Patient-reported outcome (PRO) measurements in chronic and malignant diseases: ten years' experience with PRO-algorithm-based patient-clinician interaction (telePRO) in AmbuFlex.

BACKGROUND: Patient-reported Outcome (PRO) measures may be used as the basis for out-patient follow-up instead of fixed appointments. The patients attend follow-up from home by filling in questionnaires developed for that specific aim and patient group (telePRO). The questionnaires are handled in real time by a specific algorithm, which assigns an outcome color reflecting clinical need. The specific questionnaires and algorithms (named solutions) are constructed in a consensus process with clinicians. We aimed to describe AmbuFlex' telePRO solutions and the algorithm outcomes and variation between patient groups, and to discuss possible applications and challenges. METHODS: TelePRO solutions with more than 100 processed questionnaires were included in the analysis. Data were retrieved together with data from national registers. Characteristics of patients, questionnaires and outcomes were tabulated for each solution. Graphs were constructed depicting the overall and within-patient distribution of algorithm outcomes for each solution. RESULTS: From 2011 to 2021, 29 specific telePRO solutions were implemented within 24 different ICD-10 groups. A total of 42,015 patients were referred and answered 171,268 questionnaires. An existing applicable instrument with cut-off values was available for four solutions, whereas items were selected or developed ad hoc for the other solutions. Mean age ranged from 10.7 (Pain in children) to 73.3 years (chronic kidney disease). Mortality among referred patients varied between 0 (obesity, asthma, endometriosis and pain in children) and 528 per 1000 patient years (Lung cancer). There was substantial variation in algorithm outcome across patient groups while different solutions within the same patient group varied little. DISCUSSION: TelePRO can be applied in diseases where PRO can reflect clinical status and needs. Questionnaires and algorithms should be adapted for the specific patient groups and clinical aims. When PRO is used as replacement for clinical contact, special carefulness should be observed with respect to patient safety.

Prognostic value of baseline functional status measures and geriatric screening in vulnerable older patients with metastatic colorectal cancer receiving palliative chemotherapy - The randomized NORDIC9-study.

INTRODUCTION: Appropriate patient selection based on functional status is crucial when considering older adults for palliative chemotherapy. This pre-planned analysis of the randomized NORDIC9-study explored the prognostic value of four functional status measures regarding progression-free survival (PFS) and overall survival (OS) in vulnerable older patients with metastatic colorectal cancer (mCRC) receiving first-line palliative chemotherapy. MATERIALS AND METHODS: Patients ≥70 years of age with mCRC not candidates for standard full-dose combination chemotherapy were randomized to receive full-dose S1 or reduced-dose S1 + oxaliplatin. At baseline, functional status was assessed using ECOG performance status (ECOG PS), frailty phenotype, Geriatric 8 (G8), and Vulnerable Elderly Survey-13 (VES-13). Multivariable regression models were applied and C-statistics were estimated. RESULTS: In total, 160 patients with a median age of 78 years (IQR: 76-81) were included. While in univariate analyses, ECOG PS, frailty phenotype, and VES-13 were statistically significantly associated with differences in OS between subgroups, G8 was not (HR = 1.55, 95%CI: 0.99-2.41, p = 0.050). In multivariable analyses adjusted for age, sex, body mass index, and treatment allocation, we found significant differences between subgroups for all applied tools and with C-statistics in the moderate range for ECOG PS and VES-13. Concerning PFS, statistically significant differences were observed between subgroups of ECOG PS, G8, and VES-13 both in uni- and multivariable analyses, but not for frailty phenotype. DISCUSSION: In this Nordic cohort of vulnerable older patients with mCRC, baseline ECOG PS, frailty phenotype, G8, and VES-13 showed prognostic value regarding overall survival, and moderate predictive value of models based on ECOG PS and VES-13 was demonstrated.

The Prognostic Value of Pre-Treatment Circulating Biomarkers of Systemic Inflammation (CRP, dNLR, YKL-40, and IL-6) in Vulnerable Older Patients with Metastatic Colorectal Cancer Receiving Palliative Chemotherapy-The Randomized NORDIC9-Study.

