2 Minute Medicine Rewind January 28, 2019

Association of HLA antigen mismatch with risk of developing skin cancer after solid-organ transplant

Immunosuppressive agents reduce the risk of graft rejection in solid-organ transplant recipients. However, immunosuppressive regimens are not without risks, increasing the risk of cancer, a major source of morbidity and mortality. In particular, the risk of squamous cell carcinoma (SCC) is increased 65-fold while the risk of melanoma is increased 3-fold in solid-organ transplant recipients. The HLA antigen major histocompatibility complex (MHC) plays an important role in solid-organ transplantation, as mismatched donor-derived MHC molecules stimulate an alloimmune response resulting in rejection. The altered expression of MHC molecules is a well-described mechanism used by cancer cells to evade immunosurveillance, however, the data on the association between HLA antigen mismatch and skin cancer incidence is limited. In this retrospective cohort study of 10,649 adults who underwent a primary solid-organ transplant were followed up to study the contribution of HLA antigen mismatch to post-transplant skin cancer risk. Researchers found that for each additional mismatched allele, a 7-8% reduction in skin cancer risk was found (HR 0.93, 95% CI 0.87 to 0.99, p=0.01). Upon performing a subgroup analysis, researchers noted this protective effect to be statistically significant in lung (HR 0.80, 95% CI 0.56 to 0.87) and heart (HR 0.75, 95% CI 0.60 to 0.93, p=0.008) transplant recipients, but not other solid-organ transplant sites. The degree of HLA-DR mismatch, but not HLA-A or HLA-B mismatch was the most statistically significant for skin cancer risk (HR 0.85, 95% CI 0.74 to 0.97, p=0.01). This study therefore shows that HLA antigen mismatch may be associated with reduction in the risk of skin cancer after solid-organ transplant among heart and lung transplant recipients.

Association of maternal probiotic supplementation with human milk oligosaccharide composition

Human milk oligosaccharides (HMO) are complex glycans, and are typically non-digestible by humans. They are, however, important substrates for an infant’s gut microbiota, and play an important role in the maturation of the intestinal mucosal immune system. It is thought that a number of factors can influence the composition of HMOs, including but not limited to maternal Secretor and Lewis blood groups. In addition, HMO abundance changes throughout lactation, though there is little data available on factors associated with HMO abundance. In this study, researchers used stored frozen colostrum samples from a previously published large, randomized controlled trial of probiotic supplementation in pregnant mothers from Helsinki, Finland, carrying fetuses at hereditary risk for allergy, to assess the association between maternal probiotic supplementation and HMO concentrations. With over 500 available mature milk samples available, 81 colostrum samples were randomly selected, with 30 samples from the placebo group and 51 from the probiotic group. Researchers found that the concentrations of 3-fucosyllactose and 3’-sialyllactose were in higher concentrations in colostrum from mothers in the probiotic supplementation group when compared to the non-supplemented group. However, mean levels of HMOs were lower in colostrum from mothers who received probiotic supplementation when compared to the control group. This study therefore shows that while HMO composition is largely genetically determined, maternal probiotic supplementation may alter HMO composition in human milk; this has important implications for disease modification in at-risk infants who are breastfed.

