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Purpose: Leukemias have been associated with oral manifestations, reflecting susceptibility to cancer therapy–induced oral mucositis. We sought to identify SNPs associated with both leukemia and oral mucositis (OM). Methods: Whole exome sequencing was performed on leukemia and non-cancer blood disorder (ncBD) patients’ saliva samples (N = 50) prior to conditioning therapy. WHO OM grading scores were determined: moderate to severe (OM2-4) vs. none to mild (OM0-1). Reads were processed using Trim Galorev0.6.7, Bowtie2v2.4.1, Samtoolsv1.10, Genome Analysis Toolkit (GATK)v4.2.6.1, and DeepVariantv1.4.0. We utilized the following pipelines: P1 analysis with PLINK2v3.7, SNP2GENEv1.4.1 and MAGMAv1.07b, and P2 [leukemia (N = 42) vs. ncBDs (N = 8)] and P3 [leukemia + OM2-4 (N = 18) vs. leukemia + OM0-1 (N = 24)] with Z-tests of genotypes and protein–protein interaction determination. GeneCardsSuitev5.14 was used to identify phenotypes (P1 and P2, leukemia; P3, oral mucositis) and average disease-causing likelihood and DGIdb for drug interactions. P1 and P2 genes were analyzed with CytoScape plugin BiNGOv3.0.3 to retrieve overrepresented Gene Ontology (GO) terms and Ensembl’s VEP for SNP outcomes. Results: In P1, 457 candidate SNPs (28 genes) were identified and 21,604 SNPs (1016 genes) by MAGMAv1.07b. Eighteen genes were associated with “leukemia” per VarElectv5.14 analysis and predicted to be deleterious. In P2 and P3, 353 and 174 SNPs were significant, respectively. STRINGv12.0 returned 77 and 32 genes (C.L. = 0.7) for P2 and P3, respectively. VarElectv5.14 determined 60 genes from P2 associated with “leukemia” and 11 with “oral mucositis” from P3. Overrepresented GO terms included “cellular process,” “signaling,” “hemopoiesis,” and “regulation of immune response.” Conclusions: We identified candidate SNPs possibly conferring susceptibility to develop leukemia and oral mucositis. [ABSTRACT FROM AUTHOR]

Cyclosporine-A (CsA) is used to prevent acute graft-versus-host disease (aGvHD). European Society for Blood and Marrow transplantation (EBMT) recommends a CsA target serum concentration of 200–300 µg/L during the first month after allogeneic hematopoietic stem cell transplantation (HSCT). With this study, we investigated whether a median CsA concentration > 200 µg/L (CsAhigh) the first month after HSCT, compared to ≤ 200 µg/L (CsAlow), increased the relapse risk of acute myloid leukemia (AML), using unrelated donors (URD) and antithymocyte globulin (ATG). Data was collected from 157 patients with AML, transplanted 2010–2016. The cumulative incidence of relapse (CIR) at 60 months was 50% in the CsAhigh versus 32% in the CsAlow group (p = 0.016). In univariate analysis, CsAhigh versus CsAlow (p = 0.028), 10-unit increase of CsA as a continuous variable (p = 0.017) and high risk disease (p = 0.003) were associated with higher CIR. The results remained after adjusting for disease risk. Death following relapse occurred more frequently in the CsAhigh group (p = 0.0076). There were no significant differences in rates of aGvHD, chronic GvHD (cGvHD), EBV/CMV-infections or overall survival (OS) between the two groups. In conclusion, we found that a median CsA concentration > 200 µg/L, the first month after HSCT, results in higher CIR of AML when combined with ATG. [ABSTRACT FROM AUTHOR]

