Prognostic factors affecting survival in children and adolescents with HIV and Hodgkin lymphoma in South Africa.

South African children with Hodgkin lymphoma (HL) and human immunodeficiency virus (HIV) have low 5-year overall survival (OS) rates. In this retrospective multicenter study, 271 South African pediatric patients with HL were studied to determine OS and prognostic factors in those with HIV and HL. Univariate risk factor analysis was performed to analyze prognostic factors. The 29 HIV-infected patients were younger (p = .021), more likely to present with wasting (0.0573), stunting (0.0332), and Stage IV disease (p = .000) than HIV-uninfected patients. The 5- and 10-year OS of HIV-infected patients of 49% and 45% versus 84% and 79%, respectively for HIV-uninfected patients (p = .0001) appeared to be associated with hypoalbuminemia (<20 g/dL) and CD4 percentage of <15%. Causes of death in the HIV-infected group included disease progression (6/14), infection (4/14), unknown (3/14), and second malignancy (1/14). HIV-infected pediatric patients with HL experience increased mortality due to post-therapy opportunistic and nosocomial infections.

Describing the evolution of myeloid-derived leucocytes in treated B-lineage paediatric acute lymphoblastic leukaemia with a data-driven granulocyte-monocyte-blast model.

Acute lymphoblastic leukaemia (ALL) is associated with a compromised myeloid system. Understanding the state of granulopoiesis in a patient during treatment, places the clinician in an advantageous position. Mathematical models are aids able to present the clinician with insight into the behaviour of myeloid-derived leucocytes. The main objective of this investigation was to determine whether a proposed model of ALL during induction therapy would be a usable descriptor of the system. The model assumes the co-occurrence of the independent leukaemic and normal marrow populations. It is comprised of four delay-differential equations, capturing the fundamental characteristics of the blood and bone marrow myeloid leucocytes and B-lineage lymphoblasts. The effect of treatment was presumed to amplify cell loss within both populations. Clinical data was used to inform the construction, calibration and examination of the model. The model is promising-presenting a good foundation for the development of a clinical supportive tool. The predicted parameters and forecasts aligned with clinical expectations. The starting assumptions were also found to be sound. A comparative investigation highlighted the differing responses of similarly diagnosed patients during treatment and further testing on patient data emphasized patient specificity. Model examination recommended the explicit consideration of the suppressive effects of treatment on the normal population production. Additionally, patient-related factors that could have resulted in such different responses between patients need to be considered. The parameter estimates require refinement to incorporate the action of treatment. Furthermore, the myeloid populations require separate consideration. Despite the model providing explanation, incorporating these recommendations would enhance both model usability and predictive capacity.

Family experiences of oncological palliative and supportive care in children: can we do better?

AIMS: Families were interviewed as a quality improvement assessment for palliative and supportive care services for children. METHODS: This exploratory qualitative study of family members of children with cancer was conducted at an academic hospital in central South Africa and a grounded theory approach was used. Face-to-face interviews using a semi-structured interview guide were conducted with 16 family members of 16 children. FINDINGS: Parents felt supported by the healthcare professionals who were caring for their child, but several shortcomings were identified. These included erratic psychosocial support, minimal financial support and poor parental access to basic needs and food provision, preventable errors in procedures and a lack of support available for siblings. It is also worth noting that healthcare professionals did not always seem sufficiently equipped to attend to palliative care patients. CONCLUSION: Strategies to improve supportive and palliative care are needed for children with cancer and their families in a hospital setting. The interviews identified a number of themes and current shortcomings that should be considered to improve services.

Treatment outcomes of children with Hodgkin lymphoma between 2000 and 2010: First report by the South African Children's Cancer Study Group.