Appropriate patient selection for palliative chemotherapy is crucial in patients with metastatic colorectal cancer (mCRC). We investigated the prognostic value of C-reactive protein (CRP), derived neutrophil-to-lymphocyte ratio (dNLR), Interleukin (IL)-6, and YKL-40 on progression-free survival (PFS) and overall survival (OS) in the NORDIC9 cohort. The randomized NORDIC9-study included patients ≥70 years with mCRC not candidates for standard full-dose combination chemotherapy. Participants received either full-dose S1 (Teysuno) or a dose-reduced S1 plus oxaliplatin. Blood samples were collected at baseline and biomarkers were dichotomized according to standard cut-offs. Multivariable analyses adjusted for age, sex, ECOG performance status, and treatment allocation; furthermore, C-statistics were estimated. In total, 160 patients with a median age of 78 years (IQR: 76−81) were included between 2015 and 2017. All investigated biomarkers were significantly elevated in patients with either weight loss, ≥3 metastatic sites, or primary tumor in situ. In multivariable analyses, all markers showed significant association with OS; the highest HR was observed for CRP (HR = 3.40, 95%CI: 2.20−5.26, p < 0.001). Regarding PFS, statistically significant differences were found for CRP and IL-6, but not for dNLR and YKL-40. Applying C-statistics, CRP indicated a good prognostic model for OS (AUC = 0.72, 95%CI: 0.67−0.76). CRP is an easily available biomarker, which may support therapeutic decision-making in vulnerable older patients with mCRC.

Clinical features affecting efficacy of immune checkpoint inhibitors in pretreated patients with advanced NSCLC: a Danish nationwide real-world study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are implemented as standard treatment for patients with advanced non-small cell lung cancer (NSCLC) in first-line and subsequent-line treatment. However, certain subgroups such as patients with older age, poor performance status (PS), and severe comorbidity are underrepresented in the randomized controlled trials (RCTs). This study aimed to assess overall survival (OS), treatment data, and clinical features affecting second- or subsequent-line ICI efficacy in an unselected, Danish, nationwide NSCLC population. METHODS: Patients with advanced NSCLC who started nivolumab or pembrolizumab as second-line or subsequent-line treatment between 1 September 2015, and 1 October 2018, were identified from institutional records of all Danish oncology departments. Clinical and treatment data were retrospectively collected. Descriptive statistics and survival analyses were performed. RESULTS: Data were available for 840 patients; 49% females. The median age was 68 years (19% were ≥75 years), 19% had PS ≥2, and 36% had moderate to severe comorbidity. The median OS (mOS) was 12.2 months; 15.1 months and 10.0 months in females and males, respectively. The median time-to-treatment discontinuation (mTTD) and median progression-free survival (mPFS) was 3.2 and 5.2 months, respectively. Patients with PS ≥2 had a mOS of 4.5 months, mTTD of 1.1 month, and mPFS of 2.0 months. In multivariable Cox regression analysis, male sex (HR = 1.35, 95% CI 1.11-1.62), PS >0 (PS 1, HR = 1.88, 95% CI 1.52-2.33; PS ≥2, HR = 4.15, 95% CI 3.13-5.5), liver metastases (HR = 1.72, 95% CI 1.34-2.22), and bone metastases (HR = 1.27, 95% CI 1.03-1.58) were significant poor prognostic OS factors. CONCLUSIONS: Danish real-world patients with advanced NSCLC treated with second- or subsequent-line ICI had an OS comparable to results from RCTs. Women, frail and older patients constituted a higher proportion than in previous RCTs. Clinical features associated with poor OS were male sex, PS ≥1 (in particular PS ≥2), bone-, and liver metastases.

Disparity in use of modern combination chemotherapy associated with facility type influences survival of 2655 patients with advanced pancreatic cancer.

