Divergent clinical presentations and outcomes among children and adolescents with Kaposi sarcoma in Malawi and Tanzania.

OBJECTIVES: The Kaposi sarcoma (KS) T0 versus T1 staging classification does not address the unique clinical features of paediatric KS in human gammaherpesvirus 8 (HHV-8) endemic regions of Africa. This study seeks to define patterns of childhood KS using a paediatric-specific approach. METHODS: The Lilongwe paediatric KS staging classification categorizes disease based on clinical phenotype: stage 1 = mild/moderate KS limited to cutaneous/oral involvement, stage 2 = primarily lymphadenopathic disease, stage 3 = woody edema KS, stage 4 = visceral and/or severe/disseminated mucocutaneous disease. Characteristics and outcomes were evaluated from paediatric referral centres in Lilongwe, Malawi, and Mbeya, Tanzania. RESULTS: Among 171 patients, the median age was 9.3 years, 37% (n = 63) were female, and 87% (n = 149) had HIV. Breakdown by stage was as follows: 18% (n = 31) stage 1, 33% (n = 56) stage 2, 19% (n = 33) stage 3, and 30% (n = 51) stage 4. Age (younger stage 2 and older stage 3), severe CD4 count suppression (lower CD4 for stages 1 and 4), and presence of severe anaemia and thrombocytopenia (worse for stages 2 and 4) differed across stages. Estimated 2-year event-free survival/progression-free survival/overall survival by stage was as follows: stage 1, 81%/81%/87%; stage 2, 50%/50%/63%; stage 3, 24%/49%/81%; and stage 4, 29%/34%/54%. Sub-analysis of stage 2 lymphadenopathic KS demonstrated superior long-term 6-year event-free survival of 70% (95% confidence interval [CI] 49-83) for younger children (aged <7 years) versus 27% (95% CI 8-51) for older children. CONCLUSIONS: This paediatric-specific staging classification categorizes patients with distinct characteristics and patterns of treatment response. This platform may guide clinicians to provide risk-stratified treatment with the hope of improving survival among children with KS.

Outcomes of Wilms tumor therapy in Lilongwe, Malawi, 2016-2021: Successes and ongoing research priorities.

INTRODUCTION: Wilms tumor therapy in low- and middle-income countries (LMICs) relies on treatment protocols adapted to resource limitations, but these protocols have rarely been evaluated in real-world settings. Such evaluations are necessary to identify high-impact research priorities for clinical and implementation trials in LMICs. The purpose of this study was to identify highest priority targets for future clinical and implementation trials in sub-Saharan Africa by assessing outcomes of a resource-adapted treatment protocol in Malawi. METHODS: We conducted a retrospective cohort study of children treated for Wilms tumor with an adapted SIOP-backbone protocol in Lilongwe, Malawi between 2016 and 2021. Survival analysis assessed variables associated with poor outcome with high potential for future research and intervention. RESULTS: We identified 136 patients, most commonly with stage III (n = 35; 25.7%) or IV disease (n = 35; 25.7%). Two-year event-free survival (EFS) was 54% for stage I/II, 51% for stage III, and 13% for stage IV. A single patient with stage V disease survived to 1 year. Treatment abandonment occurred in 36 (26.5%) patients. Radiotherapy was indicated for 55 (40.4%), among whom three received it. Of these 55 patients, 2-year EFS was 31%. Of 14 patients with persistent metastatic pulmonary disease at the time of nephrectomy, none survived to 2 years. Notable variables independently associated with survival were severe acute malnutrition (hazard ratio [HR]: 1.9), increasing tumor stage (HR: 1.5), and vena cava involvement (HR: 3.1). CONCLUSION: High-impact targets for clinical and implementation trials in low-resource settings include treatment abandonment, late presentation, and approaches optimized for healthcare systems with persistently unavailable radiotherapy.

Evasion of opsonization of macromolecules using novel surface-modification and biological-camouflage-mediated techniques for next-generation drug delivery.

