Nordcan.R: a new tool for federated analysis and quality assurance of cancer registry data.

Aim of the article: We present our new GDPR-compliant federated analysis programme (nordcan.R), how it is used to compute statistics for the Nordic cancer statistics web platform NORDCAN, and demonstrate that it works also with non-Nordic data. Materials and methods: We chose R and Stata programming languages for writing nordcan.R. Additionally, the internationally used CRG Tools programme by International Agency for Research on Cancer (IARC/WHO) was employed. A formal assessment of (GDPR-compliant) anonymity of all nordcan.R outputs was performed. In order to demonstrate that nordcan.R also works with non-Nordic data, we used data from the Netherlands Cancer Registry. Results: nordcan.R, publicly available on Github, takes as input cancer and general population data and produces tables of statistics. Each NORDCAN participant runs nordcan.R locally and delivers its results to IARC for publication. According to our anonymity assessment the data can be shared with international organizations, including IARC. nordcan.R incidence results on Norwegian and Dutch data are highly similar to those produced by two other independent methods. Conclusion: nordcan.R produces accurate cancer statistics where all personal and sensitive data are kept within each cancer registry. In the age of strict data protection policies, we have shown that international collaboration in cancer registry research and statistics reporting is achievable with the federated analysis approach. Undertakings similar to NORDCAN should consider using nordcan.R.

Were cancer patients worse off than the general population during the COVID-19 pandemic? A population-based study from Norway, Denmark and Iceland during the pre-vaccination era.

Background: In a population-based setting, we investigated the risks of testing positive for SARS-CoV-2 and developing severe COVID-19 outcomes among cancer patients compared with the general population. Methods: In nationwide cohorts, we identified all individuals in Norway, Denmark and Iceland who tested positive for SARS-CoV-2 or had a severe COVID-19 outcome (hospitalisation, intensive care, and death) from March until December 2020, using data from national health registries. We estimated standardised incidence ratios (SIRs) with 95% confidence intervals (CIs) comparing cancer patients with the general population. Findings: During the first wave of the pandemic, cancer patients in Norway and Denmark had higher risks of testing SARS-CoV-2 positive compared to the general population. Throughout 2020, recently treated cancer patients were more likely to test SARS-CoV-2 positive. In Iceland, cancer patients experienced no increased risk of testing positive. The risk of COVID-19-related hospitalisation was higher among cancer patients diagnosed within one year of hospitalisation (Norway: SIR = 2.43, 95% CI 1.89-3.09; Denmark: 2.23, 1.96-2.54) and within five years (Norway: 1.58, 1.35-1.83; Denmark: 1.54, 1.42-1.66). Risks were higher in recently treated cancer patients and in those diagnosed with haematologic malignancies, colorectal or lung cancer. Risks of COVID-19-related intensive care and death were higher among cancer patients. Interpretation: Cancer patients were at increased risk of testing positive for SARS-CoV-2 during the first pandemic wave when testing availability was limited, while relative risks of severe COVID-19 outcomes remained increased in cancer patients throughout 2020. Recent cancer treatment and haematologic malignancy were the strongest risk factors. Funding: Nordic Cancer Union.

The impact of the COVID-19 pandemic on cancer diagnosis based on pathology notifications: A comparison across the Nordic countries during 2020.

The severity of the COVID-19 pandemic and subsequent mitigation strategies have varied across the Nordic countries. In a joint Nordic population-based effort, we compared patterns of new cancer cases and notifications between the Nordic countries during 2020. We used pathology notifications to cancer registries in Denmark, the Faroe Islands, Finland, Iceland, Norway and Sweden to determine monthly numbers of pathology notifications of malignant and in situ tumours from January to December 2020 compared to 2019 (2017-2019 for Iceland and the Faroe Islands). We compared new cancer cases per month based on unique individuals with pathology notifications. In April and May 2020, the numbers of new malignant cases declined in all Nordic countries, except the Faroe Islands, compared to previous year(s). The largest reduction was observed in Sweden (May: -31.2%, 95% CI -33.9, -28.3), followed by significant declines in Finland, Denmark and Norway, and a nonsignificant decline in Iceland. In Denmark, Norway, Sweden and Finland the reporting rates during the second half of 2020 rose to almost the same level as in 2019. However, in Sweden and Finland, the increase did not compensate for the spring decline (annual reduction -6.2% and -3.6%, respectively). Overall, similar patterns were observed for in situ tumours. The COVID-19 pandemic led to a decline in rates of new cancer cases in Sweden, Finland, Denmark and Norway, with the most pronounced reduction in Sweden. Possible explanations include the severity of the pandemic, temporary halting of screening activities and changes in healthcare seeking behaviour.

