A novel method for continuous measurements of clinical practice guideline adherence.

Introduction: Clinical practice guidelines (hereafter 'guidelines') are crucial in providing evidence-based recommendations for physicians and multidisciplinary teams to make informed decisions regarding diagnostics and treatment in various diseases, including cancer. While guideline implementation has been shown to reduce (unwanted) variability and improve outcome of care, monitoring of adherence to guidelines remains challenging. Real-world data collected from cancer registries can provide a continuous source for monitoring adherence levels. In this work, we describe a novel structured approach to guideline evaluation using real-world data that enables continuous monitoring. This method was applied to endometrial cancer patients in the Netherlands and implemented through a prototype web-based dashboard that enables interactive usage and supports various analyses. Method: The guideline under study was parsed into clinical decision trees (CDTs) and an information standard was drawn up. A dataset from the Netherlands Cancer Registry (NCR) was used and data items from both instruments were mapped. By comparing guideline recommendations with real-world data an adherence classification was determined. The developed prototype can be used to identify and prioritize potential topics for guideline updates. Results: CDTs revealed 68 data items for recording in an information standard. Thirty-two data items from the NCR were mapped onto information standard data items. Four CDTs could sufficiently be populated with NCR data. Conclusion: The developed methodology can evaluate a guideline to identify potential improvements in recommendations and the success of the implementation strategy. In addition, it is able to identify patient and disease characteristics that influence decision-making in clinical practice. The method supports a cyclical process of developing, implementing and evaluating guidelines and can be scaled to other diseases and settings. It contributes to a learning healthcare cycle that integrates real-world data with external knowledge.

Radical prostatectomy versus external beam radiotherapy with androgen deprivation therapy for high-risk prostate cancer: a systematic review.

BACKGROUND: To summarize recent evidence in terms of health-related quality of life (HRQoL), functional and oncological outcomes following radical prostatectomy (RP) compared to external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) for high-risk prostate cancer (PCa). METHODS: We searched Medline, Embase, Cochrane Database of Systematic Reviews, Cochrane Controlled Trial Register and the International Standard Randomized Controlled Trial Number registry on 29 march 2021. Comparative studies, published since 2016, that reported on treatment with RP versus dose-escalated EBRT and ADT for high-risk non-metastatic PCa were included. The Newcastle-Ottawa Scale was used to appraise quality and risk of bias. A qualitative synthesis was performed. RESULTS: Nineteen studies, all non-randomized, met the inclusion criteria. Risk of bias assessment indicated low (n = 14) to moderate/high (n = 5) risk of bias. Only three studies reported functional outcomes and/or HRQoL using different measurement instruments and methods. A clinically meaningful difference in HRQoL was not observed. All studies reported oncological outcomes and survival was generally good (5-year survival rates > 90%). In the majority of studies, a statistically significant difference between both treatment groups was not observed, or only differences in biochemical recurrence-free survival were reported. CONCLUSIONS: Evidence clearly demonstrating superiority in terms of oncological outcomes of either RP or EBRT combined with ADT is lacking. Studies reporting functional outcomes and HRQoL are very scarce and the magnitude of the effect of RP versus dose-escalated EBRT with ADT on HRQoL and functional outcomes remains largely unknown.

Factors influencing the quality and functioning of oncological multidisciplinary team meetings: results of a systematic review.