Opsonization plays a pivotal role in hindering controlled drug release from nanoformulations due to macrophage-mediated nanoparticle destruction. While first and second-generation delivery systems, such as lipoplexes (50-150 nm) and quantum dots, hold immense potential in revolutionizing disease treatment through spatiotemporal controlled drug delivery, their therapeutic efficacy is restricted by the selective labeling of nanoparticles for uptake by reticuloendothelial system and mononuclear phagocyte system via various molecular forces, such as electrostatic, hydrophobic, and van der Waals bonds. This review article presents novel insights into surface-modification techniques utilizing macromolecule-mediated approaches, including PEGylation, di-block copolymerization, and multi-block polymerization. These techniques induce stealth properties by generating steric forces to repel micromolecular-opsonins, such as fibrinogen, thereby mitigating opsonization effects. Moreover, advanced biological methods, like cellular hitchhiking and dysopsonic protein adsorption, are highlighted for their potential to induce biological camouflage by adsorbing onto the nanoparticulate surface, leading to immune escape. These significant findings pave the way for the development of long-circulating next-generation nanoplatforms capable of delivering superior therapy to patients. Future integration of artificial intelligence-based algorithms, integrated with nanoparticle properties such as shape, size, and surface chemistry, can aid in elucidating nanoparticulate-surface morphology and predicting interactions with the immune system, providing valuable insights into the probable path of opsonization.

Long-term outcomes for children and adolescents with Kaposi sarcoma.

OBJECTIVES: Kaposi sarcoma (KS) is one of the most common childhood cancers in eastern and central Africa. It has become a treatable disease with increasing availability of antiretroviral therapy (ART) and chemotherapy. We aimed to fill the data gap in establishing whether long-term survival is achievable for children in low-income countries. METHODS: We retrospectively analysed data for children and adolescents aged ≤ 18.9 years diagnosed with HIV-related or endemic KS from 2006 to 2015 who received standardized institutional treatment regimens utilizing chemotherapy plus ART (if HIV-positive) at a tertiary care public hospital in Lilongwe, Malawi. Long-term survival was analysed and mortality was associated with KS for those with refractory/progressive disease at the time of death. RESULTS: There were 207 children/adolescents with KS (90.8% HIV-related); 36.7% were alive, 54.6% had died, and 8.7% had been lost to follow-up. The median follow-up time for survivors was 6.9 years (range 4.2-13.9 years). Death occurred at a median of 5.3 months after KS diagnosis (range 0.1-123 months). KS progression was associated with mortality for most (61%) early deaths (survival time of < 6 months); conversely, KS was associated with a minority (31%) of late-onset deaths (after 24 months). The 7-year overall survival was 37% [95% confidence interval (CI) 30-44%] and was higher for those diagnosed between 2011 and 2015 compared to 2006-2010: 42% (95% CI 33-51%) versus 29% (95% CI 20-39%), respectively (P = 0.01). Among the 66 HIV-positive survivors, 58% were still on first-line ART. CONCLUSIONS: Long-term survival is possible for pediatric KS in low-resource settings. Despite better survival in more recent years, there remains room for improvement.

The Burden of Malnutrition in Childhood Cancer in Malawi - Risk Regardless of Age.

Malnutrion among children with childhood cancer in low and middle income countries (LMICs) is prevelant. While national nutrition programs focus on children under 5 years, childhood cancer can occur regardless of their age. Through a single-center retrospective cohort in Lilongwe, Malawi, we aim to characterize the burden of age-related malnutrition among children diagnosed with cancer in Lilongwe, Malawi, and evaluate them for any associations with mortality. Four hundred and sixty-three children (63.5% ≥5 years and 58.3% males) were identified.The majority of children (63.3%) were malnourished; 23.1% had moderate acute malnutrition (MAM) and 40.2% had severe acute malnutrition (SAM). Malnutrition was more common in children ≥5 years (70.0%) compared to children <5 years (51.8%); p < 0.0001. Age <5 years (HR 1.6; 95%CI 1.1-2.3, p = 0.016) and presence of sever acute malnutrition (HR 1.6, 95%CI 1.1-2.3, p = 0.012) were both associated with increased mortality risk. Acute malnutrition was highly prevalent among children with cancer above 5 years of age. This age group is not prioritized among malnutrition programs in LMICs, hence there is a direct need to include children with cancer regardless of age in national nutrition guidelines in LMICs to give them acces to adequate nutritional support.

Factors influencing diagnostic delays of pediatric cancers in Botswana.