BACKGROUND: Children with Hodgkin lymphoma (HL) have excellent survival rates in high-income countries, but there are minimal outcome data in South African patients. Differing approaches to treatment are used in centres across South Africa, and the South African Children's Cancer Study Group (SACCSG) embarked on a programme to audit outcomes to improve survival rates. PATIENTS AND METHODS: A multicentre study was conducted to analyse outcomes and prognostic factors of children with HL in South Africa. Ten dedicated South African paediatric oncology units participated in a retrospective data review. All patients with HL treated consecutively between January 2000 and December 2010 were included. Kaplan-Meier curves and Cox regression model were employed to determine survival rates and prognostic factors. RESULTS: Two hundred and ninety-four patients were eligible for inclusion. The median age at presentation was 9.6 years (range 2.9-18.8); 55.4% of the patients presented with Stage III and IV disease and 9.9% were human immunodeficiency virus (HIV) positive. First-line therapy consisted of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) in 158 patients, vincristine, procarbazine/etoposide, prednisone and doxorubicin in 97 and adriamycin, bleomycin, vincristine and dacarbazine-chlorambucil, vinblastine, prednisone and procarbazine in 23 patients. The 5-year overall survival (OS) was 79% (95% confidence interval 73-84%). Multivariate analysis demonstrated that HIV infection (P = 0.018) and Ann Arbor Stage III and IV disease (P = 0.006) conferred a poor prognosis, while treatment with ABVD was associated with higher survival rates (P = 0.028). CONCLUSION: OS rates are encouraging for a middle-income country, although economic disparities continue to impact negatively on outcomes. Study results will form the basis for the development of national protocol and continued advocacy to rectify disparities.

Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia.

Fanconi anemia (FA) is a rare disorder of DNA repair, associated with various somatic abnormalities but characterized by hematological disease that manifests as bone marrow aplasia and malignancy. The mainstay of treatment, in developed nations, is hematopoietic stem cell transplantation (HSCT) with subsequent surveillance for solid organ and non-hematological malignancies. In South Africa, FA in the Black population is caused by a homozygous deletion mutation in the FANCG gene in more than 80% of cases. Many affected patients are not diagnosed until late in the disease course when severe cytopenia and bone marrow aplasia are already present. Most patients are not eligible for HSCT at this late stage of the disease, even when it is available in the state health care system. In this study, the hematological presentation and disease progression in 30 Black South African patients with FA, confirmed to have the FANCG founder mutation, were evaluated and compared to those described in other FA cohorts. Our results showed that patients, homozygous for the FANCG founder mutation, present with severe cytopenia but progress to bone marrow failure at similar ages to other individuals affected with FA of heterogeneous genotype. Further, the incidence of myelodysplastic syndrome is similar to that which has been previously described in other FA cohorts. Although severe cytopenia at presentation may be predicted by a higher number of somatic anomalies, the recognition of the physical FA phenotype in Black South African patients is challenging and may not be useful in expediting referral of suspected FA patients for tertiary level investigations and care. Given the late but severe hematological presentation of FA in Black South African patients, an investigative strategy is needed for earlier recognition of affected individuals to allow for possible HSCT and management of bone marrow disease.

Childhood cancer survival rates in two South African units.

INTRODUCTION: Childhood cancer is relatively rare, but there is a very good chance of cure. While overall survival rates of >70% are reported from developed countries, survival is much less likely in developing countries and unknown in many countries in Africa. OBJECTIVE: To analyse survival rates of childhood cancers in two South African paediatric oncology units. METHODS: This retrospective review included all children (0 - 15 years) admitted with a malignancy at two paediatric oncology units (Universitas Hospital Academic Complex in Bloemfontein, Free State, and Tygerberg Hospital in Cape Town, Western Cape) between 1987 and 2011. The protocols used in the units were similar, and all the diagnoses were confirmed histologically. RESULTS: There were 3 241 children, 53.5% of whom were males. Median follow-up was 17 months. The most common cancers were leukaemia (25.0%), brain tumours (19.5%), lymphoma (13.0%) and nephroblastoma (10.0%). The prevalences of neuroblastoma and retinoblastoma were similar at 5.8% and 5.7%, respectively. Overall survival was calculated to be 52.1%. Lymphoma and nephroblastoma had the highest survival rates at 63.9% and 62.6%, respectively. Brain tumours had the lowest survival rate at 46.4%. A comparison between ethnic groups showed white children to have the highest survival rate (62.8%); the rate for children of mixed racial origin was 53.8% and that for black children 48.5%. CONCLUSIONS: Overall survival rates for children admitted to two paediatric cancer units in South Africa were lower than data published from developed countries, because many children presented with advanced disease. New strategies to improve cancer awareness are urgently required.

Malignancies in South African children with HIV.

