Tanzanian malignant lymphomas: WHO classification, presentation, ploidy, proliferation and HIV/EBV association.

BACKGROUND: In Tanzania, the International Working Formulation [WF] rather than the WHO Classification is still being used in diagnosing malignant lymphomas (ML) and the biological characterization including the HIV/EBV association is sketchy, thus restraining comparison, prognostication and application of established therapeutic protocols. METHODS: Archival, diagnostic ML biopsies (N = 336), available sera (N = 35) screened by ELISA for HIV antibodies and corresponding clinical/histological reports at Muhimbili National Hospital (MNH) in Tanzania between 1996 and 2006 were retrieved and evaluated. A fraction (N = 174) were analyzed by histopathology and immunohistochemistry (IHC). Selected biopsies were characterized by flow-cytometry (FC) for DNA ploidy (N = 60) and some by in-situ hybridization (ISH) for EBV-encoded RNA (EBER, N = 37). RESULTS: A third (38.8%, 109/281) of the ML patients with available clinical information had extranodal disease presentation. A total of 158 out of 174 biopsies selected for immunophenotyping were confirmed to be ML which were mostly (84. 8%, 134/158) non-Hodgkin lymphoma (NHL). Most (83.6%, 112/134) of NHL were B-cell lymphomas (BCL) (CD20+), of which 50.9%, (57/112) were diffuse large B-cell (DLBCL). Out of the 158 confirmed MLs, 22 (13.9%) were T-cell [CD3+] lymphomas (TCL) and 24 (15.2%) were Hodgkin lymphomas (HL) [CD30+]. Furthermore, out of the 60 FC analyzed ML cases, 27 (M:F ratio 2:1) were DLBCL, a slight majority (55.6%, 15/27) with activated B-cell like (ABC) and 45% (12/27) with germinal center B-cell like (GCB) immunophenotype. Overall, 40% (24/60) ML were aneuploid mostly (63.0%, 17/27) the DLBCL and TCL (54.5%, 6/11). DNA index (DI) of FC-analyzed ML ranged from 1.103-2.407 (median = 1.51) and most (75.0%) aneuploid cases showed high (>40%) cell proliferation by Ki-67 reactivity. The majority (51.4%, 19/37) of EBER ISH analyzed lymphoma biopsies were positive. Of the serologically tested MLs, 40.0% (14/35) were HIV positive, mostly with high (> or =40.0%) Ki-67 reactivity. CONCLUSIONS: According to the 2001 WHO Classification, most subtypes are represented in Tanzanian ML. Extranodal presentation was common among MNH lymphoma patients who also showed high aneuploidy, tumor proliferation (KI-67) and EBER positivity. DLBCL was frequent and phenotype heterogeneity appeared similar to observations in Western countries suggesting applicability of established intervention approaches. HIV was apparently associated with high ML cell proliferation but extended studies are needed to clarify this.

In the name of global health: trends in academic institutions.

This paper describes accelerating development of programs in global health, particularly in North American academic institutions, and sets this phenomenon in the context of earlier programs in tropical medicine and international health that originated predominantly in Europe. Like these earlier programs, the major focus of the new global health programs is on the health needs of developing countries, and perhaps for this reason, few similar programs have emerged in academic institutions in the developing countries themselves. If global health is about the improvement of health worldwide, the reduction of disparities, and protection of societies against global threats that disregard national borders, it is essential that academic institutions reach across geographic, cultural, economic, gender, and linguistic boundaries to develop mutual understanding of the scope of global health and to create collaborative education and research programs. One indication of success would be emergence of a new generation of truly global leaders working on a shared and well-defined agenda--and doing so on equal footing.

Oral Kaposi's sarcoma in Tanzania: presentation, immunopathology and human herpesvirus-8 association.