BACKGROUND: A major barrier in improving cancer outcomes in Botswana and other low- and middle-income countries is timely access to care. Understanding time to diagnosis of pediatric cancers in Botswana and evaluating factors contributing to delays was necessary to inform interventions. METHODS: A retrospective cohort study of children diagnosed with cancer at Princess Marina Hospital from 2008 to 2015 was performed utilizing the Botswana Pediatric Oncology Database. The time to diagnosis, pretreatment center delay, and pathology turnaround time were calculated. Time to diagnosis was analyzed using univariate and multivariate analyses to determine association with age, sex, distance to a treatment center, HIV status, cancer type, outcome, and presence of metastasis at diagnosis. RESULTS: The median time to diagnosis was 10.7 weeks, median pretreatment center delay was 9.6 weeks, and median pathology turnaround time was 3 weeks. Longer time to diagnosis was significantly correlated with presence of metastasis at diagnosis. Age, sex, distance to a treatment center, HIV status, cancer type, and outcome were not significantly associated with diagnostic delay. CONCLUSION: Children with cancer in Botswana have more than three months of symptoms prior to diagnosis, which is associated with metastasis at diagnosis. Efforts should be made to empower and promote awareness of pediatric cancer symptoms among caregivers and community healthcare providers in order to shorten time to presentation at a treatment center.

Infantile Pyknocytosis: An Uncommon Cause of Newborn Hemolytic Anemia.

Infantile pyknocytosis is a rare cause of neonatal hemolytic anemia, which presents in the first few weeks of life. We report a classic case of infantile pyknocytosis that presented to our institution with rebound hyperbilirubinemia after receiving phototherapy. The infant was found to have a hemoglobin of 5.8 g/dL, requiring a total of 15 mL/kg of red blood cells (in 2 separate transfusions) before discharge. The diagnosis was ultimately made by a review of the peripheral blood smear. We review the literature and suggest pediatricians consider infantile pyknocytosis on their differential when hemolytic anemia presents in the newborn period.

Kaposi Sarcoma Herpesvirus Inflammatory Cytokine Syndrome-like Clinical Presentation in Human Immunodeficiency Virus-infected Children in Malawi.

We describe 7 human immunodeficiency virus-infected Malawian children with Kaposi sarcoma who met criteria for Kaposi sarcoma herpesvirus (KSHV) inflammatory cytokine syndrome. Each presented with persistent fevers, bulky lymphadenopathy, massive hepatosplenomegaly, and severe cytopenias. Plasma analyses were performed in 2 patients, both demonstrating extreme elevations of KSHV viral load and interleukin 6.

KSHV viral load and Interleukin-6 in HIV-associated pediatric Kaposi sarcoma-Exploring the role of lytic activation in driving the unique clinical features seen in endemic regions.

Kaposi sarcoma (KS) is among the most common childhood malignancies in central, eastern, and southern Africa. Although its unique clinical features have been established, biological mechanisms related to the causative agent, KS-associated herpes-virus (KSHV), have yet to be explored in children. We performed a prospective observational pilot study to explore associations between KSHV viral load (VL), human interleukin-6 (IL-6) and IL-10 levels, and clinical characteristics of 25 children with KS in Lilongwe, Malawi from June 2013-August 2015. The median age was 6.4 years. Lymphadenopathy was the most common site of KS involvement (64%), followed by skin and oral mucosa (44% each), woody edema (12%), and pulmonary (8%). Baseline samples for plasma KSHV VL, IL-6 and IL-10 analyses were available for 18/25 patients (72%) at time of KS diagnosis. KSHV VL was detectable at baseline in 12/18 (67%) patients, the median baseline IL-6 level was 8.53 pg/mL (range 4.31-28.33), and the median baseline IL-10 level was 19.53 pg/mL (range 6.91-419.69). Seven (39%) patients presented with an IL-6 level > 10 pg/mL (exceeding twice the upper limit of normal). Detectable KSHV VL was significantly associated with lymphadenopathic KS (p = 0.004), while having undetectable KSHV VL was associated with a higher likelihood of presenting with hyperpigmented skin lesions (p = 0.01). Detectable KSHV VL and elevated IL-6 levels are present in a subset of children with KS. Lytic activation of KSHV and associated elevation in KSHV VL may contribute to the unique clinical manifestations of pediatric KS in KSHV-endemic regions of Africa.

Identifying opportunities to bridge disparity gaps in curing childhood cancer in Malawi: Malignancies with excellent curative potential account for the majority of diagnoses.