AIM: Academic and high volume hospitals have better outcome for pancreatic cancer (PC) surgery, but there are no reports on oncological treatment. We aimed to determine the influence of facility types on overall survival (OS) after treatment with chemotherapy for inoperable PC. MATERIAL AND METHODS: 2,657 patients were treated in Denmark from 2012 to 2018 and registered in the Danish Pancreatic Cancer Database. Facilities were classified as either secondary oncological units or comprehensive, tertiary referral cancer centers. RESULTS: The average yearly number of patients seen at the four tertiary facilities was 71, and 31 at the four secondary facilities. Patients at secondary facilities were older, more frequently had severe comorbidity and lived in non-urban municipalities. As compared to combination chemotherapy, monotherapy with gemcitabine was used more often (59%) in secondary facilities than in tertiary (34%). The unadjusted median OS was 7.7 months at tertiary and 6.1 months at secondary facilities. The adjusted hazard ratio (HR) of 1.16 (confidence interval 1.07-1.27) demonstrated an excess risk of death for patients treated at secondary facilities, which disappeared when taking type of chemotherapy used into account. Hence, more use of combination chemotherapy was associated with the observed improved OS of patients treated at tertiary facilities. Declining HR's per year of first treatment indicated improved outcomes with time, however the difference among facility types remained significant. DISCUSSION: Equal access to modern combination chemotherapy at all facilities on a national level is essential to ensure equality in treatment results.

Nationwide Survival Benefit after Implementation of First-Line Immunotherapy for Patients with Advanced NSCLC-Real World Efficacy.

Background The selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) treatment remains challenging. This real-world study aimed to compare the overall survival (OS) before and after the implementation of ICIs, to identify OS prognostic factors, and to assess treatment data in first-line (1L) ICI-treated patients without epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Methods Data from the Danish NSCLC population initiated with 1L palliative antineoplastic treatment from 1 January 2013 to 1 October 2018, were extracted from the Danish Lung Cancer Registry (DLCR). Long-term survival and median OS pre- and post-approval of 1L ICI were compared. From electronic health records, additional clinical and treatment data were obtained for ICI-treated patients from 1 March 2017 to 1 October 2018. Results The OS was significantly improved in the DLCR post-approval cohort (n = 2055) compared to the pre-approval cohort (n = 1658). The 3-year OS rates were 18% (95% CI 15.6-20.0) and 6% (95% CI 5.1-7.4), respectively. On multivariable Cox regression, bone (HR = 1.63) and liver metastases (HR = 1.47), performance status (PS) 1 (HR = 1.86), and PS ≥ 2 (HR = 2.19) were significantly associated with poor OS in ICI-treated patients. Conclusion OS significantly improved in patients with advanced NSCLC after ICI implementation in Denmark. In ICI-treated patients, PS ≥ 1, and bone and liver metastases were associated with a worse prognosis.

Quality of Life in Vulnerable Older Patients with Metastatic Colorectal Cancer Receiving Palliative Chemotherapy-The Randomized NORDIC9-Study.

Quality of life data from randomized trials are lacking in older patients with metastatic colorectal cancer (mCRC). In the randomized NORDIC9-study, reduced-dose S1+oxaliplatin (SOx) showed superior efficacy compared to full-dose S1 monotherapy. We hypothesized that treatment with SOx does not result in inferior quality of life. Patients with mCRC aged ≥70 years and that were not a candidate for standard combination chemotherapy were included and randomly assigned to receive either S1 or SOx. The EORTC QLQ-C30 questionnaire was completed at baseline, after 9, and 18 weeks. The primary endpoint was global Quality of Life (QoL) at 9 weeks. For statistical analysis, a non-inferiority design was chosen applying linear mixed effects models for repeated measurements. The results were interpreted according to statistical significance and anchor-based, clinically relevant between-group minimally important differences (MID). A total of 160 patients aged (median (Interquartile range (IQR))) 78 years (76-81) were included. The QLQ-C30 questionnaire was completed by 150, 100, and 60 patients at baseline, at 9, and 18 weeks, respectively. The difference at 9 weeks in global QoL was 6.85 (95%CI-1.94; 15.65) and 7.37 (0.70; 14.05) in the physical functioning domain in favor of SOx exceeding the threshold for MID. At 18 weeks, the between-group MID in physical functioning was preserved. Dose-reduced combination chemotherapy may be recommended in vulnerable older patients with mCRC, rather than full-dose monotherapy.