OBJECTIVES: In 2008 the South African Children's Cancer Study Group decided to review the epidemiology, management, and chemotherapy response of HIV-positive children with malignancy. METHODS: This is a retrospective analysis of data collected from the records of HIV-positive children diagnosed with malignancy at 7 university-based pediatric oncology units serving 8 of the 9 provinces in South Africa. RESULTS: Two hundred eighty-eight HIV-positive children were diagnosed with 289 malignancies between 1995 and 2009. Age at diagnosis ranged from 17 days to 18.64 years; median 5.79 years. Of the 220 HIV-associated malignancies, there were 97 Kaposi sarcomas, 61 Burkitt lymphomas, 47 other B-cell lymphomas including 2 primary central nervous system lymphomas, 12 Hodgkin lymphomas, and 3 leiomyosarcomas. Sixty-nine patients presented with non-AIDS-defining malignancies. More than 80% presented with advanced disease. Most patients (76.7%) were naive to antiretroviral therapy; 22.2% did not have access because it only became available in public hospitals in 2004. One hundred ninety-seven children were treated with curative intent; 91 received palliative care due to advanced malignancy and/or advanced HIV disease. Nearly one third had coexisting pathology, mostly tuberculosis. Overall survival for the whole group was 33.7%, but was 57.8% for those treated with antiretroviral therapy and chemotherapy. CONCLUSIONS: The study shows more Kaposi sarcoma and fewer primary central nervous system lymphomas among HIV-positive children than that is reported in the developed world, but confirms a higher incidence of non-Burkitt B-cell lymphoma than in HIV-negative children. The high number of non-AIDS-defining malignancies underscores the prevalence of HIV-AIDS in South Africa. The overall survival should improve with universal access to antiretrovirals and earlier diagnosis.

Phenotypic consequences in black South African Fanconi anemia patients homozygous for a founder mutation.

PURPOSE: Fanconi anemia is a genotypically and phenotypically heterogeneous condition, characterized microscopically by chromosomal instability and breakage. Affected individuals manifest growth restriction and congenital physical abnormalities; most progress to hematological disease including bone marrow aplasia. Black South African Fanconi anemia patients share a common causative founder mutation in the Fanconi G gene in 80% of cases (637_643delTACCGCC). The aim of this study was to investigate the genotype-physical phenotype correlation in a cohort of individuals homozygous for this mutation. METHODS: Thirty-five black patients were recruited from tertiary level hematology/oncology clinics in South Africa. Participants were subjected to a comprehensive clinical examination, documenting growth, congenital anomalies, and phenotypic variability. RESULTS: Descriptive statistical analysis showed significant growth abnormalities in many patients and a high frequency (97%) of skin pigmentary anomalies. Subtle anomalies of the eyes, ears, and hands occurred frequently (≥70%). Apart from malformations of the kidney (in 37%) and gastrointestinal tract (in 8.5%), congenital anomalies of other systems including the cardiovascular and central nervous systems, genitalia, and vertebrae were infrequent (<5%). CONCLUSION: The diagnosis of Fanconi anemia in black South African patients before the onset of hematological symptoms remains a clinical challenge, with the physical phenotype unlikely to be recognized by those without dysmorphology expertise.

Children with cancer and HIV infection: what is different about them?

BACKGROUND: Children with HIV and cancer show an excess of non-Hodgkin lymphoma and leiomyosarcoma when compared with children with malignancy but without HIV. This study aimed at: (1) comparing the distribution of various cancers in South African children with malignancies and HIV versus children with malignancies but without HIV and (2) comparing the outcomes after therapy. PROCEDURE: This is a retrospective comparative study of 84 black children with cancer and HIV, consecutively admitted at Tygerberg Children's Hospital, Cape Town and Universitas Hospital, Bloemfontein, between 1995 and 2010, compared with 570 HIV-negative black children with malignant diseases, consecutively admitted at the 2 hospitals, between 2002 and 2010. Variables studied included age, sex ratio, number of cases of each malignancy, length of follow-up, treatment abandonment, and mortality. The statistical significance was tested with the Student t test and χ test for P≤0.05. Kaplan-Meyer survival curves were constructed. RESULTS: The most frequent cancer was Kaposi sarcoma (39.3%), seen exclusively in children with HIV. Burkitt lymphoma was found more often (20.2%) in the HIV-positive group than in the HIV-negative one (2.8%, P<0.0001). Leiomyosarcoma, described as the second most frequent neoplasm encountered in HIV-positive children, was found in this series only once. The survival figures are much worse in the HIV-positive group: 26.2% versus 47.7% (P<0.0001), mainly due to drug toxicity. CONCLUSIONS: Kaposi sarcoma and Burkitt lymphoma occurred more often in children with HIV. These children have a lower tolerance of chemotherapy, even when combined with HAART.