The majority of African children with cancer die without access to resources. We describe efforts to build a public treatment program with curative intent for childhood cancer in Lilongwe, Malawi despite severe limitations in diagnostic and therapeutic resources. We retrospectively analyzed a cohort of childhood cancer patients at Kamuzu Central Hospital from 12/2011-6/2013. Consistently available chemotherapeutic agents were limited to cyclophosphamide, vincristine, doxorubicin, bleomycin, methotrexate, and prednisone. Of 258 newly diagnosed childhood malignancies, 17 patients with retinoblastoma were excluded from clinical analyses due to insufficient clinical data. Among the remainder of the cohort (n = 241), 42% were female with median age 8.4 years (range 0.6-17.9). Forty-six (19%) were HIV-infected (42 Kaposi sarcoma, 3 Burkitt lymphoma, 1 Hodgkin lymphoma). The most common clinical presentations were palpable abdominal mass (41%), peripheral lymphadenopathy (33%), and jaw mass (17%). Nearly two-thirds of total diagnoses were accounted for by Burkitt lymphoma (n = 74), Kaposi sarcoma (n = 52), Hodgkin lymphoma (n = 21), and Wilms tumor (n = 19). Twelve-month overall survival for these 4 most common diagnoses was 54% (95% confidence interval 46-61) versus 19% (95% confidence interval 11-30) for all other diagnoses (median follow-up 19 months). Treatment-related mortality was highest in patients with non-Wilms solid tumors of the abdomen (48% versus 10% for the overall cohort, p < 0.001), while treatment abandonment was highest in patients with bone and soft-tissue sarcomas (29% versus 14% overall, p = 0.05). Childhood cancers with excellent curative potential accounted for the majority of patients, establishing an opportunity to build treatment programs with curative intent despite severe limitations.

Mapping the Epidemiology of Kaposi Sarcoma and Non-Hodgkin Lymphoma Among Children in Sub-Saharan Africa: A Review.

Children with human immunodeficiency virus (HIV) have an increased risk of developing Kaposi Sarcoma (KS) and non-Hodgkin lymphoma (NHL) compared to HIV-negative children. We compiled currently published epidemiologic data on KS and NHL among children in sub-Saharan Africa (SSA). Among countries with available data, the median incidence of KS was 2.05/100,000 in the general pediatric population and 67.35/100,000 among HIV-infected children. The median incidence of NHL was 1.98/100,000 among the general pediatric population, while data on NHL incidence among HIV-infected children were lacking. Larger regional studies are needed to better address the dearth of epidemiologic information on pediatric KS and NHL in SSA.

Profound Vitamin B12 Deficiency in a 1-Year-Old Child in Botswana: A Call to Initiate Early Empiric Therapy.

Vitamin B12 deficiency is a rare diagnosis in young children. We present the case of a 1-year-old Zimbabwean child with profound anemia. Further testing revealed undetectable levels of vitamin B12 and positive intrinsic factor antibodies that were drawn after the initiation of empiric treatment with parenteral vitamin B12. We report the evaluation and management of vitamin B12 deficiency in a resource-limited setting. Vitamin B12 deficiency should be considered in children presenting with unexplained cytopenias with consideration of empiric treatment with parenteral vitamin B12, as developmental and neurological complications of vitamin B12 deficiency can be devastating and permanent.

ACR Appropriateness Criteria® Sepsis.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. A search for the underlying cause of infection typically includes radiological imaging as part of this investigation. This document focuses on thoracic and abdominopelvic causes of sepsis. In 2017, the global incidence of sepsis was estimated to be 48.9 million cases, with 11 million sepsis-related deaths (accounting for nearly 20% of all global deaths); therefore, understanding which imaging modalities and types of studies are acceptable or not acceptable is imperative. The 5 variants provided include the most commonly encountered scenarios in the setting of sepsis along with recommendations and data for each imaging study. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Essential medicines for pediatric oncology in developing countries.

The burden of cancer in children in low and middle income countries (LMICs) is substantial, comprising at least 80% of incident cases globally, and an even higher proportion of cancer-related deaths. With survival rates exceeding 80% in high income countries, it is imperative to transfer these successes to LMICs. A major challenge is the poor availability of safe, cost-effective chemotherapy. A list of 51 drugs-chemotherapeutics, infectious disease agents, and supportive care medications-is proposed as essential to improving the survival of children with cancer in LMICs with an additional 13 drugs identified as being of further value.

Clinical characteristics and outcomes of HIV-infected children diagnosed with Kaposi sarcoma in Malawi and Botswana.

