Kirtika Patel

Distinct Viral and Mutational Spectrum of Endemic Burkitt Lymphoma

Endemic Burkitt lymphoma (eBL) is primarily found in children in equatorial regions and represents the first historical example of a virus-associated human malignancy. Although Epstein-Barr virus (EBV) infection and MYC translocations are hallmarks of the disease, it is unclear whether other factors may contribute to its development. We performed RNA-Seq on 20 eBL cases from Uganda and showed that the mutational and viral landscape of eBL is more complex than previously reported. First, we found the presence of other herpesviridae family members in 8 cases (40%), in particular human herpesvirus 5 and human herpesvirus 8 and confirmed their presence by immunohistochemistry in the adjacent non-neoplastic tissue. Second, we identified a distinct latency program in EBV involving lytic genes in association with TCF3 activity. Third, by comparing the eBL mutational landscape with published data on sporadic Burkitt lymphoma (sBL), we detected lower frequencies of mutations in MYC, ID3, TCF3 and TP53, and a higher frequency of mutation in ARID1A in eBL samples. Recurrent mutations in two genes not previously associated with eBL were identified in 20% of tumors: RHOA and cyclin F (CCNF). We also observed that polyviral samples showed lower numbers of somatic mutations in common altered genes in comparison to sBL specimens, suggesting dual mechanisms of transformation, mutation versus virus driven in sBL and eBL respectively.

Wilms tumor survival in Kenya

PURPOSE Survival from Wilms Tumor (WT) exceeds 90% at 5 years in developed nations, whereas at last report, 2-year event-free survival (EFS) in Kenya reached only 35%. To clarify factors linked to these poor outcomes in Kenya, we established a comprehensive web-based WT registry, comprised of patients from the four primary hospitals treating childhood cancers. MATERIALS AND METHODS WT patients diagnosed between January 2008 and January 2012 were identified. Files were abstracted for demographic characteristics, treatment regimens, and enrollment in the Kenyan National Hospital Insurance Fund (NHIF). Children under 15 years of age having both a primary kidney tumor on imaging and concordant histology consistent with WT were included. RESULTS Two-year event-free survival (EFS) was 52.7% for all patients (n=133), although loss to follow up (LTFU) was 50%. For the 33 patients who completed all scheduled standard therapy, 2-year EFS was 94%. Patients enrolled in NHIF tended to complete more standard therapy and had a lower hazard of death (Cox 0.192, p < 0.001). CONCLUSION Survival of Kenyan WT patients has increased slightly since last report. Notably, WT patients completing all phases of standard therapy experienced 2-year survival approaching the benchmarks of developed nations. Efforts in Kenya should be made to enhance compliance with WT treatment through NHIF enrollment.

Risk factors for abandonment of Wilms tumor therapy in Kenya

Survival from Wilms tumor (WT) in sub‐Saharan Africa remains dismal as a result of on‐therapy mortality and treatment abandonment. Review of patients diagnosed from 2008 to 2011 in our Kenyan Wilms Tumor Registry showed a loss to follow up (LTFU) rate approaching 50%. The purpose of this study was to trace those LTFU, estimate the survival rate, and identify risk factors for treatment abandonment.

TP53 mutations, human papilloma virus DNA and inflammation markers in esophageal squamous cell carcinoma from the Rift Valley, a high-incidence area in Kenya

BackgroundSquamous Cell Carcinoma of Esophagus is one of the most common malignancies in both men and women in eastern and south-eastern Africa. In Kenya, clinical observations suggest that this cancer is frequent in the Rift Valley area. However, so far, there has been no report on the molecular characteristics of esophageal squamous cell carcinoma (ESCC) in this area.ResultsWe have analyzed TP53 mutations, the presence of human papilloma virus (HPV) DNA and expression of inflammation markers Cyclooxygenase 2 (Cox-2) and Nitrotyrosine (NTyR) in 28 cases (13 males and 15 females) of archived ESCC tissues collected at the Moi Teaching and Referral Hospital in Eldoret, Kenya. Eleven mutations were detected in TP53 exons 5 to 8 (39%). All ESCC samples were negative for HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 70, 73 and 82. Immunohistochemical analysis of Cox-2 and NTyR showed a low proportion of positive cases (17.4% and 39.1%, respectively). No association between the above markers and suspected risk factors (alcohol or tobacco use, hot tea drinking, use of charcoal for cooking) was found.ConclusionOur findings suggest that mechanisms of esophageal carcinogenesis in eastern Africa might be different from other parts of the world. Low prevalence of TP53 mutation compared with other intermediate or high incidence areas of the world highlights this hypothesis. Our data did not support a possible ole of HPV in this series of cases. Further studies are needed to assess and compare the molecular patterns of ESCC from Kenya with those of high-incidence areas such as China or Central Asia.

