Impact of HLA-DPB1 allelic and single amino acid mismatches on HSCT

The interpretation of the role of HLA-DPB1 in unrelated haematopoietic stem cell transplantation (HSCT) is subject to discussion. We have investigated the role of HLA-DPB1 allele matching in HSCT outcomes in 161 recipients who were HLA - A , - B , - C , - DRB1 and - DQB1- matched with their unrelated donors at the allelic level (10/10). In addition, we analysed the association of polymorphic amino acid mismatches of DPB1 molecule with HSCT end-points, and a previously published permissiveness concept. HLA-DPB1 allele mismatches were significantly associated with an increased incidence of acute graft-versus-host disease (aGvHD) and worse overall survival (OS). The mismatch at amino acid position 69 significantly increased the risk for transplant-related mortality (TRM). Risk factors for aGvHD also included mismatches at positions 8, 9, 35, 76 and 84. This is to our knowledge, the first report of an in vivo effect of single amino acid mismatches on HSCT outcomes. In this study, grouping of allelic mismatches into permissive and non-permissive categories and their association with transplantation end-points was relevant for TRM but not for other clinical end-points.     

Neoadjuvant Therapy in Rectal Cancer Patients With Clinical Stage II to III Across European Countries: Variations and Outcomes

Background

Neoadjuvant therapy improves survival of patients with clinical stage II and III rectal cancer in clinical trials. In this study, we investigated the administration of neoadjuvant radiotherapy (neo-RT) and neoadjuvant chemoradiotherapy (neo-CRT) and its association with survival in resected patients in 2 European countries (The Netherlands and Sweden) and at 3 specialist centers.

Comparison and combination of blood DNA methylation at smoking‐associated genes and at lung cancer‐related genes in prediction of lung cancer mortality

Epigenome‐wide association studies have established methylation patterns related to smoking, the major risk factor of lung cancer (LC), which are distinct from methylation profiles disclosed in LC patients. This study simultaneously investigated associations of smoking‐associated and LC‐related methylation markers with LC mortality. DNA methylation was determined by HM450K assay in baseline blood samples of 1,565 older adults in a population‐based case–cohort study. The associations of 151 smoking‐associated CpGs (smoCpGs) and 3,806 LC‐related CpGs (caCpGs) with LC mortality were assessed by weighted Cox regression models, controlling for potential confounders. Multi‐loci methylation scores were separately constructed based on smoCpGs and caCpGs. During a median follow‐up of 13.8 years, 60 participants who had a first diagnosis of LC died from LC. The average time between sample collection and LC diagnosis was 5.8 years. Hypomethylation at 77 smoCpGs and 121 caCpGs, and hypermethylation at 4 smoCpGs and 66 caCpGs were associated with LC mortality. The associations were much stronger for smoCpGs than for caCpGs. Hazard ratios (95% CI) were 7.82 (2.91–21.00) and 2.27 (0.75–6.85), respectively, for participants in highest quartile of Score I (based on 81 smoCpGs) and Score II (based on 187 caCpGs), compared with participants in the corresponding lower three quartiles. Score I outperformed Score II, with an optimism‐corrected C‐index of 0.87 vs. 0.77. In conclusion, although methylation changes of both smoking‐associated and LC‐related genes are associated with LC mortality, only smoking‐associated methylation markers predict LC mortality with high accuracy, and may thus serve as promising candidates to identify high risk populations for LC screening.     

SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients

Oxaliplatin is frequently used as part of a chemotherapeutic regimen with 5‐fluorouracil in the treatment of colorectal cancer (CRC). The cellular availability of oxaliplatin is dependent on metabolic and transporter enzymes. Variants in genes encoding these enzymes may cause variation in response to oxaliplatin and could be potential predictive markers. Therefore, we used a two‐step procedure to comprehensively investigate 1,444 single nucleotide polymorphisms (SNPs) from these pathways for their potential as predictive markers for oxaliplatin treatment, using 623 stage II–IV CRC patients (of whom 201 patients received oxaliplatin) from a German prospective patient cohort treated with adjuvant or palliative chemotherapy. First, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Second, one model was created by backward elimination on all SNP*oxaliplatin interactions of the selected genes. The statistical procedure was evaluated using bootstrap analyses. Nine genes differentially associated with overall survival according to oxaliplatin treatment (unadjusted p values < 0.05) were selected. Model selection resulted in the inclusion of 14 SNPs from eight genes (six transporter genes, ABCA9, ABCB11, ABCC10, ATP1A1, ATP1B2, ATP8B3, and two metabolism genes GSTM5, GRHPR), which significantly improved model fit. Using bootstrap analysis we show an improvement of the prediction error of 3.7% in patients treated with oxaliplatin. Several variants in genes involved in metabolism and transport could thus be potential predictive markers for oxaliplatin treatment in CRC patients. If confirmed, inclusion of these variants in a predictive test could identify patients who are more likely to benefit from treatment with oxaliplatin.     

