Evidence-based data and rare cancers: The need for a new methodological approach in research and investigation

Rare cancers are not so rare, their incidence is increasing and, as a group, they have worse survival than the common cancers. These factors emphasise the societal need to ensure sufficient focus on research into their biological basis, aetiological factors, new more effective therapies and organisation of healthcare to improve access to best practice and innovation. Accuracy of diagnosis is one of the first hurdles to be overcome, with around one third of tumours being reclassified – by type or risk group – when subject to a centralised pathology review process. Timely access to appropriate expert knowledge is a second challenge for patients – in Europe this is being addressed by the establishment of European Reference Networks (ERNs) as part of the EU cross border healthcare initiative. There are ERNs for adult solid and haematological cancers and childhood cancers, all of which are individually rare. These ERNs will facilitate creation of large databases of rare tumours that will incorporate knowledge of their molecular features and build an evidence base for the effectiveness of innovative, biology-directed therapies. With an increasing focus on ‘real world’ outcome data, research methodologies are evolving, to include randomised registry trials and data linkage approaches that exploit the ever-richer information held on patients in routine health care data. The inclusion of genomic analysis into cancer diagnosis, treatment and risk prediction raises many issues for the conduct of clinical research and cohort studies and personal data sharing. Sophisticated means of pseudonymisation, together with full involvement of affected and ‘at risk’ patients, are supporting novel research designs and access to data that will continue to build the evidence base to improve outcomes for patients with rare cancers.     

Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity.

Isozymes of alcohol and other dehydrogenases convert ethanol and retinol to their corresponding aldehydes in vitro. In addition, new pathways of retinol metabolism have been described in hepatic microsomes that involve, in part, cytochrome P450s, which can also metabolize various drugs. In view of these overlapping metabolic pathways, it is not surprising that multiple interactions between retinol, ethanol, and other drugs occur. Accordingly, prolonged use of alcohol, drugs, or both, results not only in decreased dietary intake of retinoids and carotenoids, but also accelerates the breakdown of retinol through cross-induction of degradative enzymes. There is also competition between ethanol and retinoic acid precursors. Depletion ensues, with associated hepatic and extrahepatic pathology, including carcinogenesis and contribution to fetal defects. Correction of deficiency through vitamin A supplementation has been advocated. It is, however, complicated by the intrinsic hepatotoxicity of retinol, which is potentiated by concomitant alcohol consumption. By contrast, beta-carotene, a precursor of vitamin A, was considered innocuous until recently, when it was found to also interact with ethanol, which interferes with its conversion to retinol. Furthermore, the combination of beta-carotene with ethanol results in hepatotoxicity. Moreover, in smokers who also consume alcohol, beta-carotene supplementation promotes pulmonary cancer and, possibly, cardiovascular complications. Experimentally, beta-carotene toxicity was exacerbated when administered as part of beadlets. Thus ethanol, while promoting a deficiency of vitamin A also enhances its toxicity as well as that of beta-carotene. This narrowing of the therapeutic window for retinol and beta-carotene must be taken into account when formulating treatments aimed at correcting vitamin A deficiency, especially in drinking populations.     

Short-term decreased post transplant lymphoproliferative disorder risk after kidney transplantation using two novel regimens