Oral Kaposi's sarcoma (OKS) from Tanzanian patients (78) at Muhimbili National Hospital/Muhimbili University College of Health Sciences corresponding to approximately 10% of KS registered during 1990-2005, were diagnosed (ELISA) as HIV-infected (OAKS) (74/78) and endemic KS (4/78). Females were 69.2% (54/78) with median age 31 and males 30.8% (24/78) with median age 38. More males (50%) had systemic KS than females (37%) and 4-times more multicentric OKS. All tested (34) oral KS patients sera had HHV-8 antibodies. Available (31/78) blood showed very low CD4+ T-lymphocyte counts. Most OKS (61.5%) had nodular histology. Immunostaining showed adult male nodular OAKS to have a significantly higher frequency of viral LANA+, endothelial CD34+ tumour spindle-cells (SC) and more Ki-67+ (median =24.1%) proliferating cells compared to females (17.2%). Juvenile nodular OAKS had more LANA+ and Ki-67+ cells than corresponding adult cases. Significantly more LANA+ and Ki-67+ cells were found in nodular OAKS compared to cutaneous HIV/AIDS Kaposi's sarcoma (CAKS). A positive correlation (60%) was found between the proliferation index (Ki-67+ cell frequency) and LANA+/CD34+ SC. OKS in Tanzania is since 1990, mostly seen in females, associated with HIV/AIDS and advanced (nodular) histopathology. Males have more systemic tumour burden while more females develop primary OAKS. HHV-8+ cells were more frequent in nodular male than female and in juvenile than adult nodular OAKS than cAKS. Higher tumoral HHV-8 content appeared to be correlated to proliferation index.

Where teachers are few: documenting available faculty in five Tanzanian medical schools.

BACKGROUND: Faced with one of the lowest physician-to-population ratios in the world, the Government of Tanzania is urging its medical schools to train more physicians. The annual number of medical students admitted across the country rose from 55 in the 1990s to 1,680 approved places for the 2015/16 academic year. These escalating numbers strain existing faculty. OBJECTIVE: To describe the availability of faculty in medical schools in Tanzania. DESIGN: We identified faculty lists published on the Internet by five Tanzanian medical schools for the 2011/12 academic year and analyzed the appointment status, rank, discipline, and qualifications of faculty members. RESULTS: The five schools reported 366 appointed faculty members (excluding visiting, part-time, or honorary appointments) for an estimated total enrolled student capacity of 3,275. Thirty-eight percent of these faculty were senior lecturers or higher. Twenty-seven percent of the appointments were in basic science, 51% in clinical science, and 21% in public health departments. The most populated disciplines (more than 20 faculty members across the five institutions) were biochemistry and molecular biology, medicine, obstetrics and gynecology, pediatrics, and surgery; the least populated disciplines (less than 10 faculty members) were anesthesiology, behavioral sciences, dermatology, dental surgery, emergency medicine, hematology, ophthalmology, orthopedics, otorhinolaryngology, oncology and radiology, psychiatry. These figures are only indicative of faculty numbers because of differences in the way the schools published their faculty lists. CONCLUSIONS: Universities are not recruiting faculty at the same rate that they are admitting students, and there is an imbalance in the distribution of faculty across disciplines. Although there are differences among the universities, all are struggling to recruit and retain staff. If Tanzanian universities, the government, donors, and international partners commit resources to develop, recruit, and retain new faculty, Tanzania could build faculty numbers to permit a quality educational experience for its doctors of tomorrow.

Modeling solutions to Tanzania's physician workforce challenge.