BACKGROUND: Discussing patients with cancer in a multidisciplinary team meeting (MDTM) is customary in cancer care worldwide and requires a significant investment in terms of funding and time. Efficient collaboration and communication between healthcare providers in all the specialisms involved is therefore crucial. However, evidence-based criteria that can guarantee high-quality functioning on the part of MDTMs are lacking. In this systematic review, we examine the factors influencing the MDTMs' efficiency, functioning and quality, and offer recommendations for improvement. METHODS: Relevant studies were identified by searching Medline, EMBASE, and PsycINFO databases (01-01-1990 to 09-11-2021), using different descriptions of 'MDTM' and 'neoplasm' as search terms. Inclusion criteria were: quality of MDTM, functioning of MDTM, framework and execution of MDTM, decision-making process, education, patient advocacy, patient involvement and evaluation tools. Full text assessment was performed by two individual authors and checked by a third author. RESULTS: Seventy-four articles met the inclusion criteria and five themes were identified: 1) MDTM characteristics and logistics, 2) team culture, 3) decision making, 4) education, and 5) evaluation and data collection. The quality of MDTMs improves when the meeting is scheduled, structured, prepared and attended by all core members, guided by a qualified chairperson and supported by an administrator. An appropriate amount of time per case needs to be established and streamlining of cases (i.e. discussing a predefined selection of cases rather than discussing every case) might be a way to achieve this. Patient centeredness contributes to correct diagnosis and decision making. While physicians are cautious about patients participating in their own MDTM, the majority of patients report feeling better informed without experiencing increased anxiety. Attendance at MDTMs results in closer working relationships between physicians and provides some medico-legal protection. To ensure well-functioning MDTMs in the future, junior physicians should play a prominent role in the decision-making process. Several evaluation tools have been developed to assess the functioning of MDTMs. CONCLUSIONS: MDTMs would benefit from a more structured meeting, attendance of core members and especially the attending physician, streamlining of cases and structured evaluation. Patient centeredness, personal competences of MDTM participants and education are not given sufficient attention.

Is smoking an independent risk factor for developing cervical intra-epithelial neoplasia and cervical cancer? A systematic review and meta-analysis.

Introduction: Cervical cancer is the fourth most common form of cancer among women. Smoking tobacco seems to be a risk factor for the development of cervical intra-epithelial neoplasia (CIN) and cervical cancer, but the exact role of smoking in the process of cervical carcinogenesis is not known. The aim of this study is to investigate the relationship between smoking and the development of CIN and cervical cancer. Areas covered: We searched Embase, Medline, Cochrane Central, Web of Science, and Google Scholar for studies on smoking and CIN and cervical cancer, published between 2009 and 2018. The following were the outcomes: CIN3 alone, CIN2 and CIN3 combined, CIN2+, CIN3+, and cervical cancer alone. We included 49 studies in our review and 45 in our meta-analyses. Expert opinion: Based on the available evidence it can be - cautiously - concluded that smoking increases the risk of cervical abnormalities. However, the high risk of bias indicates that for future studies, it will be important to adjust for relevant predictors, to separate CIN from cervical cancer as outcome measures, and to report research methods in detail.

Exposure to ultraviolet radiation and risk of malignant lymphoma and multiple myeloma--a multicentre European case-control study.

BACKGROUND: Three recent studies have reported a decreased risk of non-Hodgkin lymphoma (NHL) for high ultraviolet (UV) radiation exposure. METHODS: We conducted a multicentre case-control study during 1998-2004 in France, Germany, Ireland, Italy and Spain, comprising 1518 cases of NHL, 268 cases of Hodgkin lymphoma, 242 cases of multiple myeloma and 2124 population or hospital controls. We collected information on sensitivity to sun and personal exposure to UV radiation in childhood and adulthood via interview, and assessed occupational exposure to UV radiation from the occupational history. RESULTS: The risk of Hodgkin and NHL was increased for increasing skin sensitivity to the sun [odds ratio (OR) for no suntan vs very brown 2.35, 95% CI 0.94-5.87 and 1.39, 95% CI 1.03-1.87, respectively]. The risk of diffuse large B-cell lymphoma was reduced for increasing adult personal (OR for highest vs lowest quartile of exposure in free days 0.62, 95% CI 0.44-0.87) and for occupational exposure to UV radiation (OR for highest vs lowest exposure tertile 0.63, 95% CI 0.37-1.04). The risk of multiple myeloma was increased for personal exposure to UV radiation during adulthood (OR for highest vs lowest quartile of exposure in free days 1.49, 95% CI 0.88-2.50). A protective effect was observed for use of sun lamps for diffuse large B-cell lymphoma (OR for 25+ times vs never 0.63, 95% CI 0.38-1.03). CONCLUSIONS: The hypothesis of a protective effect of UV radiation on lymphoma is supported by our results. The underlying mechanisms might differ from those operating in skin carcinogenesis. The increased risk of multiple myeloma is worth replication.

Chromosome damage and cancer risk in the workplace: the example of cytogenetic surveillance in Croatia.