BACKGROUND: Kaposi sarcoma (KS) is the most common HIV-associated malignancy in sub-Saharan Africa. The presentation and outcomes of pediatric KS are not well understood. PROCEDURE: We performed a retrospective cohort analysis of 81 HIV-infected children with KS at the Baylor Children's Clinical Centres of Excellence in Malawi and Botswana from March 2003 to October 2009. RESULTS: Eighty-one children with KS were identified whose median age was 8.0 (inter-quartile range 5.1-11.3) years. KS lesions were presented primarily on the skin (83%), lymph nodes (52%), and oral mucosa (41%). Occasionally disease was limited to the lymph nodes only (10%). Severe immunosuppression (70%), anemia (29%), and thrombocytopenia (17%) were common laboratory findings. Highly active antiretroviral therapy (HAART) was administered to 94% of children, including 77% who received HAART plus chemotherapy. KS immune reconstitution inflammatory syndrome (IRIS) occurred in 22%. Disease status 12 months after KS diagnosis was determined for 69 children: 43% were alive and 57% had died. Severe immunosuppression was independently associated with mortality in multivariate analysis (OR = 4.3; 95% CI 1.3-14.6; P = 0.02). CONCLUSION: KS occurs in a significant number of HIV infected children in sub-Saharan Africa. Pediatric KS is distinct from KS in adults. Lymph node involvement was a common manifestation of KS in children, and severe immunosuppression was associated with the highest mortality risk. Though overall mortality was high in children with KS, patients did achieve clinical remission in settings with limited diagnostic and therapeutic resources.

Dual role of autophagy for advancements from conventional to new delivery systems in cancer.

Autophagy, a programmed cell-lysis mechanism, holds significant promise in the prevention and treatment of a wide range of conditions, including cancer, Alzheimer's, and Parkinson's disease. The successful utilization of autophagy modulation for therapeutic purposes hinges upon accurately determining the role of autophagy in disease progression, whether it acts as a cytotoxic or cytoprotective factor. This critical knowledge empowers scientists to effectively manipulate tumor sensitivity to anti-cancer therapies through autophagy modulation, while also circumventing drug resistance. However, conventional therapies face limitations such as low bioavailability, poor solubility, and a lack of controlled release mechanisms, hindering their clinical applicability. In this regard, innovative nanoplatforms including organic and inorganic systems have emerged as promising solutions to offer stimuli-responsive, theranostic-controlled drug delivery systems with active targeting and improved solubility. The review article explores a variety of organic nanoplatforms, such as lipid-based, polymer-based, and DNA-based systems, which incorporate autophagy-inhibiting drugs like hydroxychloroquine. By inhibiting the glycolytic pathway and depriving cells of essential nutrients, these platforms exhibit tumor-suppressive effects in advanced forms of cancer such as leukemia, colon cancer, and glioblastoma. Furthermore, metal-based, metal-oxide-based, silica-based, and quantum dot-based nanoplatforms selectively induce autophagy in tumors, leading to extensive cancer cell destruction. Additionally, this article discusses the current clinical status of autophagy-modulating drugs for cancer therapy with valuable insights of progress and potential of such approaches.

Pediatric HIV+ Kaposi sarcoma exhibits clinical, virological, and molecular features different from the adult disease.

BACKGROUNDKaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown.METHODSThis was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were characterized for viral and human transcription, and KSHV genomes were determined when possible.RESULTSSeventy participants with pediatric KS were enrolled between June 2013 and August 2019 in Malawi and compared with adult patients with KS. They exhibited high KSHV genome copy numbers and IL-6/IL-10 levels. Four biopsies (16%) had a viral transcription pattern consistent with lytic viral replication.CONCLUSIONThe unique features of pediatric KS may contribute to the specific clinical manifestations and may direct future treatment options.FUNDINGUS National Institutes of Health U54-CA-254569, PO1-CA019014, U54-CA254564, RO1-CA23958.

Numerical Simulation of Stresses in Functionally Graded HCS-MgO Cylinder Using Iterative Technique and Finite Element Method.

In this study, a thick hollow axisymmetric functionally graded (FG) cylinder is investigated for steady-state elastic stresses using an iteration technique and the finite element method. Here, we have considered a functionally graded cylinder tailored with the material property, namely, Young's modulus, varying in an exponential form from the inner to outer radius of the cylinder. A mathematical formulation for stress analysis of functionally graded cylinder under internal and external pressure conditions is developed using constitutive relations for stress-strain, strain-displacement relations and the equation of equilibrium. The effect of the in-homogeneity parameter on radial displacement, radial and tangential stresses in a functionally graded cylinder made up of a High Carbon Steel (HCS) metal matrix, reinforced with Magnesium Oxide (MgO) ceramic is analyzed. The iterative method implemented is fast and converges to the solution which can be further improved by considering a higher number of iterations. This is depicted graphically by using radial displacement and stresses in a pressurized functionally graded cylinder obtained for the first two iterations. An iterative solution for non-FGM (or homogeneous material) is validated using the finite element method. The mechanical responses of the functionally graded cylinder obtained from the iterative method and the finite element method are then compared and found to be in good agreement. Results are presented in graphical and tabular form along with their interpretations.