Prior dengue virus infection and risk of Zika: a pediatric cohort in Nicaragua

Acute Zika infection is often asymptomatic, though affected individuals commonly present with symptoms including rash, low-grade fever, arthralgias and conjunctivitis. The virus responsible, Zika virus (ZIKV), shares extensive homology with dengue virus (DENV), and throughout the Americas, a precipitous decrease in the number of dengue cases was observed followed widespread Zika epidemics. This suggests that ZIKV infection may induce cross-protective immune responses against DENV. In this prospective cohort study, researchers describe the introduction of ZIKV into the Pediatric Dengue Cohort Study (PDCS) (n=3,893), a long-standing pediatric dengue cohort established in 2004 in Managua, Nicaragua, to establish the incidence of symptomatic and inapparent ZIKV infections from January 1, 2016 to February 28, 2017. Researchers found that over the course of the study period, 560 symptomatic ZIKV infections and 1,356 total ZIKV infections (symptomatic and inapparent) were identified, for an overall incidence of 14.0 symptomatic infections (95% CI 12.9 to 15.2) and 36.5 total infections (95% CI 34.7 to 38.6) per 100 person-years. The incidence of symptomatic and total ZIKV infections was higher in females and older children. In examining the effect of prior DENV infection in 3,027 participants with documented DENV infection histories, 743 (24.5%) had experienced at least 1 prior DENV infection during cohort follow-up. Interestingly, prior DENV infection was inversely associated with the risk of symptomatic ZIKV infection in the total cohort population (IRR 0.63, 95% CI 0.48 to 0.81, p<0.005) as well as with the risk of symptomatic presentation (IRR 0.62, 95% CI 0.44 to 0.86) when adjusted for age, sex, and recent DENV infection. Recent DENV infection was significantly associated with decreased risk of symptomatic ZIKV infection when adjusted for age and sex (IRR 0.57, 95% CI 0.35 to 0.92), but not when adjusted for prior DENV infection (IRR 0.80, 95% CI 0.47 to 1.34). Prior or recent DENV infection did not affect the rate of total ZIKV infections. This study therefore shows that prior DENV infection may be protective against from symptomatic Zika infection. Further studies are needed in addressing possible immunological mechanisms of cross-protection between ZIKV and DENV.

Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study

Tumour necrosis factor (TNF) alpha inhibitors have greatly improved disease control and quality of life in patients affected by rheumatoid arthritis; however, up to one third of patients fail to respond to these agents. Alternative non-TNF targeted biologics have also emerged, including rituximab, abatacept and tocilizumab. In this prospective population-based study, 3162 adults with rheumatoid arthritis were followed up to investigate the effectiveness of rituximab, abatacept and tocilizumab in the treatment of longstanding and refractory rheumatoid arthritis. The primary outcome measured was drug retention without failure at 24 months of follow-up. Researchers found that among patients that were using rituximab at the study onset, 68.6% of patients were still using rituximab without failure. In patients using abatacept, 39.3% of patients continued to use abatacept without failure. In patients using tocilizumab, 63.4% were using tocilizumab at the end of the follow-up period without failure. Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. At 24 months of follow-up, more participants treated with rituximab or tocilizumab than with abatacept showed a good or moderate EULAR (European League Against Rheumatism) response. This study therefore shows that among patients with refractory rheumatoid arthritis, the use of rituximab and tocilizumab non-TNG targeted biologics was associated with greater improvements in outcomes when compared to abatacept.

Accelerated hypofractionated radiation therapy for elderly frail bladder cancer patients unfit for surgery or chemotherapy

The standard of care for T2-T4aN0M0 muscle-invasive bladder cancer (MIBC) and high-risk non-MIBC in fit patients is radical cystectomy (RC). In patients unfit for RC, or in cases where bladder preservation is desired, trimodality therapy (TMT) incorporating maximal transurethral resection of bladder tumour (TURBT) and radiation therapy (RT) with concurrent chemotherapy (CMT) can be considered, with comparable efficacy in terms of overall, cancer-specific and disease-free survival. As many elderly patients are not considered suitable surgical candidates, TMT is often considered in this patient population. However, these patients may also be unfit for chemo-radiation. Hypofractionation has been investigated as a strategy to increase the efficacy of radiation therapy in this patient population. The purpose of this cohort study was to assess the treatment outcomes of definitive image-guided accelerated hypofractionated radiation therapy in 17 elderly patients with MIBC not considered suitable candidates for surgery or TMT. All patients underwent TURBT, however, in 64.7% of patients this was concluded as incomplete due to deep tumour involvement of the bladder wall or wide area of spread. The median overall treatment time was 20 days, with no patients receiving neoadjuvant chemotherapy. Researchers found that complete local response at 3-month cystoscopy was 69%, where 6 patients (35%) developed a local recurrence, and 2 patients (11.7%) developed distant metastases. Overall survival at 1 year and 2 years were 85% and 63%, respectively. This study therefore shows that accelerated hypofractionated radiotherapy alone may provide good control in elderly patients unfit for combination chemotherapy and radiation.

Image: PD

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