The Effect of Urinary Incontinence on Sexual Quality of Life in Women with Chronic Physical Diseases

This study was conducted in order to determine the effect of the presence of urinary incontinence on sexual quality of life in women diagnosed with chronic physical diseases. The sample of the cross sectional and comparative study consisted of 67.5 % (n = 191) female inpatients with and 32.5 % (n = 92) female inpatients without urinary incontinence complaints being treated for chronic physical diseases in the internal diseases clinic of a public hospital. Data was collected using the patient identification form, the International Incontinence Consultation Questionnaire-Short Form and the Sexual Quality of Life Scale for Women. The average score that women with urinary incontinence took from the sexual quality of life scale (61.50 ± 19.10) was lower than the average score of women without urinary incontinence (77.19 ± 18.75) (p < 0.01). There was a negative meaningful relationship between the frequency, amount, and effect of urinary incontinence and sexual quality of life (p < 0.05). The sexual quality of life of women who were 50 years of age and above, who had respiratory system diseases, had a duration of illness between 6 and 10 years, perceived their general health as bad, parity and gave normal birth, were in their menopausal period, and had hysterectomies was significantly lower (p < 0.05). As a result, in women with chronic physical diseases and urinary incontinence, the sexual quality of life is affected in a worse level compared to those who do not have urinary incontinence.     

Impact of genomic risk factors on survival after haematopoietic stem cell transplantation for patients with acute leukaemia

The EBMT risk score is an established tool successfully used in the prognosis of survival post‐HSCT and is applicable for a range of haematological disorders. One of its main advantages is that score generation involves summation of clinical parameters that are available pretransplant. However, the EBMT risk score is recognized as not being optimal. Previous analyses, involving patients with various diagnoses, have shown that non‐HLA gene polymorphisms influence outcome after allogeneic HSCT. This study is novel as it focuses only on patients having acute leukaemia (N = 458) and attempts to demonstrate how non‐HLA gene polymorphisms can be added to the EBMT risk score in a Cox regression model to improve prognostic ability for overall survival. The results of the study found that three genetic factors improved EBMT risk score. The presence of MAL (rs8177374) allele T in the patient, absence of glucocorticoid receptor haplotype (consisting of rs6198, rs33389 and rs33388) ACT in the patient and absence of heat‐shock protein 70‐hom (+2437) (rs2227956) allele C in the patient were associated with decreased survival time. When compared to the EBMT risk score, the scores combining EBMT risk score with the genetic factors had an improved correlation with clinical outcome and better separation of risk groups. A bootstrapping technique, involving repeated testing of a model using multiple validation sets, also revealed that the newly proposed model had improved predictive value when compared to the EBMT risk score alone. Results support the view that non‐HLA polymorphisms could be useful for pretransplant clinical assessment and provide evidence that polymorphisms in the recipient genotype may influence incoming donor cells, suppressing the initiation of the graft versus leukaemia effect and reducing survival.     

Lhermitte-Duclos disease associated with neurofibromatosis type-1 and non-ossifying fibroma

Lhermitte-Duclos disease (LDD) is a rare cerebellar disorder of uncertain pathogenesis characterized by enlargement of cerebellar folia. Magnetic resonance imaging is the diagnostic modality of choice and usually distinguishes the LDD by its characteristic "striated or laminated pattern" appearance. Various additional abnormalities have been reported in association with LDD. We report a case of LDD coexisting with neurofibromatosis type 1 (NF-1) and non-ossifying fibroma.     

