Cancer and palliative care in COVID-19 and other challenging situations—highlights from the Uganda Cancer Institute—Palliative Care Association of Uganda 3rd Uganda Conference on Cancer and Palliative Care, 23–24 September 2021, held in Kampala, Uganda and virtually.

The 3rd Uganda Conference on Cancer and Palliative Care was held in September 2021 with the theme: cancer and palliative care in COVID-19 and other challenging situations. It was hosted by the Uganda Cancer Institute and the Palliative Care Association of Uganda (UCI-PCAU). The conference was held virtually, with a mix of pre-recorded sessions, plenary sessions being broadcast live on television (TV) by the Uganda Broadcasting Corporation TV, live speakers at the studio and others presenting in real time via Zoom. The conference brought together >350 participants who participated on Zoom, along with those attending in person at the studio and those watching the plenary sessions on TV. At the heart of this joint UCI-PCAU conference was the commitment to not only continue but to improve the provision of cancer care and palliative care within Uganda. Key themes from the conference included: the importance of Universal Health Coverage; the impact of COVID-19 on the provision of cancer and palliative care; that both cancer care and palliative care are available in Uganda; education for all; the importance of working together to provide care and overcome challenges, e.g. through technology; the resilience shown by those working in cancer and palliative care; the grief experienced by so many people who have lost loved ones during the pandemic; the importance of good health seeking behaviour - prevention is better than cure; the challenge of funding; the need for health care equity for marginalised and vulnerable populations and finally we can't wait for the world to stop COVID-19 - COVID-19 is here to stay - we need to find solutions. The last few years have seen significant challenges due to the COVID-19 pandemic; however, despite this, cancer and palliative care service provision has continued. This conference, whilst unique and very different from previous conferences, was a great opportunity to share not only amongst each other, but also to share key messages with the public through the live broadcasting of the plenary sessions of the conference

Eradication of the latent HIV viral reservoir: Targeted disruption of the integrated HIV provirus using engineered meganucleases and quantitation of the latent HIV reservoir using multiplex ddPCR

Thesis (Ph.D.)--University of Washington, 2016-09The major barrier to HIV cure is the establishment of a long-lived latent viral reservoir that is not affected by combination ant-retroviral therapy and is not cleared by the immune system. When HIV positive patients on combination anti-retroviral therapy with undetectable viremia interrupt therapy, viremic rebound occurs within two weeks of discontinuing cART. This viral rebound is due to stochastic reactivation of HIV transcription and replication in the long-lived viral reservoir. HIV cure necessitates eradication of this long-lived reservoir. To eradicate the HIV proviral reservoir, we are using HIV-specific engineered meganucleases. Mutations in essential HIV genes can disrupt the integrated provirus and could prevent reactivation from latency. I demonstrate that engineered meganucleases can introduce mutations in an integrated HIV provirus. The HIV-specific engineered meganucleases also cleave and introduce mutations in genomic off-target sites. We show that a second generation of an HIV-specific meganuclease developed using structure guided protein engineering, has an improved off-target toxicity profile and retains activity at the HIV target site. I further demonstrate that expression of the three prime repair exonuclease-2 (Trex2) in combination with either the meganuclease or fusion megaTALs increases the frequency of mutations at the HIV target site. The compact size of meganucleases and the increasing ease with which they can be redesigned to recognize new DNA sequences makes meganucleases an attractive tool for HIV cure applications. HIV cure also requires precise quantitation of the viral reservoir. Current assays used to measure the HIV viral reservoir are imprecise and tend to either over or underestimate the size of the functional reservoir. In the setting of both structured and analytical treatment interruptions it is critical that the reservoir is measured accurately so that patients do not discontinue cART in the setting of large functional reservoirs. I describe here a multiplex ddPCR assay that can simultaneously detect up to six viral genes in the same reaction. The multiplex ddPCR assay gives an estimate of the completeness of the integrated provirus, which can be used to measure levels of functional integrated HIV provirus. I hypothesize that this multiplex ddPCR assay gives a truer estimate of the size of the functional HIV reservoir