Patterns of Palliative Chemotherapy and Survival in Patients With Pancreatic Cancer Focusing on Age: A Nationwide Real-World Danish Registry Study.

OBJECTIVES: The aim of this study was to identify patterns of palliative chemotherapy (CTh) and the associated overall survival (OS) in patients with pancreatic cancer, with specific focus on age. METHODS: Between May 1, 2011, and April 30, 2016, 4260 patients were registered in the Danish Pancreatic Cancer Database. The 1715 patients receiving palliative CTh were retrieved. Age was grouped into less than 70, 70 to less than 75, and 75 years or more. RESULTS: Of the 1715 patients receiving first-line CTh, 586 (34%) underwent second-line CTh and 151 (9%) third-line CTh. First-line gemcitabine resulted in a significant worse survival compared with combination CTh, hazard ratio 1.51. For combination CTh, OS differed between the age groups, P < 0.01. The median OS in the less than 70 years (n = 547), 70 to less than 75 years (n = 163), and 75 years or more (n = 67) groups were 9.3, 9.6, and 7.2 months, respectively. No differences in survival were observed among patients receiving first-line gemcitabine (P = 0.35). CONCLUSIONS: Our findings are useful in treatment-related decision making in patients with pancreatic cancer. A significant survival benefit was observed for all patients after first-line combination CTh. The effect of combination CTh was most prominent among patients aged less than 75 years. By age, no differences in survival were observed in those receiving gemcitabine.

Patient-Reported Outcome Measures Used in Routine Care Predict for Survival at Disease Progression in Patients With Advanced Lung Cancer.

BACKGROUND: Patient-reported outcome (PRO) measures have been increasingly implemented in routine care to aid in clinical decision-making. However, the prognostic value of PRO measures as a tool for decision making is not easily interpreted by clinicians. Our aims were to explore the prognostic value of PRO measures at disease progression and the changes in PRO measures between treatment start (baseline) and disease progression. PATIENTS AND METHODS: Since 2014, patients with lung cancer have completed an electronic version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 and LC-13 before every outpatient visit at the Department of Oncology, Hospital Unit West, Jutland, Denmark. The patients' responses were used in routine care. Patients receiving palliative antineoplastic treatment were eligible for analysis if the questionnaire had been completed at the initiation of first-line treatment and at disease progression. The prognostic value of the scores was evaluated using a Cox proportional hazard model. A P value < .01 was considered statistically significant. RESULTS: A total of 94 screened patients were included. At disease progression, survival could be predicted from the absolute score of the global health scale, 3 functional scales (physical, role, emotional), and 7 symptom scales (fatigue, pain, dyspnea, hemoptysis, lung cancer dyspnea, chest pain). In addition, changes in hemoptysis, dysphagia, dyspnea, and chest pain predicted for survival at progression. CONCLUSION: PRO measures used in routine care can provide clinicians with relevant prognostic information about patients with lung cancer at disease progression. These results show the potential value of PRO measures when used in clinical decision-making.

Electronic symptom monitoring in patients with metastatic lung cancer: a feasibility study.