The South African Paediatric Tumour Registry - 25 years of activity.

The South African Children's Tumour Registry was established 25 years ago as it was essential to collect data on malignant disease in the paediatric population that can be used for statistical research in an efficient and sustainable way. The Registry is a useful and significant repository of specific paediatric data, along with the recently revitalised National Cancer Registry, to serve the needs of the cancer research community.

Kaposi sarcoma in South African children.

BACKGROUND: The incidence of Kaposi's sarcoma (KS) in sub-Saharan Africa, increased tens of times since the onset of the AIDS epidemic. There is, however, very little literature concerning the clinical features of this disease, its management and outcome in HIV-positive children in Africa. This study describes retrospectively the clinical presentation of the malignancy, its management and outcome, in a series of HIV-positive children. PATIENTS AND METHODS: Seventy children with KS and HIV infection were admitted consecutively from January 1998 to December 2009 in South African hospitals. Clinical data were extracted from tumor registries and patient records and analyzed. RESULTS: The average age in this series was 73 months. The males/females ratio was 1.59:1. Skin lesions were present in 36 out of 63 cases (57.14%), followed by lymph node lesions (28 cases, 44.44%). The mean CD4+ lymphocyte count was 440 (SD = 385). The average CD4+ percentage was 12.20% (SD = 9.13). Only 14 patients (20%) were taking combined antiretrovirals at the time of diagnosis; a further 35 were given HIV treatment after diagnosis. Thirty-two patients (45.71%) survived only 4 months on average; 10 were lost to follow-up; and 28 (40%) were alive, with an average follow-up of 16 months. Antiretrovirals improved survival (P = 0.001). CONCLUSIONS: The often present skin lesions facilitated the diagnosis; lymphadenopathy was less frequently seen than skin lesions. Antiretroviral drugs were associated with higher survival rate. The mortality remains high in spite of antiretrovirals and cytostatics.

Infection with human immunodeficiency virus-1 (HIV) among children with cancer in South Africa.

UNLABELLED: BACKGROUND IN ADULTS,: HIV increases the risk of certain cancers known, or thought, to have an underlying infectious etiology; the impact on the risk of cancer in children is less clear. METHODS: Here, we report results of an on-going study at four pediatric oncology centers in South Africa in which children diagnosed with cancer are tested routinely for HIV. Odds ratios (OR) for the prevalence of various malignancies were calculated (with adjustment for age, sex, and center) for the children infected with HIV using all children with cancer and non-malignant conditions, but not infected with HIV, as a comparison group. RESULTS: Of 882 children with cancer, 38 were HIV infected (for 12 the HIV status was unknown). HIV was associated with Kaposi sarcoma (all 10 cases were HIV infected; P < 0.001) and with Burkitt lymphoma (OR = 46.2, 95% confidence interval (CI) 16.4-130.3; 13/33). For non-Burkitt non-Hodgkin lymphoma (NHL), 2/39 were HIV infected (OR = 5.0, 95% CI 0.9-27.0). No other cancer type was significantly associated with HIV, including lymphoid leukemias (OR = 0.4, 95% CI 0.04-2.9; 1/172). CONCLUSIONS: Only Kaposi sarcoma and Burkitt lymphoma were significantly associated with HIV infection although results for non-Burkitt NHL were suggestive. Notably, we did not identify an association between infection with HIV and lymphoid leukemias, for which an underlying infectious etiology has been suggested.

How much does it cost to treat children with Hodgkin lymphoma in Africa?

Hodgkin lymphoma (HL) is a common B-cell childhood neoplasm and it has a higher incidence in the 0-14 year age group in developing countries compared to developed countries. Treatment achieves a cure rate of about 80%. In African countries with a small gross domestic product per capita the cost of treating HL in children may be prohibitive. To determine the direct costs of treatment of HL in South Africa and to propose a more cost-effective approach to investigation and treatment for children diagnosed with HL in Africa, tumor registry data for 138 children with HL from two South African hospitals were analysed retrospectively. The cost of treatment for stage 2 disease was calculated, including investigations and chemotherapy. The analysis included the cost of a follow-up period of 2 years. Stage 2 was the most common stage seen, and ABVD protocol was the most common protocol used. The total cost of diagnosing, staging, treating with chemotherapy and following up a child with stage 2 HL for 2 years post-therapy was ZAR 53178.20 = USD 6647.27 = EUR 4431.51. Follow-up expenditure was much higher than initial chemotherapy costs. The major factors driving the cost for the whole group of 138 patients were as follows: stage, radiologic imaging, radiotherapy, second-line chemotherapy, hospitalisation and febrile neutropenia. The total cost of treatment of HL is affordable for first world countries, but it remains expensive for developing countries, especially in Africa where the GDP is often under USD 2000 per head. Early diagnosis, use of less toxic protocols such as ABVD, close monitoring to prevent complications and elimination of unnecessary tests and investigations may reduce the overall cost.