Introduction: Chronic graft-versus-host disease (cGVHD) is a debilitating side effect of allogeneic hematopoietic cell transplantation (HCT), affecting the quality of life of patients. We used whole exome sequencing to identify candidate SNPs and complete a multi-marker gene-level analysis using a cohort of cGVHD(+) (N = 16) and cGVHD(−) (N = 66) HCT patients. Methods: Saliva samples were collected from HCT patients (N = 82) pre-conditioning in a multi-center study from March 2011 to May 2018. Exome sequencing was performed and FASTQ files were processed for sequence alignments. Significant SNPs were identified by logistic regression using PLINK2v3.7 and Fisher’s exact test. One cGVHD(−) patient sample was excluded from further analysis since no SNP was present in at least 10% of the sample population. The FUMA platform’s SNP2GENE was utilized to annotate SNPs and generate a MAGMA output. Chromatin state visualization of lead SNPs was completed using Epilogos tool. FUMA’s GENE2FUNC was used to obtain gene function and tissue expression from lead genomic loci. Results: Logistic regression classified 986 SNPs associated with cGVHD(+). SNP2GENE returned three genomic risk loci, four lead SNPs, 48 candidate SNPs, seven candidate GWAS tagged SNPs, and four mapped genes. Fisher’s exact test identified significant homozygous genotypes of four lead SNPs (p < 0.05). GENE2FUNC analysis of multi-marker SNP sets identified one positional gene set including lead SNPs for KANK1 and KDM4C and two curated gene sets including lead SNPs for PTPRD, KDM4C, and/or KANK1. Conclusions: Our data suggest that SNPs in three genes located on chromosome 9 confer genetic susceptibility to cGVHD in HCT patients. These genes modulate STAT3 expression and phosphorylation in cancer pathogenesis. The findings may have implications in the modulation of pathways currently targeted by JAK inhibitors in cGVHD clinical trials. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is a common cancer among men, and preventive strategies are warranted. Benzoxazinoids (BXs) in rye have shown potential against PC in vitro but human studies are lacking. The aim was to establish a quantitative method for analysis of BXs and investigate their plasma levels after a whole grain/bran rye vs refined wheat intervention, as well as exploring their association with PSA, in men with PC. A quantitative method for analysis of 22 BXs, including novel metabolites identified by mass spectrometry and NMR, was established, and applied to plasma samples from a randomized crossover study where patients with indolent PC (n = 17) consumed 485 g whole grain rye/rye bran or fiber supplemented refined wheat daily for 6 wk. Most BXs were significantly higher in plasma after rye (0.3–19.4 nmol/L in plasma) vs. refined wheat (0.05–2.9 nmol/L) intake. HBOA-glc, 2-HHPAA, HBOA-glcA, 2-HPAA-glcA were inversely correlated to PSA in plasma (p < 0.04). To conclude, BXs in plasma, including metabolites not previously analyzed, were quantified. BX metabolites were significantly higher after rye vs refined wheat consumption. Four BX-related metabolites were inversely associated with PSA, which merits further investigation. [ABSTRACT FROM AUTHOR]

Objectives: To investigate signs of infection and infection-related complications of apical periodontitis (AP) in patients who underwent chemotherapy for lymphoma. Materials and methods: Data were collected retrospectively from the dental and medical records of patients receiving chemotherapy for lymphoma. Based on the findings from a dental evaluation made in conjunction with chemotherapy, the patients were divided into two groups, patients with or without teeth with AP. Results: Eighty-six of the 213 patients had one or more teeth with AP and received no planned dental treatment for this condition, while 127 patients had no AP-affected teeth. During chemotherapy, seven patients (8%) developed local symptoms related to teeth with AP, while no patients in the control group developed symptoms of AP. No significant differences were found with respect to the administration of antibiotics related to dental infection or hospital admission events due to fever or infection, between the group with AP and the group without AP. Conclusions: AP is a common finding and exacerbation seems more common in patients diagnosed with chronic AP than in patients without chronic AP. The presence of chronic AP in patients treated with chemotherapy for lymphoma is not linked to additional medical complications that require hospital admission owing to fever/infection. Clinical relevance: Knowledge regarding infection-related complications of AP in patients with lymphoma treated with chemotherapy will guide clinical decision-making by identifying those patients who warrant treatment. This will allow dental interventions to be postponed until completion of chemotherapy, without serious medical complications. The results of this study serve as a basis for larger prospective studies. [ABSTRACT FROM AUTHOR]