OBJECTIVES: To design an electronic questionnaire for symptom monitoring and to evaluate the feasibility, usability and acceptability when applied to patients with metastatic lung cancer. SETTING: Single-centre feasibility study. PARTICIPANTS: Patients with stage IV lung cancer in antineoplastic treatment. INTERVENTIONS: This study describes the first three phases of a complex intervention design: phase 1, development of the intervention; phase 2, feasibility testing and phase 3, evaluation of the intervention. In phase 1, items were selected for the questionnaire and adjusted following patient interviews. In phase 2, patients completed the electronic questionnaire weekly during a 3-week feasibility test. In case of symptom deterioration, a nurse was notified with the aim to contact the patient. In phase 3, patients evaluated phase 2 by paper questionnaires, and interviews were conducted with the participating nurses. PRIMARY OUTCOME MEASURES: The study outcomes: phase 1, usability and relevance; phase 2, recruitment rate, compliance and threshold functionality and phase 3, usability, acceptability and relevance. RESULTS: In phase 1, a questionnaire was designed and reviewed by patients (n=8). The interviews revealed high usability and relevance of the intervention.For phases 2 and 3, 20 of 29 approached patients (69%) responded to the questionnaire on a weekly basis. Two patients did not complete any questionnaires (compliance 90%). The remaining 18 patients completed 65 of a total of 72 possible questionnaires (7 missed, 93% completed). Reported symptoms led to a phone call from a nurse in 30% of the responses.The patients reported high usability and acceptability of questionnaire and software. The substance of the telephonic conversations was relevant, and the study set-up was logistically acceptable. CONCLUSIONS: An electronic questionnaire designed for symptom monitoring revealed high usability, acceptability and relevance in the target population. In conclusion, the study set-up was considered feasible for a randomised controlled trial. TRIAL REGISTRATION NUMBER: NCT03529851.

Surveillance With PET/CT and Liquid Biopsies of Stage I-III Lung Cancer Patients After Completion of Definitive Therapy: A Randomized Controlled Trial (SUPER).

Despite increased focus on prevention as well as improved treatment possibilities, lung cancer remains among the most frequent and deadliest cancer diagnoses worldwide. Even lung cancer patients treated with curative intent have a high risk of relapse, leading to a dismal prognosis. More knowledge on the efficacy of surveillance with both current and new technologies as well as on the impact on patient treatment, quality of life, and survival are urgently needed. We therefore designed a randomized phase 3 trial. In one arm, every other computed tomography (CT) scan is replaced by positron emission tomography/CT, the other arm is the standard follow-up scheme with CT. The standard arm is identical to the current national Danish follow-up program. The primary endpoint is to compare the number of relapses treatable with curative intent in the 2 arms. We aim to include 750 patients over a 3-year period. Additionally, we will test the feasibility of noninvasive lung cancer diagnostics and surveillance in the form of circulating tumor DNA analysis. For this purpose, blood samples are collected before treatment and at each following control. The blood samples are stored in a biobank for later analysis and will not be used for guiding patient treatment decisions.

Reduced-dose combination chemotherapy (S-1 plus oxaliplatin) versus full-dose monotherapy (S-1) in older vulnerable patients with metastatic colorectal cancer (NORDIC9): a randomised, open-label phase 2 trial.