BackgroundBelatacept is employed alongside calcineurin inhibitor (CNI) therapy to prevent graft rejection in kidney transplant patients who are Epstein-Barr virus (EBV) seropositive. Preliminary data suggested that rates of post-transplant lymphoproliferative disorder (PTLD) were higher in individuals treated with belatacept compared to CNI therapy alone.MethodsThe records of 354 adults who underwent kidney only transplantation from January 2015 through September 2021 at one medical center were evaluated. Patients underwent treatment with either low-doses of mycophenolate, tacrolimus and sirolimus (B⁰, n = 235) or low-doses of mycophenolate, tacrolimus and belatacept (B¹, n = 119). All recipients underwent induction with antithymocyte globulin and a rapid glucocorticosteroid taper. Relevant donor and recipient information were analyzed and endpoints of PTLD were assessed.ResultsThere were no cases of PTLD in either cohort within the study period. Recipients in the belatacept cohort experienced lower estimated glomerular filtration rates at 12 months (B⁰: 67.48 vs. B¹: 59.10, p = 0.0014). Graft failure at 12 (B⁰: 1.28% vs. B¹: 0.84%, p = 1.0) and 24 months (B⁰:2.55% vs. B¹: 0.84%, p = 0.431) were similar. There was no difference in rejection rates at 12 (B⁰: 1.27% vs. B¹: 2.52%, p = 0.408) or 24 months (B⁰: 2.12% vs. B¹: 2.52%, p = 1.000). Both groups had similar rates of malignancy, mortality and CMV/BK viremia.ConclusionNon-belatacept (MMF, tacrolimus and sirolimus) and belatacept-based (MMF, tacrolimus and belatacept) regimens do not appear to pose any increased risk of early onset PTLD. Both cohorts benefited from low rates of rejection, malignancy, mortality and graft failure. Recipients will continue to be monitored as PTLD can manifest as a long-term complication.     

Prevalence and predictors of HCV among a cohort of opioid treatment patients in Dar es Salaam,Tanzania

BackgroundThe government of Tanzania launched an opioid treatment program (OTP), using methadone, in Dar es Salaam in February of 2011. Hepatitis C virus (HCV) is a leading cause of morbidity and mortality globally, especially among people who inject drugs (PWID). We conducted a cross-sectional study among PWID engaged in OTP in Dar es Salaam to describe the prevalence and predictors of HCV antibody serostatus.MethodsRoutine programmatic data on patients enrolled in Muhimbili National Hospital’s OTP clinic from February 2011 to January 2013 were utilized. Multivariable Poisson regression was used to examine factors associated with HCV antibody serostatus.ResultsA total of 630 PWID enrolled into the OTP clinic during the study period, seven percent of which were women. The overall seroprevalence of HCV antibody was 57% (95% Confidence interval: 53–61%). In adjusted analysis, methadone patients who used heroin for 5–10 years (adjusted prevalence ratio; aPR = 1.41; 95% CI: 1.10–1.81) and >10 years (aPR = 1.48; 95% CI: 1.17–1.88) were more likely to be HCV antibody positive, compared to patients who used heroin for <5 years. Patients who reported sharing needles or other equipment at their last injection (aPR = 1.20; 95% CI: 1.01–1.41; p = 0.022), being arrested (aPR = 1.20; 95% CI: 1.04–1.40; p = 0.012) and who were HIV-positive (aPR = 1.84; 95% CI: 1.56–2.16; p < 0.001) were also more likely to be HCV antibody positive than their counterparts.ConclusionOur observed HCV antibody prevalence among PWID engaged in OTP is higher than previously reported estimates in Dar es Salaam. Predictors of HCV antibody serostatus in this sample were similar to those found among PWID in many other settings. Integrating HCV care and treatment into OTP clinics should be considered, leveraging lessons learned from the integration of HIV services into OTP. Global efforts to develop HCV care and treatment programs in low and middle-income countries are critical, especially among PWID who have a high burden of HCV.     

Distribution and characteristics of SGI1/PGI2 genomic island from Proteus strains in China

