Groesbeck P. Parham

Interleukin-10 Increases Th1 Cytokine Production and Cytotoxic Potential in Human Papillomavirus-Specific CD8+ Cytotoxic T Lymphocytes

Interleukin-10 (IL-10) is widely known as an immunosuppressive cytokine by virtue of its ability to inhibit macrophage-dependent antigen presentation, T-cell proliferation, and Th1 cytokine secretion. However, several studies have challenged the perception of IL-10 solely as an immunosuppressive cytokine. As part of an investigation on potentiation of the cytotoxic activity of human papillomavirus E7-specific CD8(+) cytotoxic T lymphocytes (CTL) for adoptive transfusions to cervical cancer patients, we found that IL-10 in combination with IL-2, unlike several other combinations, including IL-2 with IL-12, gamma interferon (IFN-gamma), tumor necrosis factor alpha, and transforming growth factor beta, was able to consistently increase cytotoxicity. This augmentation in cytotoxic activity correlated with a significant increase in the cytoplasmic accumulation of perforin as detected by fluorescence-activated cell sorter. Surface expression of both the alpha and beta chains of the CD8 heterodimeric coreceptor and CD56 molecules was increased by exposure of CTL to IL-10. More importantly, we found that administration of IL-10 in combination with IL-2 after antigen stimulation consistently increased the intracellular expression of Th1 cytokines (i.e., IFN-gamma and IL-2) compared to results for control CD8(+) T cells cultured in IL-2 alone. In kinetic studies, proliferation, intracellular perforin levels, cytotoxic activity, and IFN-gamma expression were consistently elevated in CTL cultures containing IL-10 compared to control cultures, both at early and late time points following stimulation. In contrast, intracellular IL-2 expression was consistently increased only at early time points following stimulation with autologous tumor cells or solid-phase anti-CD3 antibody. Taken together, these data support the use of IL-10 in combination with IL-2 for the in vitro expansion and potentiation of tumor-specific CTL for clinical use in the therapy of cancer.

The disparity of cervical cancer in diverse populations

Significant disparities in cervical cancer incidence and mortality rates among minority groups have been documented in the United States, despite an overall decline in these rates for the population as a whole. Differences in cervical cancer screening practices have been suggested as an explanation for these disparities, as have differences in treatment among various racial and ethnic groups. A number of factors are attributed to these observed differences. As minority populations continue to grow in size over the next 50 years, persistent disparities will place an ever increasing burden on these populations and on the national healthcare system. Strategies to reduce cervical cancer disparities need to be employed in order to reverse these trends.

Prevalence and distribution of HPV genotypes among HIV-infected women in Zambia.

We screened 145 HIV-infected non-pregnant women at a tertiary care centre in Lusaka, Zambia. Liquid-based cytology and human papillomavirus (HPV) genotyping with PGMY09/11 biotinylated primers (Roche Linear Array® HPV genotyping test) maximised sensitivity of cytology and HPV assessments. Among high-risk (HR) types, HPV 52 (37.2%), 58 (24.1%) and 53 (20.7%) were more common overall than HPV 16 (17.2%) and 18 (13.1%) in women with high-grade squamous intraepithelial lesions or squamous cell carcinoma (SCC) on cytology. High-risk HPV types were more likely to be present in women with CD4+ cell counts <200 μ l−1 (odds ratios (OR): 4.9, 95% confidence intervals (CI): 1.4–16.7, P=0.01) and in women with high-grade or severe cervical cytological abnormalities (OR: 8.0, 95% CI: 1.7–37.4, P=0.008). Human papillomavirus diversity in high-grade lesions and SCC on cytology suggests that HPV 16- and 18-based vaccines may not be adequately polyvalent to induce protective immunity in this population.