The use of cytogenetic assays in the surveillance of populations occupationally exposed to genotoxic carcinogens originates from the assumption that chromosomal alterations might be causally involved in early stages of carcinogenesis. Historical cohort studies have since 1990s consistently reported an association between the level of chromosomal aberrations (CA) in peripheral lymphocytes of healthy subjects and the risk of cancer. Only in few cases, have these results been transformed into a regulatory tool for improving occupational safety. The cytogenetic surveillance program adopted for more than two decades in the Republic of Croatia is one of these few examples. Croatian workers exposed to genotoxic agents were systematically screened for CA, to identify occupational settings needing a priority intervention. Significant increases of mean CA frequency were observed in groups exposed to ionizing radiation, chemical agents, and mixed exposures when compared with a group of unexposed referents. CA data on 736 men and 584 women, monitored between 1987 and 2000, have been associated with cancer incidence. Although the small size of the cohort did not allow for reaching statistical significance, the medium tertile of the CA frequency distribution was associated with a doubling of cancer incidence rate ratio (IRR=2.40; 95% CI 0.85-6.77) when compared with the lowest tertile. For chromosome-type CA, IRR was non-significantly increased for both the medium (IRR 1.53, 95% CI 0.58-3.99) and high categories (IRR 1.69; 95% CI 0.61-4.72). Recommendations for future strategies comprise the inclusion of predictive biomarkers in surveillance programs, the definition of a regulatory framework, and their possible use for the identification of individual risk profiles.

Chromosomal aberrations and cancer risk: results of a cohort study from Central Europe.

A high level of chromosomal aberrations in peripheral blood lymphocytes may be an early marker of cancer risk, but data on risk of specific cancers and types of chromosomal aberrations (chromosome type and chromatid type) are limited. A total of 6,430 healthy individuals from nine laboratories in Croatia, Hungary, Lithuania, Poland, and Slovakia, included in chromosomal aberration surveys performed during 1978-2002, were followed up for cancer incidence or mortality for an average of 8.5 years; 200 cancer cases were observed. Compared with that for the low-tertile level of chromosomal aberrations, the relative risks of cancer for the medium and high tertiles were 1.78 (95% confidence interval: 1.19, 2.67) and 1.81 (95% confidence interval: 1.20, 2.73), respectively. The relative risk for chromosome-type aberrations above versus below the median was 1.50 (95% confidence interval: 1.12, 2.01), while that for chromatid-type aberrations was 0.97 (95% confidence interval: 0.72, 1.31). The analyses of risk of specific cancers were limited by small numbers, but the association was stronger for stomach cancer. This study confirms the previously reported association between level of chromosomal aberrations and cancer risk and provides novel information on the type of aberrations more strongly predictive of cancer risk and on the types of cancer more strongly predicted by chromosomal aberrations.

Cumulative genetic defects in carcinogen metabolism may increase breast cancer risk (The Netherlands).

Variants in the metabolic genes NAT1, NAT2, GSTM1 or GSTT1, may cause differences in individual detoxifying capacity of possible carcinogens. We examined the cumulative effect of putative at risk genotypes on breast cancer risk and we examined the extent to which these polymorphisms modify the association between smoking and breast cancer. A case cohort study was conducted in the DOM cohort with 676 breast cancer cases and a random sample of 669 individuals. No effect of the NAT1, NAT2 or GSTM1 genotypes on breast cancer risk was observed. However, women with GSTT1 null genotype had a 30% increased breast cancer risk compared to women with GSTT1 present (RR = 1.30 (95% confidence interval (CI) 1.04-1.64)). Smoking did not influence breast cancer risk nor did genetic variations in NAT1, NAT2 or GSTM1 in combination with smoking. Compared to women who never smoked with GSTT1 present, women with GSTT1 null genotype and who formerly smoked showed an increased breast cancer risk (RR = 2.55 (95% CI 1.10-5.90)), but current smokers who smoked 20 cigarettes or more per day did not (RR = 1.06 (95% CI 0.51-2.18)). Increasing numbers of putative at risk genotypes increased breast cancer risk in a dose dependent manner (p for trend 0.01). The risk was more than doubled in women with all four risk genotypes, RR = 2.45 (95% CI 1.24-4.86), compared to women with zero putative at risk genotypes. In conclusion, the results of this study suggest that presence of three or more putative at risk genotypes increases breast cancer risk.

