Cancer is increasingly recognized as a complication of HIV infection in both resource-rich and resource-limited areas. The traditional AIDS-defining cancers, including Kaposi sarcoma, cervical ...cancer, and non-Hodgkin lymphoma, have become common comorbidities afflicting HIV-positive individuals and lack adequate prevention and management options. Additionally, several non-AIDS-defining cancers have increased in incidence in resource-limited regions, including Hodgkin lymphoma, hepatocellular carcinoma, and lung cancer. This review outlines the epidemiology of HIV-associated malignancies in resource-poor and resource-rich areas, including the impact of highly active antiretroviral therapy on the incidence of these cancers. The pathogenesis of HIV-associated cancers is considered in relation to potential strategies for their prevention and treatment.
Summary Background Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the ...best treatment for the disease. We assessed the safety and efficacy of siltuximab—a chimeric monoclonal antibody against interleukin 6—in HIV-negative patients with multicentric Castleman's disease. Methods We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castleman's disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov , number NCT01024036. Findings We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1–54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 47% vs 14 54%) and serious adverse events (12 23% vs five 19%) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days range 1–1031 vs 152 days 23–666). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). Interpretation Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. Funding Janssen Research & Development.
Intra-host tumor virus variants may influence the pathogenesis and treatment responses of some virally-associated cancers. However, the intra-host variability of Kaposi sarcoma-associated herpesvirus ...(KSHV), the etiologic agent of Kaposi sarcoma (KS), has to date been explored with sequencing technologies that possibly introduce more errors than that which occurs in the viral population, and these studies have only studied variable regions. Here, full-length KSHV genomes in tumors and/or oral swabs from 9 Ugandan adults with HIV-associated KS were characterized. Furthermore, we used deep, short-read sequencing using duplex unique molecular identifiers (dUMI)-random double-stranded oligonucleotides that barcode individual DNA molecules before library amplification. This allowed suppression of PCR and sequencing errors to ~10-9/base as well as afforded accurate determination of KSHV genome numbers sequenced in each sample. KSHV genomes were assembled de novo, and rearrangements observed were confirmed by PCR and Sanger sequencing. 131-kb KSHV genome sequences, excluding major repeat regions, were successfully obtained from 23 clinical specimens, averaging 2.3x104 reads/base. Strikingly, KSHV genomes were virtually identical within individuals at the point mutational level. The intra-host heterogeneity that was observed was confined to tumor-associated KSHV mutations and genome rearrangements, all impacting protein-coding sequences. Although it is unclear whether these changes were important to tumorigenesis or occurred as a result of genomic instability in tumors, similar changes were observed across individuals. These included inactivation of the K8.1 gene in tumors of 3 individuals and retention of a region around the first major internal repeat (IR1) in all instances of genomic deletions and rearrangements. Notably, the same breakpoint junctions were found in distinct tumors within single individuals, suggesting metastatic spread of rearranged KSHV genomes. These findings define KSHV intra-host heterogeneity in vivo with greater precision than has been possible in the past and suggest the possibility that aberrant KSHV genomes may contribute to aspects of KS tumorigenesis. Furthermore, study of KSHV with use of dUMI provides a proof of concept for utilizing this technique for detailed study of other virus populations in vivo.
Treatment of cancer in sub-Saharan Africa Kingham, T Peter, Dr; Alatise, Olusegun I, MD; Vanderpuye, Verna, MD ...
The lancet oncology,
04/2013, Letnik:
14, Številka:
4
Journal Article
Recenzirano
Summary Cancer is rapidly becoming a public health crisis in low-income and middle-income countries. In sub-Saharan Africa, patients often present with advanced disease. Little health-care ...infrastructure exists, and few personnel are available for the care of patients. Surgeons are often central to cancer care in the region, since they can be the only physician a patient sees for diagnosis, treatment (including chemotherapy), and palliative care. Poor access to surgical care is a major impediment to cancer care in sub-Saharan Africa. Additional obstacles include the cost of oncological care, poor infrastructure, and the scarcity of medical oncologists, pathologists, radiation oncologists, and other health-care workers who are needed for cancer care. We describe treatment options for patients with cancer in sub-Saharan Africa, with a focus on the role of surgery in relation to medical and radiation oncology, and argue that surgery must be included in public health efforts to improve cancer care in the region.
Epstein-Barr virus (EBV) causes infectious mononucleosis and can lead to lymphoproliferative diseases. We evaluated the effects of valganciclovir on oral EBV shedding in a randomized, double-blind, ...placebo-controlled study. Twenty-six men received oral valganciclovir or daily placebo for 8 weeks, followed by a 2-week "washout period" and then 8 weeks of the alternative treatment. Valganciclovir reduced the proportion of days with EBV detected from 61.3% to 17.8% (relative risk, 0.28; 95% confidence interval CI, .21–.41; P < .001), and quantity of virus detected by 0.77 logs (95% CI, .62–.91 logs; P < .001). Further investigations into the impact of valganciclovir on EBV-associated diseases are needed.
Background. Human herpesvirus (HHV) infections are common during infancy. Primary infections are frequently asymptomatic and best studied prospectively by using direct viral detection. Methods. ...Oropharyngeal swab specimens were collected weekly from Ugandan newborn infants, their mothers, and other children in the household. Blood specimens were collected every 4 months. Samples were tested for herpes simplex virus (HSV) types 1 and 2, Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6A, HHV-6B, and HHV-8, using quantitative polymerase chain reaction. Results. Thirty-two infants, 32 mothers, and 49 other household children were followed for a median of 57 weeks. Seventeen mothers had human immunodeficiency virus type 1 (HIV) infection; no infants acquired HIV-1. The 12-month incidence of postnatal infection was 76% for HHV-6B, 59% for CMV, 47% for EBV, 8% for HSV-1, and 0% for HHV-8. The quantity of oropharyngeal shedding by contacts was associated with HHV-6A or HHV-6B transmission. Maternal HIV-1 infection was associated with EBV transmission, while breastfeeding and younger child contacts were associated with CMV transmission. Except for HSV-1, primary HHV infections were subclinical. Conclusions. By capturing exposures and acquisition events, we found that the incidence and risk factors of infection vary by HHV type. HSV-1 infection, unlike other HHV infections, caused acute clinical illness in these infants.