Development of immunohistochemistry services for cancer care in western Kenya: Implications for low- and middle-income countries

Background Cancer is becoming a major cause of mortality in low- and middle-income countries. Unlike infectious disease, malignancy and other chronic conditions require significant supportive infrastructure for diagnostics, staging and treatment. In addition to morphologic diagnosis, diagnostic pathways in oncology frequently require immunohistochemistry (IHC) for confirmation. We present the experience of a tertiary-care hospital serving rural western Kenya, which developed and validated an IHC laboratory in support of a growing cancer care service. Objectives, methods and outcomes Over the past decade, in an academic North-South collaboration, cancer services were developed for the catchment area of Moi Teaching and Referral Hospital in western Kenya. A major hurdle to treatment of cancer in a resource-limited setting has been the lack of adequate diagnostic services. Building upon the foundations of a histology laboratory, strategic investment and training were used to develop IHC services. Key elements of success in this endeavour included: translation of resource-rich practices to a resource-limited setting, such as using manual, small-batch IHC instead of disposable- and maintenance-intensive automated machinery, engagement of outside expertise to develop reagent-efficient protocols and supporting all levels of staff to meet the requirements of an external quality assurance programme. Conclusion Development of low- and middle-income country models of services, such as the IHC laboratory presented in this paper, is critical for the infrastructure in resource-limited settings to address the growing cancer burden. We provide a low-cost model that effectively develops these necessary services in a challenging laboratory environment.

Clinicopathologic features and early surgical outcome of astrocytomas in Eldoret, Kenya

Background: Astrocytomas are primary central nervous system tumors arising from astrocytes and accounting for up to 37.8% of all brain tumors seen in hospital-based studies from Africa. Despite being common, their patterns and short-term outcomes remain poorly studied in Kenya. Materials and Methods: A prospective, descriptive study involving consecutive patients with a histological diagnosis of astrocytoma seen in three hospitals located in Eldoret, Kenya. Clinicopathologic characteristics and outcomes were recorded and patients followed up for 12 weeks. Results: Thirty-one patients were recruited over a 1-year period. Majority of them were female (51.6%). Headache (83.9%) and focal neurological deficits (64.5%) were the most common presenting features. Among patients with high-grade tumors, mean duration of illness was 106.03 ± 162.16 days, median functional status was Karnofsky performance status (KPS) score 50, mean tumor size was 110.22 ± 46.16 cm3, and median magnetic resonance imaging (MRI) score was 17. Among patients with low-grade astrocytomas, mean duration of illness was 213.03 ± 344.93 days, median functional status was KPS score 40, mean tumor size was 53.49 ± 54.96 cm3 and median MRI score was 9. Glioblastoma multiforme (GBM) (71%) and diffuse astrocytoma (22.6%) were the predominant histological subtypes. The median Ki-67 proliferative index was 6% for pilocytic astrocytoma, 1.6% for diffuse astrocytoma, and 60% for GBM. Systemic and regional surgical complications occurred in 6.5% and 38.7% of patients, respectively. In-hospital mortality was 19.4% and increased to 25.8% at 12 weeks. The KPS score at discharge was 50 and improved to 60 at 12 weeks. Only 9.7% of patients had acceptable functional status at 12 weeks follow-up. Conclusions: In this locality, headache, focal neurological deficits, and reduced functional status are the most common presenting features of astrocytomas while GBM is the most common histological subtype. Tumors are highly proliferative and in the short-term, both surgical and functional outcome are suboptimal.