Treatment Delay in Kaposi Sarcoma Patients in Uganda

<p>Abstract</p><p>Background</p><p>Significant delay occurs in initiating cancer treatment worldwide. In Uganda, there has been an increase in HIV/AIDS related malignancies due to the large number of people with HIV/AIDS. One particular cancer that has had a very large increase in prevalence is Kaposi Sarcoma. Despite the availability of chemotherapy for Kaposi Sarcoma at the Uganda Cancer Institute, many patients will present with advanced disease. Most studies on delay in cancer have been done in developed countries and very few have been done in Africa. Even fewer studies have been done in the context of HIV/AIDS and KS where patients are under continuous care. This study sought to establish the causes of treatment delay and describe the pathway to care in KS patients in Uganda.</p><p>Methods</p><p>The study was a cross sectional study carried out at the Uganda Cancer Institute. The study enrolled adult consenting patients that presented to the Uganda Cancer Institute with histologically diagnosed Kaposi Sarcoma. The study used an interviewer-administered survey that comprised questions on demography, socio-economic status as well as different aspects of HIV/AIDS and KS care. The study lasted from July to August 2011.</p><p>Findings</p><p>180 patients were enrolled in the study, and 27% experienced delays in treatment initiation lasting more than 3 months. 44% of the study participants used traditional healers and of these, 33% experienced delays greater than 3 months (P value=0.05) compared to 23% in those that did not use traditional healers. The odds of delay in those who visited traditional healers was 2 times the odds of delay in those who did not use traditional healers (P Value= 0.07). Other factors that were correlated with delay were education status, attendance of HIV care clinics, use of HAART and marriage.</p><p>Discussion</p><p>Treatment delay still remains a significant problem in cancer patients in Uganda despite the increasing knowledge about cancer, and in HIV/AIDS related malignancies, despite the availability of evaluation in HIV care clinics. Some of the factors responsible for treatment delay use of traditional healers, and knowledge of cancer and the potential care, which is available. It is important that we address the lack of knowledge about cancer symptoms in the patients if we are to address treatment delay sufficiently. It is also imperative that we address the challenges in the health care systems that contribute to delay in order to ensure access to diagnostic and treatment services.</p>Thesi

Mobile cancer prevention and early detection outreach in Uganda: Partnering with communities toward bridging the cancer health disparities through “asset‐based community development model”

Abstract Background Communities in low‐income countries are characterized by limited access to cancer prevention and early detection services, even for the commonest types of cancer. Limited resources for cancer control are one of the contributors to cancer health disparities. We explored the feasibility and benefit of conducting outreaches in partnership with local communities using the “asset‐based community development (ABCD)” model. Methods We analyzed the quarterly Uganda cancer institute (UCI) community outreach cancer health education and screening output reported secondary data without individual identifiers from July 2016 to June 2019 to compare the UCI‐hospital‐based and community outreach cancer awareness and screening services based on the ABCD model. Results From July 2016 to June 2019, we worked with 107 local partners and conducted 151 outreaches. Of the total number of people who attended cancer health education sessions, 201 568 (77.9%) were reached through outreaches. Ninety‐two (95%) cancer awareness TVs and radio talk‐shows conducted were sponsored by local partners. Of the total people screened; 22 795 (63.0%) cervical, 22 014 (64.4%) breast, and 4904 (38.7%) prostate screening were reached through community outreach model. The screen‐positive rates were higher in hospital‐based screening except for Prostate screening; cervical, 8.8%, breast, 8.4%, prostate, 7.1% than in outreaches; cervical, 3.2%, breast, 2.2%, prostate, 8.2%. Of the screened positive clients who were eligible for precancer treatment like cryotherapy for treatment of precervical cancer lesions, thousands‐folds monetary value and productive life saved relative to the market cost of cancer treatment and survival rate in Uganda. When the total number of clients screened for cervical, breast, and prostate cancer are subjected to the incremental cost of specific screening, a greater portion (98.7%) of the outreach cost was absorbed through community partnership. Conclusions Outreaching and working in collaboration with communities as partners through asset‐based community development model are feasible and help in cost‐sharing and leverage for scarce resources to promote primary prevention and early detection of cancer. This could contribute to bridging the cancer health disparities in the target populations

T-Cell Receptor Sequencing of Kaposi Sarcoma Tumors to Identify Candidate Tumor-Reactive T Cells