Ethnicity and characteristics of Hodgkin lymphoma in children.

AIM: To identify ethnic group differences in the prognostic of Hodgkin lymphoma (HL) in South African children. PATIENTS AND METHODS: In order to create a larger database, cases were pooled from two South African hospitals: Tygerberg in the Western Cape and Bloemfontein Academic Complex in Free State. Self-assigned ethnicity was used to allocate the children to the following groups: black, white, and colored (historical descendants of couples of distinct ethnicity, the "Cape colored" are the largest population group in Western Cape). Retrospective data over 21 years were obtained from the tumor registry. Age at presentation, sex, ethnic group, stage, histological type, treatment protocol, event-free survival interval, and mortality were analyzed. The statistical significance of the findings was tested using the chi-square, Mann-Whitney U, and Kruskal-Wallis tests, as indicated. RESULTS: The study population of 138 comprised 78 black (56.5%), 38 colored (27.5%), and 22 white (16%) children under 15 years of age. There was a 3:1 predominance of the male gender. The median age at diagnosis was 8 years 11 months. Black patients presented at the youngest age (median 103 months), whereas white patients were the oldest at presentation (median age 133 months; P = 0.04).Forty-five percent of all patients were seen in stage 2. Black and colored patients presented with significantly more advanced stage disease (P = 0.04) than whites. B symptoms were evenly distributed among ethnic groups; they increased the mortality ratio from 10% to 33% (P = 0.0019). Histologically, mixed cellularity was seen in 50% of the black children, while nodular sclerosis was found in 50% of whites. The overall survival rate is 79%, with 68% in whites, 84% in patients of mixed ethnicity, and 79% in blacks (P = 0.35). CONCLUSIONS: White children had the worst HL prognosis in this series, in spite of a less advanced stage at presentation.

Hepatocellular carcinoma and liver tumors in South African children: a case for increased prevalence.

BACKGROUND: The high regional incidence of hepatocellular carcinoma (HCC) in South Africa also may be present in children of the region, although the link to hepatitis B (HBV) appears less clear. The objective of this study was to assess the incidence and probable causes of HCC in South African children. METHODS: Data were obtained from seven participating pediatric oncology units and from the tumor registry to review hepatic tumors in children in South Africa. RESULTS: One hundred ninety-four children (ages 0-14 years) presented with malignant primary hepatic tumors (1988-2003). One hundred twelve tumors (57%) were hepatoblastoma (HB), 68 tumors (35%) were hepatocellular carcinoma (HCC) (including 9 patients with the fibrolamellar variant, 6 of which occurred in black children), 10 tumors (5%) were sarcoma of the liver, and 4 tumors were lymphoma. The ratio of HB to HCC (1.67) was markedly lower compared with other reports, suggesting a greater prevalence of HCC. Correlation with population statistics indicated an incidence of 1.066 malignant liver tumors per year per 10(6) children age < 14 years (HB, 0.61 per 10(6) children; HCC, 0.39 per 10(6)). Two-thirds of patients with HCC were positive for HBV surface antigen (HBsAg), and HCC occurred mostly in black African patients (93%). The mean age of onset was 1.47 years for HB and 10.48 years for HCC. A preponderance of males (3.5:1.0) was noted in the HBsAg-positive group that was not reflected elsewhere. Serum alpha-fetoprotein (AFP) levels were raised both in patients with HB (100%; most AFP levels were very high) and in patients with HCC (69%), although 15% of patients with HCC had low or normal AFP levels. CONCLUSIONS: It appeared from the current results that HCC is more prevalent among children in South Africa compared with the children in more developed countries, although their rates were lower that the rates noted in adults. A collaborative approach will be required to improve their diagnosis and management.