Perspectives on the molecular epidemiology of aerodigestive tract cancers.

Improving laboratory techniques and the greater availability of genetic data have led to a flurry of publications from molecular epidemiologic studies on aerodigestive tract cancers. Inconsistent results have been observed in studies of sequence variants, due to limitations such as small sample size, possible detection of false positives, moderate prior probabilities that each SNP confers a substantial increase in cancer risk, and publication bias. Meta- and pooled-analyses were shown to be effective in elucidating modest increases in aerodigestive tract cancer risk attributable to sequence variants. Phenotypic assays developed to quantify an individual's DNA repair capacity have been applied to epidemiological studies on aerodigestive tract cancers. Epigenetic events have also been studied in tumor progression and as susceptibility factors for aerodigestive tract cancers, in smaller scale studies. It is imperative that limitations of previous studies are addressed for future research in the molecular epidemiology of aerodigestive tract cancers. Some recommendations for future research are to: (i) incorporate multiple markers of different types (ex. genotype and phenotype data), (ii) enhance statistical power by conducting studies with larger sample size, and developing consortia to coordinate research efforts, (iii) improve marker selection via a hybrid strategy of incorporating data on evolutionary biology and physico-chemical properties of amino acids, with haplotype/tag SNP data, (iv) employ novel statistical methods such as hierarchical modeling with Bayesian adjustments, false positive reporting probability and modeling of complex pathways. Consortia have been initiated for head and neck cancer (International Head and Neck Cancer Epidemiology Consortium (INHANCE)) and lung cancer (International Lung Cancer Consortium (ILCCO)) with the aim to share comparable data, to focus on rare subgroups such as nonsmokers and to coordinate laboratory analyses. Such collaborative efforts and integration across disciplines will be essential in contributing to the elucidation of genetic susceptibility to aerodigestive tract cancers.

Renal cell carcinoma in relation to cigarette smoking: meta-analysis of 24 studies.

Renal cell carcinoma (RCC) accounts for 3% of adult deaths from cancer. The risk factors for its development are still under intense investigation. Although tobacco smoke is a risk factor, the data are inconsistent and the extent of the increased risk is unclear. Estimates from 19 case-control and 5 cohort studies were used. The case-control reports included 8,032 cases and 13,800 controls; the cohort estimates were based on 1,457,754 participants with 1,326 cases of RCC. The relative risk (RR) for RCC for ever smokers as compared to lifetime never smokers was 1.38 (95% confidence interval [CI] = 1.27-1.50). The RR for male smokers was 1.54 (95% CI = 1.42-1.68) and for female smokers was 1.22 (95% CI = 1.09-1.36). For men and women there was a strong dose-dependent increase in risk. Ever smoker men who had smoked 1-9, 10-20 or 21 or more cigarettes/day had a RR of 1.60 (95% CI = 1.21-2.12), 1.83 (95% CI = 1.30-2.57), or 2.03 (95% CI = 1.51-2.74), respectively. For women, the relative risks were 0.98 (95% CI = 0.71-1.35), 1.38 (95% CI = 0.90-2.11), or 1.58 (95% CI = 1.14-2.20), respectively. The advantages of smoking cessation were confirmed by a reduction in RR for those who had quit smoking for >10 years as compared to those who had quit for 1-10 years. Inhaled tobacco smoke is clearly implicated in the etiology of RCC, with a strong dose-dependent increase in risk associated with numbers of cigarettes smoked per day and a substantial reduction in risk for long-term former smokers.

GSTM1 null genotype, red meat consumption and breast cancer risk (The Netherlands).