The emergence of multidrug-resistant Salmonella genomic island 1 (SGI1) and Proteus genomic island (PGI) bearing P. mirabilis present a serious threat to public health. In this study, we screened 288 Proteus isolates recovered from seven provinces in China. Fourteen strains (4.9%) all belonged to P. mirabilis were positive for SGI1/PGI2, including twelve from clinical samples (5.3%) and two from food (3.3%). A Blastn search against GenBank and phylogenetic analyses identified eight different SGI1 variants and one PGI2 variant from the fourteen SGI1/PGI2 variants. All SGI1 variants shared a common backbone and harbored different resistance gene(s), except the sul1 gene at its multidrug-resistant (MDR) region. Among the variants, three novel SGI1 variants, designated as SGI1-PmCA11, SGI1-PmCA14 and SGI1-PmCA46, contained different gene cassettes, which were similar to sequences in plasmids or class 1 integrons of Klebsiella pneumoniae, P. mirabilis, Escherichia coli and Salmonella. Moreover, one novel PGI2, designated as PGI2-PmCA72, had an identical gene cassette to the first class 1 integron from PGI2 (GenBank accession no. MG201402.1) in P. mirabilis, but varied due to missing, replaced, inserted and inverted gene clusters. The four novel SGI1/PGI2 variants contained the cmlA5, dfrA14, bla_OXA-10, aadA15, bla_OXA-1, catB3 and dfrA16 resistance genes, which have never been reported in SGI1/PGI2 variants. Phenotypically, all fourteen SGI1/PGI2-containing strains showed multidrug resistance. All except four strains were resistant to the first, or the second and/or-third generation cephalosporins. Considering the increasing number and the emergence of new SGI1/PGI2 variants, further surveillance is needed to prevent the spreading of the MDR genomic islands among Proteus isolates from human and food.     

Lifestyle behaviors and cardiovascular risk profiles among parous women by gestational diabetes status, 2007–2018

Background and aimsWomen with prior gestational diabetes mellitus (GDM) are at elevated risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors among parous U.S. women ages 20–44 by history of GDM.Methods and resultsUsing data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018, 3537 parous women were classified by self-reported GDM history. We compared anthropometric measures, glycemia, blood pressure, lipids, lifestyle factors, cardiovascular health, and cardiometabolic disease prevalence by GDM status. NHANES survey design was taken into account. Women without history of GDM were younger and, after adjusting for age, race/ethnicity, and education, had more favorable cardiometabolic risk factor profiles for measures of anthropometry, glycemia, diabetes, many lipids, physical activity, diet, and overall cardiovascular health than women with history of GDM. Many patterns persisted after further adjustment for lifestyle factors. In analyses stratified by race/ethnicity, many patterns persisted, though there were key differences. Hypertension prevalence differed by GDM history only among Hispanic women. In women of other race/ethnicity, there was no difference in healthy eating or body mass index by GDM history. In non-Hispanic Black women, there was no difference in healthy eating by GDM history.ConclusionAmong parous U.S. women ages 20–44, those with history of GDM had less favorable cardiometabolic risk factor profiles than those without history of GDM. This highlights the importance of continued efforts to develop and test multilevel interventions to improve cardiometabolic risk factors among reproductive-age women with a history of GDM.     

Serum uric acid levels threshold for mortality in diabetic individuals: The URic acid Right for heArt Health (URRAH) project

Background and aimThe URRAH (URic acid Right for heArt Health) Study has identified cut-off values of serum uric acid (SUA) predictive of total mortality at 4.7 mg/dl, and cardiovascular (CV) mortality at 5.6 mg/dl. Our aim was to validate these SUA thresholds in people with diabetes.Methods and resultsThe URRAH subpopulation of people with diabetes was studied. All-cause and CV deaths were evaluated at the end of follow-up.A total of 2570 diabetic subjects were studied. During a median follow-up of 107 months, 744 deaths occurred. In the multivariate Cox regression analyses adjusted for several confounders, subjects with SUA ≥5.6 mg/dl had higher risk of total (HR: 1.23, 95%CI: 1.04–1.47) and CV mortality (HR:1.31, 95%CI:1.03–1.66), than those with SUA <5.6 mg/dl. Increased all-cause mortality risk was shown in participants with SUA ≥4.7 mg/dl vs SUA below 4.7 mg/dl, but not statistically significant after adjustment for all confounders.ConclusionsSUA thresholds previously proposed by the URRAH study group are predictive of total and CV mortality also in people with diabetes. The threshold of 5.6 mg/dl can predict both total and CV mortality, and so is candidate to be a clinical cut-off for the definition of hyperuricemia in patients with diabetes.