Correlation of Hsp70-1 and Hsp70-2 gene expression with the degree of graft-versus-host reaction in a rat skin explant model

BACKGROUND: Graft-versus-host disease (GVHD) is the most serious complication after allogeneic hematopoietic stem-cell transplantation. A human skin explant assay has been used to predict the risk of GVHD in patients by histological grading of graft-versus-host reactions (GVHR). New molecular markers of GVHR might help to further increase the predictive value of the assay. METHODS: A rat skin explant assay has been developed to further aid in identifying potential novel molecular markers. RESULTS: In inbred rat strains GVHR were observed in skin explants co-cultured with allogeneic lymphocytes stimulated against minor or major histocompatibility antigens. The histological signs of GVHR were similar to those observed in human skin explant assays and acute GVHD lesions occurring in rats after experimental bone marrow transplantation. Heat shock protein (HSP) 70 has been shown to be expressed during GVHR. We therefore investigated the expression of the three major histocompatibility complex (MHC)-linked HSP70 genes in rat skin explants. The two major stress-inducible genes Hsp70-1 and Hsp70-2 were found to be upregulated in the allogeneic rat skin explant assays. The increase in mRNA correlated with the GVHR grade (I-IV). Interestingly, the expression of the third MHC-linked Hsp70 gene Hsp70-3 was not found to be augmented during GVHR. CONCLUSION: The observed induction of the MHC-encoded Hsp70-1 and Hsp70-2 genes might serve as new markers of GVHR and as potentially novel diagnostic tools for GVHD.     

Genetic variation in UGT genes modify the associations of NSAIDs with risk of colorectal cancer: Colon cancer family registry

The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal neoplasia. Previous studies have reported that polymorphisms in NSAID‐metabolizing enzymes central to NSAID metabolism including UDP‐glucuronosyltransferases (UGT) and cytochrome P450 (CYP) 2C9 may modify this protective effect. We investigated whether 35 functionally relevant polymorphisms within CYP2C9 and UGT genes were associated with colorectal cancer risk or modified the protective effect of NSAIDs on colorectal cancer susceptibility, using 1,584 colorectal cancer cases and 2,516 unaffected sibling controls from the Colon Cancer Family Registry. A three‐SNP genotype in UGT1A6 (G–A–A; Ala7–Thr181–Arg184) and the Asp85 variant in UGT2B15 increased the risk of colorectal cancer (OR 3.87; 95% CI 1.04–14.45 and OR 1.34; 95% CI 1.10–1.63, respectively). We observed interactions between UGT1A3 Thr78Thr (A>G) and NSAID use (P‐interaction = 0.02), a three‐SNP genotype within UGT2B4 and ibuprofen use (P‐interaction = 0.0018), as well as UGT2B15 Tyr85Asp (T>G) and aspirin use (P‐interaction = 0.01). The interaction with the UGT2B4 and the UGT2B15 polymorphisms were noteworthy at the 25% FDR level. This study highlights the need for further pharmacogenetic studies to identify individuals who might benefit from NSAID use as part of developing effective strategies for prevention of colorectal neoplasia. © 2014 Wiley Periodicals, Inc.     

Administration of adjuvant chemotherapy for stage II‐III colon cancer patients: An European population‐based study

The advantage of adjuvant chemotherapy (ACT) for treating Stage III colon cancer patients is well established and widely accepted. However, many patients with Stage III colon cancer do not receive ACT. Moreover, there are controversies around the effectiveness of ACT for Stage II patients. We investigated the administration of ACT and its association with overall survival in resected Stage II (overall and stratified by low‐/high‐risk) and Stage III colon cancer patients in three European countries including The Netherlands (2009–2014), Belgium (2009–2013) and Sweden (2009–2014). Hazard ratios (HR) for death were obtained by Cox regression models adjusted for potential confounders. A total of 60244 resected colon cancer patients with pathological Stages II and III were analyzed. A small proportion (range 9–24%) of Stage II and over half (range 55–68%) of Stage III patients received ACT. Administration of ACT in Stages II and III tumors decreased with higher age of patients. Administration of ACT was significantly associated with higher overall survival in high‐risk Stage II patients (in The Netherlands (HR; 95%CI = 0.82 (0.67–0.99), Belgium (0.73; 0.59–0.90) and Sweden (0.58; 0.44–0.75)), and in Stage III patients (in The Netherlands (0.47; 0.43–0.50), Belgium (0.46; 0.41–0.50) and Sweden (0.48; 0.43–0.54)). In Stage III, results were consistent across subgroups including elderly patients. Our results show an association of ACT with higher survival among Stage III and high‐risk Stage II colon cancer patients. Further investigations are needed on the selection criteria of Stages II and III colon cancer patients for ACT.