OBJECTIVE: We studied whether polymorphisms in N-acetyltransferase 1 and 2 and Glutathione S-transferase M1 and T1 genes modify the association between meat consumption and breast cancer. METHODS: A nested case control was conducted in a Dutch prospective cohort. Breast cancer cases (229) and controls (264) were frequency matched on age, town and menopausal status. RESULTS: There is no relation between any type of meat consumption ( i.e., total meat, processed meat, fresh meat, red meat and white meat) and breast cancer risk. Neither presence of NAT1 or NAT2 rapid genotype, or GSTT1 null genotype, alone or in combination with meat consumption affects breast cancer risk. Absence of GSTM1 shows 46% increased breast cancer risk (OR = 1.46 (95% confidence interval, 95% CI = 1.02-2.09)). When stratifying according to combined 'GSTM1 genotype-meat consumption' categories, breast cancer risk is slightly increased with consumption of red meat both in women with genotype GSTM1 presence (OR = 1.49 and 1.75 for intermediate and high versus low consumption) and in GSTM1 null genotype (OR = 1.18 and 1.02). These increases are statistically not significant. In postmenopausal women a suggestion of an effect of red meat consumption is observed: effects are slightly stronger, although still not statistically significant and without a clear dose-response relation: OR = 1.79 (95% CI = 0.92-3.50) and 1.46 (1.46 (95% CI = 0.76-2.82) for intermediate and high compared to low red meat consumption respectively. Reliable evaluation of interaction is not possible due to the small number of cancers. CONCLUSION: GSTM1 null genotype increases breast cancer risk. Red meat consumption slightly increases breast cancer risk, but the relation is not statistically significant and GSTM1, NAT1, NAT2 and GSTT1 polymorphisms do not modify this relation.

Heterozygosity for the Cys282Tyr mutation in the HFE gene and the risk of colorectal cancer (Netherlands).

BACKGROUND & AIMS: Heterozygosity for the Cys282Tyr transition in the HFE-gene is associated with slightly increased iron levels and may therefore be a potential risk factor for colorectal cancer. METHODS: We studied the relationship between Cys282Tyr-heterozygosity and colorectal cancer using a case-control design. The 240 colorectal cancer cases and 635 controls in our study were derived from a prospective cohort study of 12,242 postmenopausal women, who were invited for an experimental breast cancer screening program in Utrecht, The Netherlands. The women were age 51-69 at time of inclusion and were followed for a period of 20 years. HFE genotyping was performed by PCR and allele-specific oligonucleotide (ASO) hybridization. RESULTS: The risk of colorectal cancer was higher for women who were heterozygous for the Cys282Tyr mutation, than for those who were Cys282Tyr-wildtypes, although this was not statistically significant (Age-adjusted OR = 1.2, 95% CI: 0.6-2.2). Cys282Tyr-heterozygotes who smoked seemed to be at higher risk of colorectal cancer, although the p-value for interaction was not significant (p-value 0.42). CONCLUSIONS: The Cys282Tyr mutation is not associated with an increased risk for colorectal cancer in postmenopausal women, although in combination with smoking a slightly increased risk cannot be excluded.

NAT2 slow acetylation and GSTM1 null genotypes may increase postmenopausal breast cancer risk in long-term smoking women.

N-acetyltransferase (NAT) 1 and 2 and glutathione S-transferase (GST) M1 and T1 are phase II enzymes that are important for activation and detoxification of carcinogenic heterocyclic and aromatic amines, as present in cigarette smoke. We studied whether genetic polymorphisms in these genes modifies the relationship between smoking and breast cancer. A nested case-control study was conducted among participants in a Dutch prospective cohort. Breast cancer cases (n=229) and controls (n=264) were frequency-matched on age, menopausal status and residence. Compared to never smoking, smoking 20 cigarettes or more per day increased breast cancer risk statistically significant only in postmenopausal women [odds ratio (OR)=2.17; 95% confidence interval (CI) 1.04-4.51]. Neither NAT1 slow genotype, or GSTT1 null genotype, alone or in combination with smoking, affected breast cancer risk. However, compared to individuals with rapid NAT2 genotype, women with the very slow acetylator genotype (NAT2*5), who smoked for 20 years showed an increased breast cancer risk (OR=2.29; 95% CI 1.06-4.95). Similarly, the presence of GSTM1 null genotype combined with high levels of cigarette smoking (OR=3.00; 95% CI 1.46-6.15) or long duration (OR=2.53; 95% CI 1.24-5.16), increased rates of breast cancer. The combined effect of GSTM1 null genotype and smoking high doses was most pronounced in postmenopausal women (OR=6.78; 95% CI 2.31-19.89). In conclusion, our results provide support for the view that women who smoke and who have a genetically determined reduced inactivation of carcinogens (GSTM1 null genotype or slow NAT2 genotype (especially very slow NAT2 genotype)) are at increased risk of breast cancer.