Abstract 60 Background: Development of Kaposi sarcoma (KS) is strongly associated with immune dysfunction in the context of HIV infection, but little is known about T-lymphocyte responses against KS tumor cells or human herpesvirus-8, the viral cause of KS. Increasing evidence suggests that treatment response in KS is attributable in part to an antitumor immune response that is mediated by tumor-infiltrating lymphocytes (TIL). The aim of this work was to identify TIL characteristics that are associated with tumor regression in patients with KS who were treated with antiretroviral therapy and chemotherapy as well as to identify a molecular signature of response. Methods: High-throughput sequencing of the T-cell receptor β chain ( TRB) was used to define the repertoire of T cells that infiltrate up to two pretreatment and two post-treatment KS tumors and matched normal skin obtained from HIV-infected adults with KS who received care at the Uganda Cancer Institute. We compared TRB repertoire in serially collected tumors to identify TRB sequences carried in candidate tumor-reactive T cells. Results: TRB sequencing was performed on KS tumor and matched normal skin samples from 12 HIV-infected adults with KS who collectively demonstrated a range of treatment responses. Unique populations of T cells were identified in pretreatment tumors but not in normal skin in all patients, which suggested the presence of KS-specific T-cell responses. Durable complete response to treatment in one patient was associated with significant expansion of a small number of T-cell clones, one of which carried a TRB sequence that was associated with a public CD8 + Epstein-Barr virus–associated T-cell receptor. Conclusion: Understanding the immune response to KS through cellular and molecular dissection of TIL will provide important insights into KS biology and may ultimately guide new immune-based strategies to stage and treat this often-refractory cancer. Funding: Solid Tumor Translational Research Transformative Team Grant, Fred Hutchinson Cancer Research Center; National Institutes of Health/National Cancer Institute Grant No. K23-CA150931. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST No COIs from the authors

Immunological and biochemical biomarker alterations among SARS-COV-2 patients with varying disease phenotypes in Uganda

Abstract Every novel infection requires an assessment of the host response coupled with identification of unique biomarkers for predicting disease pathogenesis, treatment targets and diagnostic utility. Studies have exposed dysregulated inflammatory response induced by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as significant predictor or cause of disease severity/prognosis and death. This study evaluated inflammatory biomarkers induced by SARS-CoV-2 in plasma of patients with varying disease phenotypes and healthy controls with prognostic or therapeutic potential. We stratified SARS-CoV-2 plasma samples based on disease status (asymptomatic, mild, severe, and healthy controls), as diagnosed by RT-PCR SARS-CoV-2. We used a solid phase sandwich and competitive Enzyme-Linked Immunosorbent Assay (ELISA) to measure levels of panels of immunological (IFN-γ, TNF-α, IL-6, and IL-10) and biochemical markers (Ferritin, Procalcitonin, C-Reactive Protein, Angiotensin II, Homocysteine, and D-dimer). Biomarker levels were compared across SARS-CoV-2 disease stratification. Plasma IFN-γ, TNF-α, IL-6, and IL-10 levels were significantly (P < 0.05) elevated in the severe SARS-CoV-2 patients as compared to mild, asymptomatic, and healthy controls. Ferritin, Homocysteine, and D-dimer plasma levels were significantly elevated in severe cases over asymptomatic and healthy controls. Plasma C-reactive protein and Angiotensin II levels were significantly (P < 0.05) higher in mild than severe cases and healthy controls. Plasma Procalcitonin levels were significantly higher in asymptomatic than in mild, severe cases and healthy controls. Our study demonstrates the role of host inflammatory biomarkers in modulating the pathogenesis of COVID-19. The study proposes a number of potential biomarkers that could be explored as SARS-CoV-2 treatment targets and possible prognostic predictors for a severe outcome. The comprehensive analysis of prognostic biomarkers may contribute to the evidence-based management of COVID-19 patients