BACKGROUND: There is a great need for physicians in Tanzania. In 2012, there were approximately 0.31 physicians per 10,000 individuals nationwide, with a lower ratio in the rural areas, where the majority of the population resides. In response, universities across Tanzania have greatly increased the enrollment of medical students. Yet evidence suggests high attrition of medical graduates to other professions and emigration from rural areas where they are most needed. OBJECTIVE: To estimate the future number of physicians practicing in Tanzania and the potential impact of interventions to improve retention, we built a model that tracks medical students from enrollment through clinical practice, from 1990 to 2025. DESIGN: We designed a Markov process with 92 potential states capturing the movement of 25,000 medical students and physicians from medical training through employment. Work possibilities included clinical practice (divided into rural or urban, public or private), non-clinical work, and emigration. We populated and calibrated the model using a national 2005/2006 physician mapping survey, as well as graduation records, graduate tracking surveys, and other available data. RESULTS: The model projects massive losses to clinical practice between 2016 and 2025, especially in rural areas. Approximately 56% of all medical school students enrolled between 2011 and 2020 will not be practicing medicine in Tanzania in 2025. Even with these losses, the model forecasts an increase in the physician-to-population ratio to 1.4 per 10,000 by 2025. Increasing the absorption of recent graduates into the public sector and/or developing a rural training track would ameliorate physician attrition in the most underserved areas. CONCLUSIONS: Tanzania is making significant investments in the training of physicians. Without linking these doctors to employment and ensuring their retention, the majority of this investment in medical education will be jeopardized.

Cervical cytological changes in HIV-infected patients attending care and treatment clinic at Muhimbili National Hospital, Dar es Salaam, Tanzania.

BACKGROUND: Tanzania is among Sub-Saharan countries mostly affected by the HIV and AIDS pandemic, females being more vulnerable than males. HIV infected women appear to have a higher rate of persistent infection by high risk types of human papillomavirus (HPV) strongly associated with high-grade squamous intraepithelial lesions (HSIL) and invasive cervical carcinoma. Furthermore, although HIV infection and cervical cancer are major public health problems, the frequency and HIV/HPV association of cervical cancer and HSIL is not well documented in Tanzania, thus limiting the development of preventive and therapeutic strategies. METHODS: A prospective unmatched, case-control study of HIV-seropositive, ≥ 18 years of age and consenting non-pregnant patients attending the care and treatment center (CTC) at Muhimbili National Hoospital (MNH) as cases was done between 2005 and 2006. HIV seronegative, non-pregnant and consenting women recruited from the Cervical Cancer Screening unit (CCSU) at ORCI were used as controls while those who did not consent to study participation and/or individuals under < 18 years were excluded. Pap smears were collected for routine cytodiagnosis and P53 immunohistochemistry (IHC). Cervical lesions were classified according to the Modified Bethesda System. RESULTS: A total of 170 participants from the two centers were recruited including 50 HIV-seronegative controls were from the CCSU. Ages ranged from 20-66 years (mean 40.5 years) for cases and 20-69 years (mean 41.6 years) for controls. The age group 36-45 years was the most affected by HIV (39.2%, n = 47). Cervicitis, squamous intraepithelial lesions (SIL) and carcinoma constituted 28.3% (n = 34), 38.3% (n = 46) and 5.8% (n = 7) respectively among cases, and 28% (n = 14), 34% (n = 17) and 2% (n = 1) for controls, although this was not statistically significant (P-value = 0.61). IHC showed that p53 was not detectable in HPV + Pap smears and cell blocks indicating possible degradation. CONCLUSIONS: The frequency of SIL and carcinoma appeared to be higher among HIV-infected women on HAART compared to seronegative controls and as expected increased with age. HIV seropositive patients appeared to present earlier with SIL compared to those HIV seronegative suggesting a role of HIV in altering the natural history of HPV infection and cervical lesions. The absence of p53 immunoreactivity in HPV + lesions is indicative of the ability of HPV E6 proteins to interact with the tumor suppressor gene and pave way for viral-induced oncogenesis in the studied Tanzanian women.

Tracking university graduates in the workforce: information to improve education and health systems in Tanzania.