Purpose: The role of body size in prostate cancer etiology is unclear and potentially varies by age and disease subtype. We investigated whether body size in childhood and adulthood, including adult weight change, is related to total, low-intermediate-risk, high-risk, and fatal prostate cancer. Methods: We used data on 1,499 incident prostate cancer cases and 1,118 population controls in Sweden. Body figure at age 10 was assessed by silhouette drawings. Adult body mass index (BMI) and weight change were based on self-reported height and weight between ages 20 and 70. We estimated odds ratios (ORs) with 95 % confidence intervals (CIs) by unconditional logistic regression. Results: Height was positively associated with prostate cancer. Overweight/obesity in childhood was associated with a 54 % increased risk of dying from prostate cancer compared to normal weight, whereas a 27 % lower risk was seen in men who were moderately thin (drawing 2) in childhood ( P = 0.01). Using BMI <22.5 as a reference, we observed inverse associations between BMI 22.5 to <25 at age 20 and all prostate cancer subtypes (ORs in the range 0.72-0.82), and between mean adult BMI 25 to <27.5 and low-intermediate-risk disease (OR 0.75, 95 % CI 0.55-1.02). Moderate adult weight gain increased the risk of disease in men with low BMI at start and in short men. Conclusions: Our comprehensive life-course approach revealed no convincing associations between anthropometric measures and prostate cancer risk. However, we found some leads that deserve further investigation, particularly for early-life body size. Our study highlights the importance of the time window of exposure in prostate cancer development. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment option for eligible patients with chronic lymphocytic leukemia (CLL). However, it is known that cure of CLL is only possible if a graft-versus-leukemia effect is present. Between 1994 and 2007, 48 adults underwent allo-SCT for poor-risk CLL in Sweden. Of these, ten (21 %) patients aged 24–53 years (median: 46 years) received myeloablative conditioning (MAC), based on TBI and cyclophosphamide. All MAC patients had refractory, poorly controlled CLL before allo-SCT (partial remission in 9/10 patients and progressive disease in one). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II–IV was 30 %. Nine patients developed chronic GVHD; extensive in four. Rates of nonrelapse mortality at 1, 3 and 10 years were 0, 10 and 20 %, respectively. Two patients relapsed 36 and 53 months after transplantation. Six patients were still alive after a median follow-up time of 11.5 years (range 5.9–13.7). The probabilities of relapse-free and overall survival from 1, 3 and 5 years after transplantation were 100, 90 and 70 %, and 100, 90 and 80 %, respectively. Nevertheless, our analysis of long-term outcome after MAC allo-SCT for CLL suggests that younger patients with poorly controlled CLL may benefit from MAC allo-SCT. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: Few randomized controlled trials have compared electrical stimulation treatment with drug therapy. Our hypothesis was that electrical stimulation treatment in women with urgency/urge incontinence would be more efficient compared to drug treatment. Methods: Women ≥18 years of age with urgency/urge incontinence were randomized to receive either ten electrical stimulation treatments vaginally and transanally over a period of 5-7 weeks or tolterodine 4 mg orally once daily. Results: Sixty-one women completed the study. There was no significant difference between the two treatment groups in micturition rate from baseline to 6 months, mean difference, −0.40 (95% confidence interval (CI), −1.61 to 0.82), but a clearly significant difference within each group for electrical stimulation, −2.8 (95% CI, −3.7 to −1.9), and for tolterodine, −3.2 (95% CI, −4.1 to −2.4). Conclusions: Both treatments reduced the number of micturitions, but electrical stimulation was not found to be superior to tolterodine. [ABSTRACT FROM AUTHOR]

The article discusses various reports published within the issue including one by Konstantinos Petrogiannis on the early childhood care and education (ECEC) in Greece, one by Sylvie Rayna on research and ECEC for children in France, and one by Eva Johansson and Anette Emilson on the life of preschoolers in Sweden.

Patients with breast or prostate cancer diagnosed during the summer season have been observed to have better survival. The extent to which this is due to biological and/or health care system related factors is unclear. Using the Swedish Cancer Register and clinical databases, we analyzed overall survival by month of diagnosis among the incident cases of breast ( n = 89,630) cancer and prostate ( n = 72,375) cancer diagnosed from 1960 to 2004. We retrieved data on tumor stage from 1976 for breast cancer and 1997 for prostate cancer. Cox proportional hazards models were used to calculate relative risk of survival by the season of diagnosis. There was a higher hazard ratio of death in men and women diagnosed with cancer in the summer with a relative hazard of 1.20 (95% confidence interval 1.15–1.25) for July for prostate cancer and 1.14 (95% confidence interval 1.09–1.19) for August for breast cancer when compared to being diagnosed in January. This difference coincided with a lower mean number of cases diagnosed per day, and a higher proportion of advanced cases diagnosed in the summer. This pattern of presentation was stronger in the later years. The difference in stage distribution explains the seasonal variation in prognosis seen in this study. The variation may be because of structure of the health care system and a strong tradition of vacationing from mid June to mid August. Thus, the health care infrastructure and the late presentation of symptomatic disease may influence cancer survival studied by season of diagnosis substantially. [ABSTRACT FROM AUTHOR]

