Real-world use of trifluridine/tipiracil for patients with metastatic colorectal cancer in Canada.

Background: Outcomes for patients with metastatic colorectal cancer (mcrc) are improving with the introduction of new treatments. Treatment for patients who are still fit after failure of all available therapies represents a significant unmet need. In the present study, we analyzed real-world treatment patterns for patients enrolled in Health Canada's trifluridine/tipiracil (ftd/tpi) Special Access Program (sap) and Taiho Pharma Canada's Patient Support Program (psp). Methods: Demographic information and clinical treatment data were collected from adults with mcrc who were previously treated with, or were not candidates for, available therapies and who were enrolled in the sap and psp. For all patients, ftd/tpi treatment status, discontinuation reasons, and prior therapies were examined. Results: The analysis included 717 Canadian patients enrolled in the ftd/tpi sap and psp from September 2017 to October 2018. In that cohort, 59.7% were men, median age was 65 years, and median duration of therapy was 77 days (25%-75% interquartile range: 43-106 days). Of treated patients, 67.1% maintained the same dose for the duration of therapy; 28.0% had a dose reduction.On multivariable analysis, duration of therapy was not influenced by sex, age, province, RAS mutation status, or prior therapies. However, prior oxaliplatin-based chemotherapy (capox or folfox) appeared to be associated with higher rates of discontinuation because of death or disease progression. Conclusions: In advanced mcrc, ftd/tpi is a well-tolerated therapy. The large number of patients enrolled in the access programs within a short period of time is reflective of major clinical need in this area, with many patients being eligible and interested in pursuing treatment in the refractory setting.

Active treatment in low-risk prostate cancer: a population-based study.

Background: Active surveillance instead of active treatment (at) is preferred for patients with low-risk prostate cancer (lr-pca), but practice varies widely. We conducted a population-based study to assess the proportion of patients who underwent at between January 2011 and December 2014, and to evaluate factors associated with at. Methods: The provincial cancer registry was linked to administrative health datasets to identify patients with lr-pca and to acquire demographic, tumour, and treatment data. The primary outcome was receipt of at during the first 12 months after diagnosis, defined as any receipt of external-beam radiotherapy, brachytherapy, radical prostatectomy, cryotherapy, or androgen deprivation. Univariate and multivariate logistic regression were used to analyze the correlation between patient and tumour factors and at. Results: Of 1565 patients with lr-pca, 554 (35.4%) underwent at within 12 months of diagnosis. Radical prostatectomy was the most common treatment (58%), followed by brachytherapy (29.6%). Younger age [odds ratio (or) 0.92; 95% confidence interval (ci): 0.91 to 0.94], lower score (≥3) on the Charlson comorbidity index (OR: 0.36; 95% ci: 0.19 to 0.68), T2 stage (or: 3.05; 95% ci: 2.03 to 4.58), higher prostate-specific antigen (psa) at diagnosis (or: 1.13; 95% ci: 1.06 to 1.21), radiation oncologist consultation (or: 3.35; 95% ci: 2.55 to 4.39), and earlier diagnosis year (2012 or: 0.46; 95% ci: 0.34 to 0.63; 2013 or: 0.45; 95% ci: 0.32 to 0.63; 2014 or: 0.33; 95% ci: 0.23 to 0.47) were associated with a higher probability of at. Conclusions: This contemporary population-based study demonstrates that approximately one third of patients with lr-pca undergo at. Patients of younger age, with less comorbidity, a higher tumour stage, higher psa, earlier year of diagnosis, and radiation oncologist consultation were more likely to undergo at. Further investigation is needed to identify strategies that could minimize overtreatment.

Association between obesity in 4- to 7-year-old children and eight types of crime: a hierarchical linear modelling approach.