The double burden of COVID-19 and cancer at the Uganda Cancer Institute

# Background Cancer is increasingly diagnosed in Africa, with more than one million new diagnoses annually. In Uganda, the Uganda Cancer Institute (UCI) is the primary cancer care facility, with patients travelling long distances to this facility to receive care. During the COVID-19 pandemic, cancer care was disrupted on several levels, including prevention, screening, diagnosis, treatment, and follow-up. National lockdowns impeded patient access to UCI and halted cancer screening. # Methods This study used qualitative interviews to obtain primary data from professionals working at UCI. Interviews were conducted from April 2022 to January 2023. KI (key informants) ’s were purposively selected, identified by colleagues at UCI and recruited through email and WhatsApp messaging. Verbal consent was obtained. Thirty to 60-minute open-ended interviews conducted virtually and in person were audio recorded and transcribed verbatim. Transcripts were coded via MAXQDA software and analyzed to identify themes. # Results Thematic analysis revealed three major challenges to cancer care during COVID-19. First, UCI experienced logistical barriers such as travel restrictions, staff shortages, and insufficient protective gear. Second, staff adapted to the inflexible national lockdown policy for chronic health care with modifications to treatment regimens. Third, KI reported a significant mental health burden and reflected on how care should be improved. # Conclusions As colleagues got infected, UCI staff organized their training, discussed treatment plans with colleagues, and continued to care for patients at personal risk. Resilience characterized UCI’s response to COVID-19. They adapted treatment protocols to their setting, many of which remain the standard of care today. At the same time, there is a need for capacity building tailored to the Ugandan context to provide cancer care effectively in case of another pandemic

Characteristics of Memory B Cells Elicited by a Highly Efficacious HPV Vaccine in Subjects with No Pre-existing Immunity

<div><p>Licensed human papillomavirus (HPV) vaccines provide near complete protection against the types of HPV that most commonly cause anogenital and oropharyngeal cancers (HPV 16 and 18) when administered to individuals naive to these types. These vaccines, like most other prophylactic vaccines, appear to protect by generating antibodies. However, almost nothing is known about the immunological memory that forms following HPV vaccination, which is required for long-term immunity. Here, we have identified and isolated HPV 16-specific memory B cells from female adolescents and young women who received the quadrivalent HPV vaccine in the absence of pre-existing immunity, using fluorescently conjugated HPV 16 pseudoviruses to label antigen receptors on the surface of memory B cells. Antibodies cloned and expressed from these singly sorted HPV 16-pseudovirus labeled memory B cells were predominantly IgG (>IgA>IgM), utilized diverse variable genes, and potently neutralized HPV 16 pseudoviruses <i>in vitro</i> despite possessing only average levels of somatic mutation. These findings suggest that the quadrivalent HPV vaccine provides an excellent model for studying the development of B cell memory; and, in the context of what is known about memory B cells elicited by influenza vaccination/infection, HIV-1 infection, or tetanus toxoid vaccination, indicates that extensive somatic hypermutation is not required to achieve potent vaccine-specific neutralizing antibody responses.</p></div

Coverage and Socioeconomic Inequalities in Cervical Cancer Screening in Low- and Middle-Income Countries Between 2010 and 2019

PURPOSECervical cancer screening is vital in addressing the global burden of cervical cancer. In this study, we describe the coverage and socioeconomic inequalities in the coverage of cervical cancer screening in low- and middle-income countries (LMICs).METHODSWe analyzed data from the women's recode files of the Demographic and Health Surveys conducted in LMICs from 2010 to 2019 with variables on cervical cancer screening. We included women 21 years or older and determined the proportion of women who were screened for cervical cancer by age categories, wealth quintile, type of place of residence, level of education, and marital status. Socioeconomic inequality was measured using the concentration index (CIX) and the slope index of inequality (SII).RESULTSA total of 269,506 women from 20 surveys in 16 countries were included in the survey. Generally, there was a low coverage of screening, with lower rates among women age 21-24 years, living in rural areas, in the poorest wealth quintile, with no formal education, and who have never been in union with or lived with a man. The CIX and SII values for screening for cervical cancer were positive (pro-rich) for all the countries except Tajikistan in 2012 where they were negative (pro-poor).CONCLUSIONThe coverage of cervical cancer screening was low in LMICs with variations by the quintile of wealth (pro-rich) and type of place of residence (pro-urban). To achieve the desired impact of cervical cancer screening services in LMICs, the coverage of cervical cancer screening programs must include women irrespective of the type of place and wealth quintiles