With a severe shortage of highly trained health professionals, Tanzania must make the best possible use of available human resources and support training institutions to educate more graduates. We highlight the overlooked but significant role of universities in collecting, managing, and using human resources data in Tanzania and in other countries struggling to build their health workforces. Although universities, professional councils, ministries of health, education, and finance, and non-governmental organizations in Tanzania all maintain databases that include details of health professionals' education, registration, and employment, they do not make the information easily accessible to one another. Using as an example Muhimbili University of Health and Allied Sciences - the leading public institution for health professions education in Tanzania - we explore how training institutions can gather and use data to target and improve the quality of education for increasing numbers of graduates. We specifically examine the substantial challenge universities face in locating more members of each graduating class and conclude with recommendations about how the situation can be improved.

Partnering on education for health: Muhimbili University of Health and Allied Sciences and the University of California San Francisco.

In 2005, Muhimbili University of Health and Allied Sciences (MUHAS) in Tanzania and the University of California San Francisco (UCSF) in the United States joined to form a partnership across all the schools in our institutions. Although our goal is to address the health workforce crisis in Tanzania, we have gained much as institutions. We review the work undertaken and point out how this education partnership differs from many research collaborations. Important characteristics include: (i) activities grew out of MUHAS's institutional needs, but also benefit UCSF; (ii) working across professions changed the discourse from 'medical education' to 'health professions education'; (iii) challenged by gaps in our respective health-care systems, both institutions chose a new focus, interprofessional team work; (iv) despite being so differently resourced, MUHAS and UCSF seek strategies to address growing class sizes; and (v) we involved a wider range of people - faculty, administrators, students, and residents - at both institutions than is usually the case with research. This partnership has convinced us to exhort other academic leaders in the health arena to seek opportunities together to enlighten and enliven our educational enterprises.

An institutional research agenda: focusing university expertise in Tanzania on national health priorities.

A well-articulated institutional health research agenda can assist essential contributors and intended beneficiaries to visualize the link between research and community health needs, systems outcomes, and national development. In 2011, Tanzania's Muhimbili University of Health and Allied Sciences (MUHAS) published a university-wide research agenda. In developing the agenda, MUHAS leadership drew on research expertise in its five health professional schools and two institutes, its own research relevant documents, national development priorities, and published literature. We describe the process the university underwent to form the agenda and present its content. We assess MUHAS's research strengths and targets for new development by analyzing faculty publications over a five-year period before setting the agenda. We discuss implementation challenges and lessons for improving the process when updating the agenda. We intend that our description of this agenda-setting process will be useful to other institutions embarking on similar efforts to align research activities and funding with national priorities to improve health and development.

Tanzania's health system and workforce crisis.

This introduction to Tanzania's health system and acute workforce shortage familiarizes readers with the context in which health professions education takes place. The paper touches on poverty rates, population growth, and characteristics of the health system. The critical shortage of trained health staff is a major challenge facing the health sector, aggravated by low motivation of the few available staff. Other challenges facing the health sector include lack of effective staff supervision, poor transport and communication infrastructure and shortage of drugs and medical equipment. We recommend appropriate action be taken by the government and other stakeholders to provide more financial and human resources for the sector while ensuring their efficient and effective utilization to improve services delivery.

Teaching and educational scholarship in Tanzania: faculty initiative to improve performance of health professions' students.

Well-educated and competent health professionals influence the health system in which they work to improve health outcomes, through clinical care and community interventions, and by raising standards of practice and supervision. To prepare these individuals, training institutions must ensure that their faculty members, who design and deliver education, are effective teachers. We describe the experience of the Muhimbili University of Health and Allied Sciences (MUHAS) in encouraging improvements in the teaching capacity of its faculty and postgraduate students triggered by a major institutional transition to competency-based education. We employed a multi-stage process that started by identifying the teaching and learning needs and challenges of MUHAS students and faculty. Collaborating with the University of California San Francisco (UCSF), MUHAS responded to these needs by introducing faculty to competency-based curricula and later to strategies for long term continuing improvement. We demonstrate that teaching faculty members are keen for local institutional support to enable them to enhance their skills as educators, and that they have been able to sustain a program of faculty development for their peers.