OBJECTIVE: Evidence of the association between childhood obesity and neighbourhood crime is inconclusive. Most previous studies have included children of all ages, and few have examined different types of crime. The objective of this study was to investigate the association between obesity and eight different types of crime (i.e. commercial robbery, street robbery, assault, other violence, commercial break and enter, residential break and enter, theft of vehicle and theft from vehicle) among 4- to 7-year-old children in a large western Canadian city. METHODS: Cross-sectional, epidemiological study (N = 10,069) using spatial analysis and hierarchical generalized linear modelling. The outcome variable was normal weight or obesity. The exposure variable was the distance between the child's residential postal code and the closest occurrence of each type of crime. RESULTS: Controlling for distance to the closest park, frequency of each type of crime in the child's neighbourhood and neighbourhood factors (proportion of visible minorities, education and median family income), there was no association between any of the crime types and childhood obesity. CONCLUSIONS: Crime did not contribute to obesity in this sample of 4- to 7-year-old children. Replication of this study in other jurisdictions would increase confidence in these results.

Robinow syndrome.

In 1969, Robinow and colleagues described a syndrome of mesomelic shortening, hemivertebrae, genital hypoplasia, and "fetal facies". Over 100 cases have now been reported and we have reviewed the current knowledge of the clinical and genetic features of the syndrome. The gene for the autosomal recessive form was identified as the ROR2 gene on chromosome 9q22. ROR2 is a receptor tyrosine kinase with orthologues in mouse and other species. The same gene, ROR2, has been shown to cause autosomal dominant brachydactyly B, but it is not known at present whether the autosomal dominant form of Robinow syndrome is also caused by mutations in ROR2.

Amplification of a 13.5-kb region of the PKD1 gene containing the 2.5-kb polypyrimidine tract in intron 21 facilitates mutation detection in this gene.

Mutation detection in the PKD1 gene proved to be difficult because two-thirds of the gene is reiterated several times on chromosome 16. Long-range PCR has been used previously to overcome this limitation, but due to a 2.5-kb polypyrimidine tract in intron 21, the screening capacity of the PKD1 gene using this technique was hindered. Here we report the measures that we have used to overcome this limitation.

Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.

The autosomal recessive form of Robinow syndrome (RRS; MIM 268310) is a severe skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly and a dysmorphic facial appearance. We previously mapped the gene mutated in RRS to chromosome 9q22 (ref. 4), a region that overlaps the locus for autosomal dominant brachydactyly type B (refs 5,6). The recent identification of ROR2, encoding an orphan receptor tyrosine kinase, as the gene mutated in brachydactyly type B (BDB1; ref. 7) and the mesomelic dwarfing in mice homozygous for a lacZ and/or a neo insertion into Ror2 (refs 8,9) made this gene a candidate for RRS. Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation that removes the tyrosine kinase domain and all subsequent 3' regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggests that RRS is caused by loss of ROR2 activity. The identification of mutations in three distinct domains (containing Frizzled-like, kringle and tyrosine kinase motifs) indicates that these are all essential for ROR2 function.

Linkage of recessive Robinow syndrome to a 4 cM interval on chromosome 9q22.

Autosomal recessive Robinow syndrome is a form of mesomelic dwarfism with multiple rib and vertebral anomalies. Using autozygosity mapping we have identified a genetic locus (RBNW1) for this syndrome at chromosome 9q22 in seven consanguineous families from Oman. Our results indicate that the gene lies within a 4 cM region between markers D9S1836 and D9S1803 (maximum multipoint LOD score 12.3). In addition, we have analysed two non-Omani families with autosomal recessive Robinow and found no genetic heterogeneity.

Location of mutations within the PKD2 gene influences clinical outcome.

BACKGROUND: Since the cloning of the gene for autosomal dominant polycystic kidney disease type 2 (PKD2), approximately 40 different mutations of that gene have been reported to be associated with the disease. The relationship between the PKD2 genotype and phenotype, however, remains unclear. METHODS: Detailed clinical information was collected for PKD2 families in which the underlying mutation had been identified. Logistic regression analysis was employed to assess the influence of age and sex on hypertension, hematuria, renal calculi, and urinary tract infections, and a clinical phenotype score was computed. Patients were then grouped according to the relative location of their mutation within the cDNA sequence, and differences in the mean phenotypic score between groups were tested for statistical significance by means of a multiple pairwise t-test. RESULTS: While phenotypic scores for each mutational group revealed a considerable degree of intragroup variability, the variability in phenotypic scores was significantly higher between mutational groups than within groups. A group-wise comparison of the mean phenotypic scores confirmed the observation of significant nonlinear variation in disease severity, with high- and low-scoring mutational groups interspersed along the gene sequence. CONCLUSION: The identification of groups of mutations in the PKD2 gene, which differ significantly with respect to clinical outcome, is to our knowledge the first description of a genotype/phenotype correlation in autosomal dominant polycystic kidney disease. It also provides evidence against complete loss of function of the mutant PKD2 gene product.