BACKGROUND: Older or vulnerable patients with metastatic colorectal cancer are seldom included in randomised trials. The multicentre NORDIC9 trial evaluated reduced-dose combination chemotherapy compared with full-dose monotherapy in older, vulnerable patients. METHODS: This randomised, open-label phase 2 trial was done in 23 Nordic oncology clinics and included patients aged 70 years or older with previously untreated metastatic colorectal cancer who were not candidates for full-dose combination chemotherapy. Patients were block randomised (1:1) using a web-based tool to full-dose S-1 (30 mg/m2 orally twice daily on days 1-14 every 3 weeks) followed by second-line treatment at progression with irinotecan (250 mg/m2 intravenously on day 1 every 3 weeks or 180 mg/m2 intravenously on day 1 every 2 weeks) or reduced-dose combination chemotherapy with S-1 (20 mg/m2 orally twice daily on days 1-14) and oxaliplatin (100 mg/m2 intravenously on day 1 every 3 weeks) followed by second-line treatment at progression with S-1 (20 mg/m2 orally twice daily on days 1-14) and irinotecan (180 mg/m2 intravenously on day 1 every 3 weeks). Use of bevacizumab (7·5 mg/kg intravenously on day 1 of each cycle) was optional. Treatment allocation was not masked and randomisation was stratified for institution and bevacizumab. The primary outcome was progression-free survival. Survival analyses were by intention to treat and safety analyses were done on the treated population. This trial is registered with EudraCT, number 2014-000394-39, and is closed to new participants. FINDINGS: From March 9, 2015, to Oct 11, 2017, 160 patients with a median age of 78 years (IQR 76-81) were randomly assigned to full-dose monotherapy (n=83) or reduced-dose combination chemotherapy (n=77). At data cutoff (Sept 1, 2018; median follow-up 23·8 months [IQR 18·8-30·9]), 81 (98%) patients in the full-dose monotherapy group and 71 (92%) patients in the reduced-dose combination group had progressed or died. Median progression-free survival was significantly longer with reduced-dose combination chemotherapy (6·2 months [95% CI 5·3-8·3]) than with full-dose monotherapy (5·3 months [4·1-6·8]; hazard ratio [HR] 0·72 [95% CI 0·52-0·99]; p=0·047). Toxicity was evaluated in 157 patients who received treatment. Significantly more patients in the full-dose monotherapy group (51 [62%] of 82 patients) experienced at least one grade 3-4 adverse event than in the reduced-dose combination group (32 [43%] of 75 patients; p=0·014). Grade 3-4 diarrhoea (12 [15%] vs two [3%]; p=0·018), fatigue (ten [12%] vs three [4%]; p=0·083), and dehydration (five [6%] vs none; p=0·060) were more frequent in the full-dose monotherapy group than in the reduced-dose combination group. Treatment-related deaths occurred in three patients during first-line treatment and three patients during second-line treatment (two in the full-dose monotherapy group vs one in the reduced-dose combination group in both cases). INTERPRETATION: Reduced-dose combination chemotherapy with S-1 and oxaliplatin for older, vulnerable patients with metastatic colorectal cancer was more effective and resulted in less toxicity than full-dose monotherapy with S-1. Reduced-dose combination chemotherapy could be a preferred treatment for this population. FUNDING: Taiho Pharmaceuticals, Nordic Group, the Danish Cancer Society, the Swedish Cancer Society, Academy of Geriatric Research (AgeCare), and Region of Southern Denmark.

[Epidemiology of the two types of gastric adenocarcinoma in Iceland according to the Laurén histological classification 1990-2009].

BACKGROUND: In the mid twentieth century gastric cancer was the most common type of cancer in Iceland. In recent decades, however, the incidence rate of gastric cancer has decreased markedly and currently only represents 2-3% of cancer cases. The Laurén classification system classifies adenocarcinoma into two types, intestinal and diffuse. The main purpose of our study was to describe the epidemiology of the two types of gastric adenocarcinoma in Iceland between the years 1990-2009. METHODS: This is a retrospective cohort study. Information on patients diagnosed with gastric cancer in Iceland between 1990 and 2009 was collected from the population based Cancer Registry. Histological descriptions were reviewed and classified according to the Laurén classification system. The records of patients diagnosed with either having intestinal or diffuse adenocarcinomas were reviewed and epidemiological information gathered. RESULTS: Between 1990 and 2009, 730 patients were diagnosed with gastric adenocarcinoma in Iceland, 447 had intestinal adenocarcinoma and 168 diffuse adenocarcinoma. Patients diagnosed with diffuse adenocarcinoma were significantly younger at diagnosis than those diagnosed with intestinal adenocarcinoma. The sex ratio for intestinal adenocarcinoma was 2.3:1 (M:F) and 1.1:1 (M:F) for diffuse adenocarcinoma. The incidence of intestinal adenocarcinoma decreased more rapidly than that of diffuse adenocarcinoma during this period (0.92/100,000 vs. 0.12/100,000). Median survival rates of intestinal and diffuse adenocarcinomas were 23.7 and 20.6 months, respectively. The difference in survival was found to be statistically significant. The hazard ratio between the two groups was 1.31 (CI 1.03-1.67), corrected for age, sex, stage, year of diagnosis and surgical outcome (radical, non-radical or no operation). CONCLUSION: The overall incidence rate of gastric cancer has decreased dramatically in the past 20 years. However, the reduction is largely limited to the intestinal adenocarcinoma sub-group. We conclude that the Laurén classification predicts prognosis in gastric adenocarcinoma with diffuse adenocarcinoma having worse prognosis. KEY WORDS: gastric cancer, Laurén classification, survival, incidence. Correspondence: Halla Sif Olafsdottir, hsolafsdottir@gmail.com.