COVID-19 in Cancer Patients, Risk Factors for Disease and Adverse Outcome, a Population-Based Study From Norway.

BACKGROUND: Cancer has been suggested as a risk factor for severe outcome of SARS-CoV-2 infection. In this population-based study we aimed to identify factors associated with higher risk of COVID-19 and adverse outcome. METHODS: Data on all confirmed SARS-CoV-2 positive patients in the period January 1 to May 31, 2020 were extracted from the Norwegian Surveillance System for Communicable Diseases. Data on cancer and treatment was available from the Cancer Registry of Norway, the Norwegian Patient Registry and the Norwegian Prescription Database. Deaths due to COVID-19 were extracted from the Cause of Death Registry. From the Norwegian Intensive Care and Pandemic Registry we retrieved data on admittance to hospital and intensive care. We determined rates of COVID-19 disease in cancer patients and the rest of the population. We also ran multivariate analyses adjusting for age and gender. RESULTS: A total of 8 410 patients were diagnosed with SARS-CoV-2 infection in Norway during the study period, of which 547 (6.5%) were cancer patients. Overall, we found similar age adjusted rates of COVID-19 in the population with cancer as in the population without cancer. Unadjusted analysis showed that patients having undergone major surgery within the past 3 months had an increased risk of COVID-19 while we did not find increased Odds Ratio (OR) related to other oncological treatment modalities. No patients treated with stem cell or bone marrow transplant were diagnosed with COVID-19. The fatality rate of COVID-19 among cancer patients was 0.10. This was similar to non-cancer patients, when adjusting for age and sex with OR (95% CI) for death= 0.99 (0.68-1.42). Patients with distant metastases had significantly increased OR of death due to COVID-19 disease of 9.31 (95% CI 2.60-33.34). For the combined outcome death and/or admittance to hospital due to COVID-19, we found significant two-fold increased risk estimates for patients diagnosed with cancer less than one 1 year ago (OR 2.08, 95% CI 1.14-3.80), for those treated with anti-cancer drugs during the past 3 months (OR 1.80, 95% CI 1.07-3.01) and for patients undergoing major surgery during the past 3 months (OR 2.19, 95% CI 1.40-3.44).

Evolution of plant RNA polymerase IV/V genes: evidence of subneofunctionalization of duplicated NRPD2/NRPE2-like paralogs in Viola (Violaceae).

