A random selection of twenty women undergoing hysterectomy for uterine fibroids at Kenyatta National Hospital was used for the studies. The myometria contained higher levels of E(2 ) (181% : P < 0.001); and P(4 ) (240.6 % : P < 0.001); as compared to the leiomyomata. On the other hand uterine leiomyomata contained significantly higher levels of ER (147.6% : P < 0.001); and PR (178.7% : P < 0.001 ); than normal myometria. These findings differ slightly from those reported in black women in developed countries, but support the proposal that manipulation of sex steroids may be useful in the treatment and management of uterine leiomyomata.