Global cancer surgery: delivering safe, affordable, and timely cancer surgery

Surgery is essential for global cancer care in all resource settings. Of the 15.2 million new cases of cancer in 2015, over 80% of cases will need surgery, some several times. By 2030, we estimate that annually 45 million surgical procedures will be needed worldwide. Yet, less than 25% of patients with cancer worldwide actually get safe, affordable, or timely surgery. This Commission on global cancer surgery, building on Global Surgery 2030, has examined the state of global cancer surgery through an analysis of the burden of surgical disease and breadth of cancer surgery, economics and financing, factors for strengthening surgical systems for cancer with multiple-country studies, the research agenda, and the political factors that frame policy making in this area. We found wide equity and economic gaps in global cancer surgery. Many patients throughout the world do not have access to cancer surgery, and the failure to train more cancer surgeons and strengthen systems could result in as much as US

Implementation of 'see-and-treat' cervical cancer prevention services linked to HIV care in Zambia.

6.2 trillion in lost cumulative gross domestic product by 2030. Many of the key adjunct treatment modalities for cancer surgery--e.g., pathology and imaging--are also inadequate. Our analysis identified substantial issues, but also highlights solutions and innovations. Issues of access, a paucity of investment in public surgical systems, low investment in research, and training and education gaps are remarkably widespread. Solutions include better regulated public systems, international partnerships, super-centralisation of surgical services, novel surgical clinical trials, and new approaches to improve quality and scale up cancer surgical systems through education and training. Our key messages are directed at many global stakeholders, but the central message is that to deliver safe, affordable, and timely cancer surgery to all, surgery must be at the heart of global and national cancer control planning.

Advancing Cervical Cancer Prevention Initiatives in Resource-Constrained Settings: Insights from the Cervical Cancer Prevention Program in Zambia

Greater than 80% of the worlds new cases and deaths due to cervical cancer occur in the developing world [1]. No more than 5% of women in these settings are screened for cervical cancer even once in their lifetimes [2]. Earlier attempts to establish population-based cervical cancer prevention programs using cytology screening in resource-limited settings have inevitably fallen short or failed [3–5]. Although many of the reasons for failure can be attributed to lack of resources and trained manpower, the multiple visit requirements of cytology-based screening programs jeopardizes success and sustainability.

Vaccination with HPV-18 E7–Pulsed Dendritic Cells in a Patient with Metastatic Cervical Cancer

Groesbeck Parham and colleagues describe their Cervical Cancer Prevention Program in Zambia, which has provided services to over 58,000 women over the past five years, and share lessons learned from the programs implementation and integration with existing HIV/AIDS programs.

The National Cancer Data Base Report on Endometrial Carcinoma in African-American Women

To the Editor: The management of disseminated carcinoma of the cervix that is no longer amenable to control with surgery or radiation therapy has not improved significantly with the advent of moder...

The global burden of women's cancers: a grand challenge in global health.

Although the incidence of uterine carcinoma is lower among African‐American women compared with white women, the mortality rates are higher for African‐American patients. This report is part of an ongoing series on gynecologic malignancies in African‐American women.

Effects of concurrent cisplatinum administration during radiotherapy vs. radiotherapy alone on the immune function of patients with cancer of the uterine cervix

Every year, more than 2 million women worldwide are diagnosed with breast or cervical cancer, yet where a woman lives, her socioeconomic status, and agency largely determines whether she will develop one of these cancers and will ultimately survive. In regions with scarce resources, fragile or fragmented health systems, cancer contributes to the cycle of poverty. Proven and cost-effective interventions are available for both these common cancers, yet for so many women access to these is beyond reach. These inequities highlight the urgent need in low-income and middle-income countries for sustainable investments in the entire continuum of cancer control, from prevention to palliative care, and in the development of high-quality population-based cancer registries. In this first paper of the Series on health, equity, and womens cancers, we describe the burden of breast and cervical cancer, with an emphasis on global and regional trends in incidence, mortality, and survival, and the consequences, especially in socioeconomically disadvantaged women in different settings.