Loss-of-function variants in ATM confer risk of gastric cancer.

Gastric cancer is a serious health problem worldwide, with particularly high prevalence in eastern Asia. Genome-wide association studies (GWAS) in Asian populations have identified several loci that associate with gastric cancer risk. Here we report a GWAS of gastric cancer in a European population, using information on 2,500 population-based gastric cancer cases and 205,652 controls. We found a new gastric cancer association with loss-of-function mutations in ATM (gene test, P = 8.0 × 10(-12); odds ratio (OR) = 4.74). The combination of the loss-of-function variants p.Gln852*, p.Ser644* and p.Tyr103* (combined minor allele frequency (MAF) = 0.3%) also associates with pancreatic and prostate cancers (OR = 3.81 and 2.18, respectively) and gives an indication of risk of breast and colorectal cancers (OR = 1.82 and 1.97, respectively). Cancers in those carrying loss-of-function ATM mutations are diagnosed at a significantly earlier age than in non-carriers. Our results confirm an association between gastric cancer in Europeans and three loci previously reported in Asians, MUC1, PRKAA1 and PSCA, refine the association signal at PRKAA1 and support a pathogenic role for the tandem repeat identified in MUC1.

Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk.

Genome-wide association studies (GWAS) have identified 3 genomic regions, at 15q24-25.1, 5p15.33, and 6p21.33, which associate with the risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P < 10(-5)) in a recently published meta-analysis. In a GWA dataset of 1,447 lung cancer cases and 36,256 controls in Iceland, 3 correlated variants on 15q15.2 (rs504417, rs11853991, and rs748404) showed a significant association with lung cancer, whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31, and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in an additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain, and the United States and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genome-wide significance (OR = 1.15, P = 1.1 × 10(-9)). Another variant at the same locus, rs12050604, showed association with lung cancer (OR = 1.09, 3.6 × 10(-6)) and remained significant after adjustment for rs748404 and vice versa. rs748404 is located 140 kb centromeric of the TP53BP1 gene that has been implicated in lung cancer risk. Two fully correlated, nonsynonymous coding variants in TP53BP1, rs2602141 (Q1136K) and rs560191 (E353D) showed association with lung cancer in our sample set; however, this association did not remain significant after adjustment for rs748404. Our data show that 1 or more lung cancer risk variants of genome-wide significance and distinct from the coding variants in TP53BP1 are located at 15q15.2.

Sequence variants at the TERT-CLPTM1L locus associate with many cancer types.

The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.

[Lung cancer--review]. / Lungnakrabbamein--Yfirlitsgrein.

Lung cancer is the second most common cancer in Iceland and the most frequent cause of cancer related deaths. Smoking is by far the most important cause but familial factors also contribute. The symptoms of lung cancer are often subtle and the diagnosis, in about 70% of cases, is made when metastases have occurred. Curative surgical treatment is therefore only possible in about a third of the cases whereas other patients receive chemotherapy and/or radiation therapy. In recent years some important advances have been made in the diagnostic and therapeutic approaches to lung cancer. New imaging techniques have improved diagnosis and staging practices and consequently also treatment. Recent evidence suggests that screening with low dose CT may improve survival. New approaches to chemotherapy have been shown to improve survival and well being of patients with advanced disease. Chemotherapeutic agents are now being used in conjunction with surgery to reduce the risk of tumour spread. Furthermore, advances in surgical techniques have made resections possible in cases deemed inoperable in the past. In this review we present important advances in the diagnosis and treatment of lung cancer as reflected by recent literature that should be of interest to a wide variety of specialists.

A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.