Background: High meat consumption could potentially increase the risk of bladder cancer, but findings from epidemiologic studies are inconsistent. We prospectively examined the association between meat intake and bladder cancer risk in a population-based cohort study.Methods: We prospectively followed 82,002 Swedish women and men who were free from cancer and completed a food-frequency questionnaire in 1997. Incident cases of bladder cancer were identified in the Swedish cancer registries. Cox proportional hazards models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI), adjusted for age, sex, education, smoking status, pack-years of smoking, and total energy intake.Results: During a mean follow-up of 9.4 years, 485 incident cases of bladder cancer (76 women and 409 men) were ascertained in the cohort. We observed no association between the intake of total or any specific type of meat and the risk of bladder cancer. The multivariate HRs (95% CIs) comparing the highest and the lowest category of intake were 1.05 (0.71-1.55) for total meat, 1.00 (0.71-1.41) for red meat, 1.01 (0.80-1.28) for processed meats, 0.96 (0.70-1.30) for chicken/poultry, and 0.92 (0.65-1.30) for fried meats/fish. The associations did not vary by sex or smoking status.Conclusions: These results do not support the hypothesis that intake of red meat, processed meat, poultry, or fried meats/fish is associated with the risk of developing bladder cancer. [ABSTRACT FROM AUTHOR]

The etiologic role of physical activity in prostate cancer development is unclear. We assessed the association between lifetime total physical activity and prostate cancer risk in a Swedish population-based case–control study comprising 1,449 incident prostate cancer cases and 1,118 unaffected population controls. Information regarding physical activity was obtained via a self-administered questionnaire assessing occupational, household, and recreational activity separately at various ages throughout an individual’s lifetime. Clinical data (TNM-classification, Gleason sum and PSA) was obtained from linkage to the National Prostate Cancer Registry. Overall, we observed no association between lifetime total physical activity and prostate cancer risk (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 0.77–1.41 for ≥49.7 vs. <41.9 metabolic equivalent-hours per day). There was a significantly increased risk of prostate cancer in the most active men compared with the least active men in household (OR = 1.44, 95% CI = 1.08–1.92) and recreational physical activity (OR = 1.56, 95% CI = 1.16–2.10). Comparing the most active with the least active men, total physical activity was not associated with either localized disease (OR = 0.95, 95% CI = 0.67–1.34) or advanced disease (OR = 1.19, 95% CI = 0.83–1.71). These findings do not support the hypothesis that physical activity uniformly protects against prostate cancer development. [ABSTRACT FROM AUTHOR]

Protective strategies to minimize the hematological toxicity in connection with bone marrow transplantation (BMT) have been successful, but toxicity to the gastrointestinal tract prevents further dose escalation and therefore limits the application of the treatment. As it is known that chemotherapy leads to disruption of the intestinal barrier and morphological changes of mitochondria in enterocytes, this study was conducted in order to investigate intestinal energy metabolism and permeability after intensive cytotoxic therapy in rats. Intestinal damage was produced by intraperitoneal administration of the cytostatic etoposide. Intestinal permeability was assessed by a [51Cr]EDTA absorption test and intestinal purine nucleotide content by a high-performance liquid chromatography (HPLC) technique. Four hours after the administration of etoposide, and the next 48 hr, there was a significant increase in the intestinal permeability (P < 0.05) and a significant reduction of the purine nucleotide content in the intestinal epithelial cells (P < 0.01) as compared to control animals. This early disturbance in enterocyte energy metabolism may be a key event in the development of the intestinal damage, induced by chemotherapy, and an explanation for the early disruption of the intestinal barrier demonstrable before morphological changes are evident. [ABSTRACT FROM AUTHOR]

We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, ∼26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 × 10−9 for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP. [ABSTRACT FROM AUTHOR]

The aim of this prospective, two center study was to investigate the dynamics of the microbial changes in relation to the development of ulcerative oral mucositis in autologous SCT (autoSCT) recipients. Fifty-one patients were diagnosed with multiple myeloma and treated with high-dose melphalan followed by autoSCT. They were evaluated before, three times weekly during hospitalization, and three months after autoSCT. At each time point an oral rinse was collected and the presence or absence of ulcerative oral mucositis (UOM) was scored (WHO scale). Oral microbiome was determined by using 16S rRNA amplicon sequencing and fungal load by qPCR. Twenty patients (39%) developed UOM. The oral microbiome changed significantly after autoSCT and returned to pre-autoSCT composition after three months. However, changes in microbial diversity and similarity were more pronounced and rapid in patients who developed UOM compared to patients who did not. Already before autoSCT, different taxa discriminated between the 2 groups, suggesting microbially-driven risk factors. Samples with high fungal load (>0.1%) had a significantly different microbial profile from samples without fungi. In conclusion, autoSCT induced significant and reversible changes in the oral microbiome, while patients who did not develop ulcerative oral mucositis had a more resilient microbial ecosystem. [ABSTRACT FROM AUTHOR]