BACKGROUND: DNA-dependent RNA polymerase IV and V (Pol IV and V) are multi-subunit enzymes occurring in plants. The origin of Pol V, specific to angiosperms, from Pol IV, which is present in all land plants, is linked to the duplication of the gene encoding the largest subunit and the subsequent subneofunctionalization of the two paralogs (NRPD1 and NRPE1). Additional duplication of the second-largest subunit, NRPD2/NRPE2, has happened independently in at least some eudicot lineages, but its paralogs are often subject to concerted evolution and gene death and little is known about their evolution nor their affinity with Pol IV and Pol V. RESULTS: We sequenced a approximately 1500 bp NRPD2/E2-like fragment from 18 Viola species, mostly paleopolyploids, and 6 non-Viola Violaceae species. Incongruence between the NRPD2/E2-like gene phylogeny and species phylogeny indicates a first duplication of NRPD2 relatively basally in Violaceae, with subsequent sorting of paralogs in the descendants, followed by a second duplication in the common ancestor of Viola and Allexis. In Viola, the mutation pattern suggested (sub-) neofunctionalization of the two NRPD2/E2-like paralogs, NRPD2/E2-a and NRPD2/E2-b. The dN/dS ratios indicated that a 54 bp region exerted strong positive selection for both paralogs immediately following duplication. This 54 bp region encodes a domain that is involved in the binding of the Nrpd2 subunit with other Pol IV/V subunits, and may be important for correct recognition of subunits specific to Pol IV and Pol V. Across all Viola taxa 73 NRPD2/E2-like sequences were obtained, of which 23 (32%) were putative pseudogenes - all occurring in polyploids. The NRPD2 duplication was conserved in all lineages except the diploid MELVIO clade, in which NRPD2/E2-b was lost, and its allopolyploid derivates from hybridization with the CHAM clade, section Viola and section Melanium, in which NRPD2/E2-a occurred in multiple copies while NRPD2/E2-b paralogs were either absent or pseudogenized. CONCLUSIONS: Following the relatively recent split of Pol IV and Pol V, our data indicate that these two multi-subunit enzymes are still in the process of specialization and each acquiring fully subfunctionalized copies of their subunit genes. Even after specialization, the NRPD2/E2-like paralogs are prone to pseudogenization and gene conversion and NRPD2 and NRPE2 copy number is a highly dynamic process modulated by allopolyploidy and gene death.

Natural killer (NK) cell function is a strong prognostic factor in colorectal carcinoma patients treated with the monoclonal antibody 17-1A.

Tumor cells might be susceptible to different effector functions of the immune system. This cytotoxic capacity has been utilized to analyze the prognostic significance of peripheral blood mononuclear cells (PBMC) in patients with metastatic colorectal carcinoma (CRC) treated with the monoclonal antibody (MAb)17-1A. Such analysis might form the basis for future patient selection and may lead to improvements in therapeutic strategies. Between 1986 and 1998, 73 patients were treated with regimens containing MAb17-1A. Prior to therapy, the lytic capability of PBMC was assayed against: K562 (4 hr assay), the CRC cell line SW948 (4 hr and 18 hr assays) and antibody-dependent cellular cytotoxicity (ADCC, 18 hr assay). Since the study was performed over 13 years, the assays were checked for time-related bias. Reproducibility over time was satisfactory. Patients exhibited a significantly higher cytotoxic capability in all 4 assays compared to healthy control donors. No correlation to clinical outcome was noted for 18 hr ADCC and 18 hr spontaneous cytotoxicity. Pretreatment natural killer (NK) cell cytotoxicity (K562) was significantly related to overall survival (OS), progression-free survival (PFS), and response rate. OS for patients with high and low NK cell cytotoxicity was 71 vs. 30 weeks, respectively (p = 0.007). NK cell cytotoxicity (K562) was an independent prognostic factor for OS (p = 0.016). Pretreatment NK cell activity is a strong prognostic factor for patients with metastatic CRC receiving MAb17-1A therapy and is a predictor for OS, PFS and response. These results should be considered when designing antibody-based therapeutic protocols.

MAb17-1A and cytokines for the treatment of patients with colorectal carcinoma.

CO17-1A/GA73-3/EpCam/KSA is a cellular adhesion molecule expressed on the majority of tumor cells in most patients with colorectal carcinoma. One of the first mouse monoclonal antibodies (MAbs) for therapeutic use was produced against this particular tumor associated antigen (MAb17-1A). MAb17-1A has served as a model for the development of antibody therapy. It exerts therapeutic effects through antibody dependent cellular cytotoxicity (ADCC), induction of an idiotypic network cascade and maybe also by complement activation. Addition of cytokines that augment these functions, mainly granulocyte macrophage-cerebrospinal fluid (GM-CSF), seemed to improve the clinical efficacy as well as chemotherapeutic agents (5-Fu). In advanced disease the clinical effect is, however, modest while the most beneficial clinical situation seems to be the adjuvant setting. Twenty years have passed since the EpCam antigen was identified as a target structure for immunotherapy, but still we do not know how to optimally use this target. The antigen might, however, be a rewarding structure to utilize for therapy. Preclinical and clinical trials are ongoing aimed at improving passive and active immunotherapy using CO17-1A/EpCam as a target antigen in colorectal carcinoma.