Curricular transformation of health professions education in Tanzania: the process at Muhimbili University of Health and Allied Sciences (2008-2011).

Tanzania requires more health professionals equipped to tackle its serious health challenges. When it became an independent university in 2007, Muhimbili University of Health and Allied Sciences (MUHAS) decided to transform its educational offerings to ensure its students practice competently and contribute to improving population health. In 2008, in collaboration with the University of California San Francisco (UCSF), all MUHAS's schools (dentistry, medicine, nursing, pharmacy, and public health and social sciences) and institutes (traditional medicine and allied health sciences) began a university-wide process to revise curricula. Adopting university-wide committee structures, procedures, and a common schedule, MUHAS faculty set out to: (i) identify specific competencies for students to achieve by graduation (in eight domains, six that are inter-professional, hence consistent across schools); (ii) engage stakeholders to understand adequacies and inadequacies of current curricula; and (iii) restructure and revise curricula introducing competencies. The Tanzania Commission for Universities accredited the curricula in September 2011, and faculty started implementation with first-year students in October 2011. We learned that curricular revision of this magnitude requires: a compelling directive for change, designated leadership, resource mobilization inclusion of all stakeholders, clear guiding principles, an iterative plan linking flexible timetables to phases for curriculum development, engagement in skills training for the cultivation of future leaders, and extensive communication.

Malignant lymphomas (ML) and HIV infection in Tanzania.

BACKGROUND: HIV infection is reported to be associated with some malignant lymphomas (ML) so called AIDS-related lymphomas (ARL), with an aggressive behavior and poor prognosis. The ML frequency, pathogenicity, clinical patterns and possible association with AIDS in Tanzania, are not well documented impeding the development of preventive and therapeutic strategies. METHODS: Sections of 176 archival formalin-fixed paraffin-embedded biopsies of ML patients at Muhimbili National Hospital (MNH)/Muhimbili University of Health and Allied Sciences (MUHAS), Tanzania from 1996-2001 were stained for hematoxylin and eosin and selected (70) cases for expression of pan-leucocytic (CD45), B-cell (CD20), T-cell (CD3), Hodgkin/RS cell (CD30), histiocyte (CD68) and proliferation (Ki-67) antigen markers. Corresponding clinical records were also evaluated. Available sera from 38 ML patients were screened (ELISA) for HIV antibodies. RESULTS: The proportion of ML out of all diagnosed tumors at MNH during the 6 year period was 4.2% (176/4200) comprising 77.84% non-Hodgkin (NHL) including 19.32% Burkitt's (BL) and 22.16% Hodgkin's disease (HD). The ML tumors frequency increased from 0.42% (1997) to 0.70% (2001) and 23.7% of tested sera from these patients were HIV positive. The mean age for all ML was 30, age-range 3-91 and peak age was 1-20 years. The male:female ratio was 1.8:1. Supra-diaphragmatic presentation was commonest and histological sub-types were mostly aggressive B-cell lymphomas however, no clear cases of primary effusion lymphoma (PEL) and primary central nervous system lymphoma (PCNSL) were diagnosed. CONCLUSION: Malignant lymphomas apparently, increased significantly among diagnosed tumors at MNH between 1996 and 2001, predominantly among the young, HIV infected and AIDS patients. The frequent aggressive clinical and histological presentation as well as the dominant B-immunophenotype and the HIV serology indicate a pathogenic association with AIDS. Therefore, routine HIV screening of all malignant lymphoma patients at MNH is necessary to enable comprehensive ARL diagnosis and formulation of preventive and therapeutic protocols.

Human herpesvirus-8 (HHV-8) sero-detection and HIV association in Kaposi's sarcoma (KS), non-KS tumors and non-neoplastic conditions.

