Abstract Context There is wide interindividual variation in response to morphine for cancer-related pain; 30% of patients do not have a good therapeutic outcome. Alternative opioids such as oxycodone ...are increasingly being used, and opioid switching has become common clinical practice. Objectives To compare clinical response to oral morphine vs. oral oxycodone when used as first-line or second-line (after switching) treatment in patients with cancer-related pain. Methods In this prospective, open-label, randomized, controlled trial (ISRCTN65155201) with a selected crossover phase, patients with cancer-related pain were randomized to receive either oral morphine or oxycodone as first-line treatment. Dose was individually titrated until the patient reported adequate pain control. Patients who did not respond to the first-line opioid (either because of inadequate analgesia or unacceptable adverse effects) were switched to the alternative opioid. Results Two hundred patients were recruited. On intention-to-treat analysis ( n = 198, morphine 98, oxycodone 100), there was no significant difference between the numbers of patients responding to morphine (61/98 = 62%) or oxycodone (67/100 = 67%) when used as a first-line opioid. Similarly, there was no significant difference in subsequent response when patients were switched to either morphine (8/12 = 67%) or oxycodone (11/21 = 52%). Per-protocol analysis demonstrated a 95% response rate when both opioids were available. There was no difference in adverse reaction scores between morphine and oxycodone either in first-line responders or nonresponders. Conclusion In this population, there was no difference between analgesic response or adverse reactions to oral morphine and oxycodone when used as a first- or second-line opioid. These data provide evidence to support opioid switching to improve outcomes.
Goals of work
Constipation is a significant problem in patients taking morphine for cancer pain. The aims of this study were (1) to assess the magnitude of constipation in this study cohort, (2) to ...analyse the constipation treatment strategies and (3) to look for evidence of inter-individual variation in both susceptibility to constipation and response to treatment with laxatives in this patient group.
Materials and methods
This was an observational study carried out in a tertiary referral cancer hospital. Two hundred seventy four patients were recruited to the study. All had a diagnosis of cancer and were on oral morphine for cancer pain. The main outcomes measured were subjective patient assessment of constipation severity in the preceding week and laxative use. Patients were asked to grade constipation in the preceding week on a four-point categorical scale: “not at all” (grade 0), “a little” (grade 1), “quite a bit” (grade 2) and “very much” (grade 3). Laxative dose groups (LDGs) were developed to assess laxative dosing.
Results
Constipation affects 72% of this cohort of patients. Constipation in this population is poorly managed. Eighty nine percent of constipated patients were on inadequate laxative therapy. Inter-individual variation in constipation on morphine exists: some patients do not experience constipation and do not need to take any laxatives, some patients do not experience constipation
because
they are taking laxatives and some patients experience constipation
despite
being on high dose laxatives. These three groups were compared in terms of cancer diagnosis, time on morphine, dose of morphine and other concomitant factors. No factor was identified to account for this inter-individual variation. Improvement in the clinical management of constipation is needed, with titration of laxatives according to individual patient need.
Conclusion
Constipation affects a large proportion of cancer patients taking oral morphine. Constipation in these patients is generally inadequately treated.
Learning Objectives
After completing this course, the reader will be able to:
Describe some of the underlying mechanisms that contribute to why patients show differential responses to different ...opioids.
Identify some of the individual genes that may influence response to different opioids.
Critically evaluate the evidence for the therapeutic maneuver of switching.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Pain is one of the most common and often most feared symptoms in patients with cancer. Ongoing or progressive pain is physically debilitating and has a marked impact on quality of life. Since a third of the population will die from cancer, and of these, 80% will experience severe pain in their final year of life, effective treatment of cancer‐related pain remains both a high priority and an ongoing challenge in clinical practice. Individuals with moderate to severe cancer‐related pain require treatment with strong analgesics, namely opioids.
There is evidence to support the therapeutic maneuver of opioid switching in clinical practice, but further evidence is needed to elucidate the underlying mechanisms for interindividual differences in response to different opioids. Large, robust clinical trials will be needed if clinical differences among side‐effect profiles of different opioids are to be clearly demonstrated. This review discusses candidate genes, which contribute to opioid response; many other genes have also been implicated in “pain” from animal or human studies. In order to continue to evaluate the genetic contributions to both pain susceptibility and analgesic response, further candidate genes need to be considered. Good pain control remains a high priority for clinicians and patients, and there is much work to be done to further individualize analgesic therapy for patients with cancer.