Interleukin-6 (IL-6) has emerged as a key factor in the pathogenesis of the atypical lymphoproliferative disorder Castleman's disease (CD). Siltuximab is a new anti-IL-6, chimeric monoclonal antibody ...with potential therapeutic benefit in patients with CD.
We report interim results from an open-label, dose-finding, seven-cohort, phase I study in which patients with symptomatic, multicentric or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals. The main efficacy end point of clinical benefit response (CBR) was defined as a composite of clinical and laboratory measures relevant to the management of CD. In addition, radiologic response was independently assessed by using modified Cheson criteria.
Eighteen (78%) of 23 patients (95% CI, 56% to 93%) achieved CBR, and 12 patients (52%) demonstrated objective tumor response. All 11 patients (95% CI, 72% to 100%) treated with the highest dose of 12 mg/kg achieved CBR, and eight patients (73%) achieved objective tumor response. Overall objective-response duration ranged from 44 to > or = 889 days, and one patient had complete response for > or = 318 days. Hemoglobin increased markedly in 19 patients (median increase, 2.1 g/dL; range, 0.2 to 4.7 g/dL) in the absence of transfusion or erythropoiesis-stimulating agents. No dose-limiting toxicity was reported, and only three patients had grade 3 or higher adverse events after a median exposure of 331 days (range, 1 to 1,148 days).
These interim results strongly suggest that siltuximab is an effective treatment with favorable safety for the management of CD. An additional study is planned to fully evaluate safety and efficacy at the recommended dose of 12 mg/kg every 3 weeks.
Current RNA vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are limited by instability of both the RNA and the lipid nanoparticle delivery system, requiring storage at ...−20°C or −70°C and compromising universally accessible vaccine distribution. This study demonstrates the thermostability and adaptability of a nanostructured lipid carrier (NLC) delivery system for RNA vaccines that has the potential to address these concerns. Liquid NLC alone is stable at refrigerated temperatures for ≥1 year, enabling stockpiling and rapid deployment by point-of-care mixing with any vaccine RNA. Alternatively, NLC complexed with RNA may be readily lyophilized and stored at room temperature for ≥8 months or refrigerated temperature for ≥21 months while still retaining the ability to express protein in vivo. The thermostability of this NLC/RNA vaccine delivery platform could significantly improve distribution of current and future pandemic response vaccines, particularly in low-resource settings.
Display omitted
RNA vaccines face challenges during storage and distribution due to their need for frozen storage. In this work, the authors utilize a nanostructured lipid carrier (NLC) delivery system for RNA that can be lyophilized in order to achieve long-term storage stability at refrigerated or room temperatures.
Adjuvant-containing subunit vaccines represent a promising approach for protection against tuberculosis (TB), but current candidates require refrigerated storage. Here we present results from a ...randomized, double-blinded Phase 1 clinical trial (NCT03722472) evaluating the safety, tolerability, and immunogenicity of a thermostable lyophilized single-vial presentation of the ID93 + GLA-SE vaccine candidate compared to the non-thermostable two-vial vaccine presentation in healthy adults. Participants were monitored for primary, secondary, and exploratory endpoints following intramuscular administration of two vaccine doses 56 days apart. Primary endpoints included local and systemic reactogenicity and adverse events. Secondary endpoints included antigen-specific antibody (IgG) and cellular immune responses (cytokine-producing peripheral blood mononuclear cells and T cells). Both vaccine presentations are safe and well tolerated and elicit robust antigen-specific serum antibody and Th1-type cellular immune responses. Compared to the non-thermostable presentation, the thermostable vaccine formulation generates greater serum antibody responses (p < 0.05) and more antibody-secreting cells (p < 0.05). In this work, we show the thermostable ID93 + GLA-SE vaccine candidate is safe and immunogenic in healthy adults.
Epstein-Barr virus (EBV) is transmitted by saliva and is a major cause of cancer, particularly in people living with HIV/AIDS. Here, we describe the frequency and quantity of EBV detection in the ...saliva of Ugandan adults with and without HIV-1 infection and use these data to develop a novel mathematical model of EBV infection in the tonsils. Eligible cohort participants were not taking antiviral medications, and those with HIV-1 infection had a CD4 count >200 cells/mm3. Over a 4-week period, participants provided daily oral swabs that we analysed for the presence and quantity of EBV. Compared with HIV-1 uninfected participants, HIV-1 coinfected participants had an increased risk of EBV detection in their saliva (IRR = 1.27, 95% CI = 1.10-1.47) and higher viral loads in positive samples. We used these data to develop a stochastic, mechanistic mathematical model that describes the dynamics of EBV, infected cells, and immune response within the tonsillar epithelium to analyse potential factors that may cause EBV infection to be more severe in HIV-1 coinfected participants. The model, fit using Approximate Bayesian Computation, showed high fidelity to daily oral shedding data and matched key summary statistics. When evaluating how model parameters differed among participants with and without HIV-1 coinfection, results suggest HIV-1 coinfected individuals have higher rates of B cell reactivation, which can seed new infection in the tonsils and lower rates of an EBV-specific immune response. Subsequently, both these traits may explain higher and more frequent EBV detection in the saliva of HIV-1 coinfected individuals.
PDF