BACKGROUND: The association of the human herpesvirus-8/Kaposi's sarcoma (KS)-associated herpesvirus (HHV-8/KSHV) serology with various malignancies in Tanzania is not currently well established while previous studies were based on either PCR or immunofluorescence assays [IFA] but not with a sensitive enzyme-linked immunosorbent assay (ELISA). Selected archival diagnostic biopsies (n = 184) and sera from indigenous patients with KS (n = 120), non-KS tumors (n = 24) and non-neoplastic lesions (n = 40) at Muhimbili National Hospital (MNH), Tanzania, were evaluated by diagnostic histopathology, immunohistology [anti-HHV-8 latency-associated nuclear antigen (LANA)] and serology for HIV (ELISA) and HHV-8 (IFA and ELISA). RESULTS: About 66.3% (n = 122) cases including AIDS-associated Kaposi's sarcoma (AKS) (n = 93), reactive conditions (n = 28) and only one non-KS tumour were HIV positive. Endemic KS (EKS) patients were mostly males (96.3%, 26/27) who were less (69.9%, 65/93) predominant in AIDS-associated (AKS). A high (89%) percentage of patients with anti-HHV-8 antibodies was found in the cohort including the HIV positive (92%) cases, males (81.2%), KS patients (93%), non-KS tumors (92%), and reactive conditions (75%). All HHV-8 seronegative KS cases were nodular stage whereas both sera and corresponding biopsies from early stage KS were HHV-8+. Assay sensitivity, positive predictive value (PPV) and specificity were 98.6%, 93.5% and 16.7% for IFA and 93.5%, 98.6% and 50.0% for ELISA respectively. CONCLUSION: HHV-8 seroprevalence at MNH appears high as expected among AKS cases and males but also in non-KS patients. ELISA showed a combination of high HHV-8 sensitivity as well as higher PPV and specificity than IFA which however, showed higher sensitivity. The apparent stage-dependent, inverted serum HHV-8 immunoreactivity supports a notion of viral immune-segregation during KS development. Routine HHV-8 screening should be considered particularly in patients at risk of KS and for selection of blood/organ donations.

AIDS and non AIDS-related malignant lymphoma in Tanzania.

BACKGROUND: Malignant lymphoma (ML) in HIV patients, are second in frequency to Kaposi's sarcoma (AKS) as AIDS-defining tumors. In Africa the frequency of AIDS-related lymphoma (ARL) is rare and the findings are controversial. Kaposi's sarcoma (KS) lesions are now causally associated with KSHV/HHV-8 but whether African ARL shows this association is not clear. METHOD: Cancer registry data was reviewed for retrospective cases. Both retrospective and prospective lymphoma cases were classified according to the revised European-American (REAL) classification. Immunephenotyping was performed on both frozen and fixed paraffin sections. Viral DNA was assessed by polymerase chain reaction (PCR) of formalin fixed or frozen biopsies. In situ hybridization (ISH) was used to determine the presence of EBV encoded RNA (EBER). OBJECTIVES: To determine the frequency and type of AIDS and non-AIDS related malignant lymphoma in Tanzania and a possible co-association with KSHV/HHV-8 and EBV. RESULTS: An overall increasing tendency for ML in Tanzania was observed during 1991-94 and a clear increase from 1993. The tumors were classified as Burkitt's (6), diffuse large cell (10), precursor-B lymphoblastic (1) and Hodgkin's disease (5) from HIV positive and negative patients. Ten (40%) high grade ML and three Hodgkin's lymphoma from HIV patients had HHV-8 DNA. These findings were not related to age, sex or type of lymphoma. There was no association of HHV-8 with the lymphoma cells. Epstein-Barr virus (EBV) was demonstrable in most (13/18; 72%) of the tested tumors and seven (31.8%) had both HHV-8 and EBV. CONCLUSIONS: This study suggests an overall increased frequency of ML patients infected with HHV-8 in Tanzania particularly in HIV patients which may result from the well established high HHV-8 prevalence in the general population, but HHV-8 was not associated with ARL pathogenesis as reflected by lack of tumor cell infection. As opposed to EBV, measures targeting HHV-8 for control of ML may therefore not be appropriate.