A glutamic acid at residue 69(Glu(69)) in the HLA-DPB1 gene (Glu(69)) is associated with chronic beryllium disease (CBD) and possibly beryllium sensitization (BeS). This study tested the hypothesis ...that MHC class II polymorphisms are important in susceptibility to BeS and CBD and that the Glu(69) variant is related to markers of disease severity. Genomic DNA was obtained from BeS (n = 50), CBD (n = 104), and beryllium-exposed nondiseased (Be-nondiseased) (n = 125) subjects. HLA-DPB1, -DRB1, and -DQB1 genotypes were determined by (sequence-specific primers) PCR. Disease severity was assessed by pulmonary function and exercise testing. A higher frequency of the DPB1 Glu(69) gene was found in CBD and BeS compared with the Be-nondiseased subjects, with odds ratios of 10.1 for CBD vs Be-nondiseased and 9.5 for BeS vs Be-nondiseased. The majority of BeS and CBD subjects displayed non-0201 Glu(69) alleles. Glu(69) homozygosity was higher in the CBD subjects, while BeS subjects were intermediate and Be-nondiseased lowest. DRB1*01 and DQB1*05 phenotypes were reduced in CBD vs Be-nondiseased subjects, while DRB1*13 and DQB1*06 were associated with CBD in the absence of Glu(69). Markers of disease severity, including a lower forced vital capacity, diffusion capacity for carbon monoxide, PaO(2) at rest, maximum workload on exercise testing, and a higher arterial-alveolar gradient at rest, were associated with Glu(69) homozygosity. We conclude that DPB1 Glu69 is a marker of sensitization and not specific for disease. Glu(69) homozygosity acts as a functional marker associated with markers of CBD severity.
Crohn's disease (CD) and ulcerative colitis (UC), the chronic inflammatory bowel diseases (CIBD), are common causes of gastro-intestinal disease in the Western world, with a combined prevalence of ...100-200/100,000 (ref. 1). Epidemiological studies, particularly concordance rates in twin pairs and siblings, strongly implicate genetic susceptibility in the pathogenesis of CIBD. In fact, the relative contribution of genetic factors to the pathogenesis of CD may be greater than in schizophrenia, asthma or hypertension, and at least equivalent to that in insulin-dependent diabetes. Systematic screening of the entire human genome now provides a strategy for the identification of susceptibility genes in complex polygenic disorders. We undertook a two-stage genome search for susceptibility genes in inflammatory bowel disease involving 186 affected sibling pairs from 160 nuclear families. We provide strong evidence for the presence of susceptibility loci for both CD and UC on chromosome 3, 7 and 12. We obtained the highest lod score (5.47; P = 2.66 x 10(-7) with the marker D12S83 and lod scores of 3.08 and 2.69 for D7S669 and D3S1573, respectively. Our data suggest that CD and UC are closely related, but distinct, polygenic disorders that share some, but not all, susceptibility genes.
Detailed knowledge of linkage disequilibrium (LD) is regarded as a prerequisite for population-based disease gene mapping. Variable patterns across the human genome are now recognized, both between ...regions and populations. Here, we demonstrate that LD may also vary within a genomic region in a haplotype-specific manner. In 864 Caucasian unrelated individuals, we describe haplotype-specific LD patterns across the human MHC by the construction of gene-specific allelic haplotypes at 25 loci between HLA-A and Tapasin. Strong and extensive LD is found across both common and rare haplotypes, suggesting that haplotype structure is influenced by factors other than genetic drift, including both selection and differential haplotype recombination. Knowledge of haplotype-specific LD in the HLA may explain the apparent discrepant data from previous studies of global LD, help delineate key areas in mapping HLA-associated diseases and, together with recombination data, provide valuable information about a population's demographic history and the selective pressures operating on it.
Abstract Background Cytomegalovirus infection in renal transplant recipients is a major clinical problem, with both short and long term sequelae. Infection can occur as a result of reactivation of ...latent virus or new infection from donor tissues. The impact of donor and recipient serostatus on viremia is well recognised, with seronegative recipients at greatest risk after transplantation of an organ from a seropositive donor. However, the impact of grafting such organs into seropositive recipients is less clear. Objectives To assess the impact of recipient serostatus on the risk of CMV antigenemia in a large renal transplant cohort. Study design We prospectively quantified CMV antigenemia over time in a cohort of 486 recipients. We analysed the antigenemia status according to donor and recipient serostatus. Results Antigenemia was most common in seronegative recipients of organs from seropositive donors (D+/R−). Nevertheless, we observed that even in CMV seropositive recipients, the impact of donor serostatus on CMV antigenemia is still substantial ( p = 0.006; OR = 2.2). Conclusions In this large study, donor serostatus clearly plays a significant role in determining CMV risk, even in seropositive recipients.
Summary
Background Despite strong evidence implicating immune dysfunction and genetic predisposition in the pathogenesis of the chronic inflammatory bowel diseases Crohn's disease and ulcerative ...colitis, the importance of the genes of the major histocompatibility complex remains uncertain. We have investigated the contribution of HLA DRB1 and DQB genes by the strategies of non-parametric linkage analysis (affected sibling pair method) as well as association study. The relation between genotype and phenotype was examined in detail.
Methods For linkage analysis 74 families in whom two or more siblings had inflammatory bowel disease were studied. A total of 83 affected sibling pairs were involved: in 42 pairs both siblings had Crohn's disease; in 29 both had ulcerative colitis; in 12 one sibling had Crohn's disease, the other ulcerative colitis. For the association study there were 175 patients with ulcerative colitis, 173 with Crohn's disease, and 472 controls. Details of sex, age of onset, disease extent, and family history were analysed. 24 patients with ulcerative colitis and 92 with Crohn's disease required surgery for refractory disease. HLA DRB1 and DQB1 gene-typing was performed by polymerase chain reaction with sequence-specific primers.