Angiotensin-converting enzyme gene I/D polymorphism and carotid artery disease in renovascular hypertension.

There is evidence linking the activation of the renin-angiotensin system (RAS) with target organ damage in renovascular hypertension (RVH). A genetic association of the DD genotype of the angiotensin-converting enzyme (ACE) gene with cardiovascular complications has been found in various clinical conditions. The aim of our study was to determine whether the insertion/deletion (I/D) polymorphism of the ACE gene is associated with the high prevalence of target organ damage reported in RVH. A total of 65 atherosclerotic patients (age 68.2 +/- 5.2 years) with RVH and 49 atherosclerotic patients (age 68.0 +/- 6.3 years) with essential hypertension (EH) were sequentially enrolled when attending the outpatient clinic for specialist assessment of their vascular disorder. Cardiac, renal, and vascular involvement were assessed in both groups and blood was taken for genetic analysis. Patients with RVH had a higher prevalence of left ventricular hypertrophy (LVH), carotid artery disease, and albuminuria than those with EH. In RVH, but not in EH, the DD genotype was significantly associated with severe arterial disease. In RVH, carotid disease (lumen narrowing >60%) was present in 62% of DD patients versus 25% of the other genotypes (OR = 4.90, 95% CI: 1.70-14.13). Such an association was also present in peripheral vascular disease: 72.4% in DD patients versus 41.6% in the other genotypes (OR = 3.67, 95% CI = 1.29-10.36). Logistic regression analysis showed that the DD genotype was the strongest predictor of risk of severe carotid disease. We conclude that, in atherosclerotic RVH, there is an association of the severity of vascular disease with the DD genotype of the ACE gene.

ACE gene polymorphism and survival in atherosclerotic renovascular disease.

Renovascular disease (RVD) is an important cause of end-stage renal disease and is associated with a high mortality rate, mostly because of coexisting cardiovascular and cerebrovascular disease. The deletion (DD) polymorphism of the angiotensin-converting enzyme (ACE) gene has been described in association with severe vascular disease affecting major organs. To investigate whether DD genotype is a risk factor for mortality in RVD, we performed a follow-up study of 61 patients with this disease. Patients (age, 68.0 +/- 6.5 years) affected by atherosclerotic vascular disease were enrolled after angiographic demonstration of a renal artery stenosis. The average follow-up was 48.1 +/- 14.9 months. Genotype was insertion/deletion (I/D) in 30 patients, DD in 27 patients, and II in 4 patients. At enrollment, a complete assessment of heart, blood vessels, and renal function was performed. During the follow-up period, 13 patients died (9 DD, 4 ID) and 7 patients evolved into end-stage renal failure. The cumulative survival rate at 5 years was 45.4% +/- 13.4%. Factors associated with mortality were analyzed with Cox proportional hazard regression. The multivariate analysis showed that DD genotype, severe carotid disease, and smoking were independent predictors of mortality. The multivariate analysis of predictors of renal failure showed that the only significant association was found with baseline serum creatinine level of 265 micromol/L or greater. We conclude that the DD genotype of the ACE gene is a marker for mortality in RVD.

Lack of association of ACE/angiotensinogen genotype with renal function in autosomal dominant polycystic kidney disease.

ACE polymorphisms have recently been shown to associate with worse renal and or cardiovascular outcome, with the D allele widely reported as a risk factor for cardiovascular disease. In autosomal dominant polycystic kidney disease (ADPKD), there are conflicting reports of an association between ACE polymorphisms and disease phenotype. There are no previous reports of any association between angiotensinogen polymorphisms and clinical phenotype in ADPKD. We examined the ACE I/D and angiotensinogen M235T polymorphisms in 176 patients with ADPKD. Patients are categorized into three groups according to the reason for initial investigation. Clinical history and examination findings were recorded at the time of first referral. A cohort of 17 patients had progressive renal impairment observed after 3 or more years of follow-up. Reciprocal creatinine against time was plotted in this group. From the patient population of 176, a total of 33 patients reached end-stage renal failure (ESRF) or a serum creatinine greater than 500 microm/liter. ACE genotype and M235T polymorphism frequencies were compared across groups. Serum creatinine and presence of hypertension and onset of ESRF were taken as outcome variables; age and source of referral were taken as confounding variables. There was no association of any genotype or allele with either creatinine, inverse creatinine, hypertension, or age at end-stage renal failure. These findings do not support the proposition that ACE genotype or angiotensinogen polymorphisms are associated with a worse prognosis in patients with ADPKD.