Rapid N-acetyltransferase 2 imputed phenotype and smoking may increase risk of colorectal cancer in women (Netherlands).

OBJECTIVE: The relationship between smoking and colorectal cancer risk and whether such effect is modified by variations in the NAT2 genotype is investigated. METHODS: In the prospective DOM (Diagnostisch Onderzoek Mammacarcinoom; 27,722 women) cohort follow-up from 1976 until 1987 revealed 54 deaths due to colon or rectal cancer, and follow-up from 1987 to 01-01-1996 revealed 204 incident colorectal cancer cases. A random sample (n = 857) from the baseline cohort was used as controls. Four NAT2 restriction fragment length polymorphisms (RFLPs) were analysed using DNA extracted from urine samples. Rapid or slow acetylator phenotype status was attributed to individuals. RESULTS: Smoking may increase the risk for colon cancer (RR = 1.36, 95% CI 0.97-1.92) as well as for rectal cancer (RR = 1.31, 95% CI 0.76-2.25), although not statistically significant. Rapid NAT2 acetylation did not increase colorectal cancer risk, but in combination with smoking the risk was statistically significant increased, compared to women who had a slow NAT2 imputed phenotype and never smoked (RR = 1.56, 95% CI 1.03-2.37). For colon cancer, but not for rectal cancer the increased risk was statistically significant (RR = 1.67, 95% CI, 1.05-2.67 versus RR = 1.30 95% CI 0.63-2.68). CONCLUSIONS: Our study points to smoking as a risk factor for colon and rectal cancer and, in addition, especially in women with rapid NAT2 imputed phenotype.

Quality of NAT2 genotyping with restriction fragment length polymorphism using DNA isolated from frozen urine.

In large studies and under field conditions common to epidemiological research, factors outside of and inside the laboratory can introduce misclassification of genetic susceptibility markers. Few reports have been made on the accuracy of genotyping individuals using DNA extracted from frozen urine that was stored for approximately 20 years. This study was performed to determine the reproducibility and accuracy of N-acetyltransferase 2 (NAT2) genotyping by RFLP analysis using DNA from stored urine. To obtain long-term frozen urine and blood samples from the same person, the databases of two large prospective studies were linked by name and date of birth. Six polymorphisms within the coding region of NAT2 were determined in 65 urine and blood samples after which, genotypes and imputed phenotypes (rapid, slow) were derived. To test reproducibility, all of the six polymorphisms were determined twice in 47 urine-blood pairs. Reproducibility of imputed phenotypes was 91.5% in urine samples and 97.9% in blood samples. To test accuracy, results for all six polymorphisms were compared between urine and blood DNA. All of the kappa's were at least 0.85 except one. Identical results for all six polymorphisms were seen in 78.5% of urine-blood pairs. Taking blood samples as a reference standard, rapid acetylators were classified as rapid in 97% of subjects (95% confidence interval, 90-100%), and slow acetylators were classified as slow also in 97% of subjects (95% confidence interval, 91-100%), when using urine. This study shows that stored urine samples can be used for DNA genotyping in large cohort studies, when blood samples are not available.

Quality and quantity of DNA isolated from frozen urine in population-based research.

In several population-based studies in the past urine samples were collected and stored for future research. We set out to determine the reliability of using such samples for genotyping DNA markers in epidemiologic research. A source of DNA extracted from exfoliated nucleated cells in urine is provided by the DOM cohort, in which specimens were collected 15-25 years ago. We have examined the quality of the DNA in 48 of these samples by measuring the amount of DNA isolated and its ability to provide an adequate PCR template for amplicons of different lengths. MTHFR polymorphism was analyzed in 644 specimens to determine the inter- and intraobserver reproducibility. Although the DNA amount was variable, 26 to 89% of the samples, depending both on the length of the PCR amplicon and on PCR conditions, yielded a visible PCR product. The intra- and interobserver agreements were comparable (kappa 0.86 and 0.88, respectively). Our results demonstrate that frozen urine samples can be used for DNA typing studies in women after prolonged periods of storage, but with sometimes unpredictable results. Ultimately, the genotype success rate was 89.3%. Urine collection can be considered as a useful method of obtaining DNA in large cohort studies and other circumstances when blood samples cannot be obtained or have not been stored.