Findings In ulcerative colitis, the sharing of alleles among affected sibling pairs provided evidence for linkage with DRB1 locus (p=0·017, X
2=5·32). Of 29 affected sibling pairs studied, only one pair shared no DRB1 DQB haplotypes. 15 shared two DRB DQB haplotypes. In contrast, no linkage was noted for Crohn's disease (42 sibling pairs; p=0·30, X
2=0·16) or for inflammatory bowel disease overall (83 sibling pairs, p=0·16, X
2=2·28). In the association study the rare DRB1*103 (8·3% vs 3·2% in controls) and DRB1*12 (8·6% vs 2·1% in controls) alleles were associated with ulcerative colitis (p=0·0074, X
2=7·22, odds ratio OR=2·9 95% Cl 1·3-6·4 and p=0·0056, X
2=12·63, OR=4·33 1·8-11·0 respectively). No association with alleles representing DR2 (p=0·55, X
2=0·34) was noted. No overall association was seen in Crohn's disease. In ulcerative colitis, the frequency of DRB1*0301 DQB*0201 (DR3 DQ2) was reduced in females (9·8% vs 26·3% in controls, p=0·037, X
2=8·39 OR=0·34 0·15-0·71), particularly in those with distal disease (2·3%, p=0·001 vs controls, X
2=11·35 OR=0·07
0·00-0·39). In both males and females, the DR3 DQ2 haplotype was predictive of extensive ulcerative colitis (32·9% vs 10·7% in distal disease, p<0·01, X
2=10·94, OR 4·09 1·70-10·6) but not of need for surgery (p=0·93, X
2=0·01).
Interpretation These data provide strong evidence for genetic heterogeneity in inflammatory bowel disease. Genes of the major histocompatibility complex are implicated as important inherited determinants of susceptibility to ulcerative colitis and may also influence the pattern of disease. In Crohn's disease, important susceptibility genes are likely to exist outside the HLA region.
Background & Aims:
We have investigated the influence of a biallelic polymorphism of the promoter region of stromelysin (matrix metalloproteinase 3) on susceptibility to primary sclerosing ...cholangitis (PSC). The 5A allele is associated with increased transcription, compared with wild-type (6A).
Methods:
An allelic association study was performed: in stage 1, 52 PSC patients (43 with inflammatory bowel disease IBD) and 99 healthy subjects (HS) were genotyped. In stage 2, 59 PSC patients (49 IBD), 84 patients with uncomplicated ulcerative colitis, and 72 HS were genotyped.
Results:
In stage 1, 5A carriage rate (90.4% vs. 72.7%;
P = 0.012) and 5A allelic frequency (65.4% vs. 48.5%;
P = 0.005) were increased, and 6A homozygosity was reduced in PSC (9.6% vs. 27.3%;
P = 0.012). In stage 2, 5A allelic carriage was increased in PSC (93.2% vs. 76.4% in HS;
P = 0.0092) and 6A homozygosity was reduced (6.8% vs. 23.8% in HS;
P = 0.0092). Portal hypertension was associated with 5A homozygosity in PSC (
P = 0.035; odds ratio OR, 3.88). In the combined data set, 5A allelic frequencies (63.5% vs. 49.4%;
P = 0.001; OR, 1.78) and 5A carriage rates (91.9% vs. 74.2%;
P = 0.0002; OR, 3.92) were increased, and 6A homozygosity was reduced in PSC (8.1% vs. 25.7%;
P = 0.0002; OR, 0.25). Overall, portal hypertension was associated with 5A homozygosity (
P = 0.0192; OR, 3.12).
Conclusions:
Stromelysin polymorphism may influence susceptibility and disease progression in PSC.
Acute allograft rejection remains an important cause of morbidity after kidney transplantation, and has been shown to be a crucial determinant of long-term graft function. Although rejection is ...mediated by recipient lymphocytes, both donor and recipient factors contribute to the local environment that influences the nature, severity, and duration of the rejection response. Cytokines are a major determinant of this milieu, and this study sought to explore the impact of donor cytokine and cytokine receptor gene polymorphisms on acute rejection after renal transplantation.
A total of 145 cadaveric renal allograft donors were selected for analysis according to the presence or absence of graft rejection in the first 30 days after transplantation. DNA was genotyped for 20 polymorphisms in 11 cytokine and cytokine receptor genes using the polymerase chain reaction with sequence specific primers. Associations were assessed using contingency table analysis and the chi2 test, using a two-set design.
A polymorphism at position -174 of the donor IL-6 gene was associated with the incidence (P=0.0002) and severity (P=0.000007) of recipient acute rejection. This finding was independent of HLA-DR matching. Acute rejection was not influenced by recipient IL-6 genotype, or by donor-recipient matching of IL-6 genotype.
This study identifies donor IL-6 genotype as a major genetic risk factor for the development of acute rejection after renal transplantation. This provides evidence that donor-derived cytokines play a major role in determining outcome after transplantation, and will contribute to the development of therapeutic algorithms to predict individuals at particularly high risk of acute rejection.
PDF