Novel mutations in the duplicated region of the polycystic kidney disease 1 (PKD1) gene provides supporting evidence for gene conversion.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human single-gene disorders, and is the most common inherited form of cystic kidney disease. It is estimated that approximately 85% of ADPKD is due to mutations in the PKD1 gene, which is located on chromosome 16p13.3. Mutation analysis in this gene is difficult, because more than two-thirds of reiterated several times at 16p13.1. In this study, mutation screening in 90 ADPKD patients was carried out on exons in the duplicated region of the PKD1 gene (23-34), using genomic long-range PCR followed by nested PCR and single-strand conformation polymorphism (SSCP), and finally cycle sequencing. Two nonconservative missense mutations were detected in exons 25 and 31, and two conservative mutations were found in exons 24 and 29. A novel splicing mutation, which is expected to cause skipping of exon 30, was detected in one case. Moreover, six intronic variants, three silent variants, and one polymorphic variant were detected in this study. Comparison between some of these changes and published sequences from the homologous genes on 16p13.1, revealed supporting evidence for the gene conversion theory as a mechanism responsible for some of the mutations in the PKD1 gene. Factors likely to facilitate gene conversion in this region of the PKD1 gene are discussed.

Splicing mutations in KCNQ1: a mutation hot spot at codon 344 that produces in frame transcripts.

BACKGROUND: Long-QT syndrome is a monogenic disorder that produces cardiac arrhythmias and can lead to sudden death. At least 5 loci and 4 known genes exist in which mutations have been shown to be responsible for the disease. The potassium channel gene KCNQ1, previously named KVLQT1, on chromosome 11p15.5 is one of these. METHODS AND RESULTS: We initially analyzed one family using microsatellite markers and found linkage to KCNQ1. Mutation detection showed a G to C change in the last base of exon 6 (1032 G-->C) that does not alter the coded alanine. Restriction digest analysis in the family showed that only affected individuals carried the mutation. A previous report suggested that a G to A substitution at the same position may act as a splice mutation in KCNQ1, but no data was given to support this hypothesis nor was the transcription product identified. We have shown by reverse-transcription polymerase chain reaction that 2 smaller bands were produced for the KCNQ1 gene transcripts in addition to the normal-sized transcripts when lymphocytes of affected individuals were analyzed. Sequencing these transcripts showed a loss of exon 7 in one and exons 6 and 7 in the other, but an in-frame transcript was left in each instance. We examined other families in whom long-QT syndrome was diagnosed and found another unreported splice-site mutation, 922-1 G-->C, in the acceptor site of intron 5, and 2 of the previously reported 1032 G-->A mutations. All these showed a loss of exons 6 and 7 in the mutant transcripts, validating the proposal that a consensus sequence is affected in the exonic mutations and that the integrity of the base at position 1032 is essential for correct processing of the transcript. CONCLUSIONS: The 6 cases already reported in the literature with the 1032 G-->A transition, the novel 1032 G-->C transversion, and a recent G-->T transversion at the same base show that codon 344 is the second most frequently mutated after codon 341, suggesting at least two hotspots for mutations in KCNQ1.

Novel mutations in the 3 region of the polycystic kidney disease 1 (PKD1) gene.

Mutation screening in 90 unrelated ADPKD1 patients was carried out on some of the exons in the single copy area (37, 38, 39, 44, 45) using genomic PCR and SSCP. Four novel mutations were found: a 15 bp in-frame deletion in exon 39 [nt11449 (del 15)], a 2 bp deletion in exon 44 [nt12252 (del 2)], a G insertion in exon 44 [nt12290 (Ins G)], and a GTT in-frame deletion in exon 45 [nt12601 (del 3)].