A lung function information system

Abstract A lung function information system (LFIS) was developed for the data analysis of pulmonary function tests at different locations. This system was connected to the hospital information system (HIS) for the retrieval of patient data and the storage of the lung function variables of patients to generate follow-up reports and to support financial and administrative management. The application programs were developed in such a way that high flexibility was obtained with respect to the patient-computer-technician interaction. The sampled data are stored on a disc to correct earlier decisions, perform recalculations and reanalyse the data for research purposes. When the measurements performed on a patient are authorized, the sampled data are deleted, except for when they are needed for future research. A distributed computer system was chosen to combine the benefits of a centralized system with those of several stand-alone systems. The main tasks of the central unit are to store collected data and computer programs, generate a final lung function report on laser printer and provide a connection to the HIS. In the satellite computers, which are located close to the lung function equipment, the signals and raw data are processed. Furthermore, the satellite computers were in use for program development and several research projects, and for the offline data processing of the lung function measurements from two other hospitals by means of a modem connection. The LFIS improved the quantity and quality of data acquisition. It resulted in an increased capacity of about 50% concerning spirometry, and facilitated time-consuming complex analyses. It also avoided miscalculations and mistakes in reports previously experienced with hand calculations

Incidence, Prevalence and Future Trends of Primary Basal Cell Carcinoma in the Netherlands

Abstract: Basal cell carcinoma (BCC) incidence rates are increasing worldwide. This study’s objective was to estimate the occurrence of BCC in the Netherlands in terms of incidence and prevalence. Data on first primary carcinomas were retrieved from the Eindhoven Cancer Registry and extrapolated to the Dutch population. Extrapolated data showed a total of 444,131, histologically confirmed cases in the Netherlands between 1973 and 2008. During this period, age-adjusted incidence rates (European Standard Population) increased approximately three-fold from 40 to 148 per 100,000 in males and from 34 to 141 in females. Lifetime risk of BCC was 1 in 5–6 for Dutch citizens. Disease prevalence in the Netherlands was 1.4% and almost four times higher than this (5.4%) in the oldest age group (age 65 years or more). Predictions of future trends showed no signs of a plateau in the number of cases. These estimates should urge Dutch policymakers to provide solutions for the growing group of patients with BCC

Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1

Click here to listen to the Podcast BACKGROUND: Form 1 of the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) serves to grade therapies with curative intent. Hitherto only few trials with curative intent have been field tested using form 1. We aimed to evaluate the applicability of the scale and to assess the reasonableness of the generated scores in early colon cancer, in order to identify shortcomings that may be rectified in future amendments. METHODS: Adjuvant studies were identified in PubMed, Food and Drug Administration and European Medicines Agency registration sites, as well as ESMO and National Comprehensive Cancer Network guidelines. Studies meeting inclusion criteria were graded using form 1 of the ESMO-MCBS V.1.1 and field tested by ESMO Colorectal Cancer Faculty. Shortcomings of the scale were identified and evaluated. RESULTS: Eighteen of 57 trials and 7 out of 14 meta-analyses identified met criteria for ESMO-MCBS V.1.1 grading. In stage III colon cancer, randomised clinical trials and meta-analyses of modulated 5-fluorouracil (5-FU) based chemotherapy versus surgery scored ESMO-MCBS grade A and randomised controlled trials (RCTs) and meta-analyses comprising oxaliplatin added to this 5-FU backbone showed a more modest additional overall survival benefit (grade A and B). For stage II colon cancer, the findings are less consistent. The fluoropyrimidine trials in stage II were graded 'no evaluable benefit' but the most recent meta-analysis demonstrated a 5.4% survival advantage after 8 years follow-up (grade A). RCTs and a meta-analysis adding oxaliplatin demonstrated no added benefit. Exploratory toxicity evaluation and annotation was problematic given inconsistent toxicity reporting and limited results of late toxicity. Field testers (n=37) reviewed the scores, 25 confirmed their reasonableness, 12 found them mostly reasonable. Moreover, they identified the inability of crediting improved convenience in non-inferiority trials as a shortcoming. CONCLUSION: Form 1 of the ESMO-MCBS V.1.1 provided very reasonable grading for adjuvant colon cancer studies

SAFEGUI: resampling-based tests of categorical significance in gene expression data made easy

Summary: A large number of websites and applications perform significance testing for gene categories/pathways in microarray data. Many of these packages fail to account for expression correlation between transcripts, with a resultant inflation in Type I error. Array permutation and other resampling-based approaches have been proposed as solutions to this problem. SAFEGUI provides a user-friendly graphical interface for the assessment of categorical significance in microarray studies, while properly accounting for the effects of correlations among genes. SAFEGUI incorporates both permutation and more recently proposed bootstrap algorithms that are demonstrated to be more powerful in detecting differential expression across categories of genes

Reconsider radiation exposure from imaging during immune checkpoint inhibitor trials to reduce risk of secondary cancers in long-term survivors?

Immune checkpoint inhibitors (ICI) have improved outcomes for patients with advanced cancers, and results in increasing numbers of long-term survivors. For registration studies, progression-free survival and disease-free survival often serve as primary endpoints. This requires repeated computed tomography (CT) scans for tumour imaging which might lead to major radiation exposure. To determine this, all immune checkpoint inhibitors trials that led to FDA approval were retrieved up to July 29, 2019. From the available protocols, imaging modalities and schedules used in each trial were identified. The anticipated cumulative number of scans made after 1, 3, 5, and 10 years study participation were calculated. The percentage of lifetime attributable cancer risk was calculated using the Biological Effects of Ionizing Radiation VII report. Fifty-one trials were identified, from which 39 protocols were retrieved. Four were adjuvant trials. All protocols required repeated chest-abdomen imaging and specified CT scans as preferred imaging modality. Median calculated cumulative numbers of chest-abdomen CT scans after 1, 3, 5, and 10 years study participation were 7, 16, 24 and 46, respectively. For ages 20-70 years at study entry, the average lifetime attributable cancer risk after 1 year of study participation ranged from 1.11 to 0.40% for men and from 1.87 to 0.46% for women. At 10 years study participation, this risk increased to a range of 5.91 to 1.96% for men and 9.64 to 2.32% for women. Given high imaging radiation exposure for long-term survivors in current ICI trials an adaptive imaging interval and imaging termination rules should be considered for long-term survivors

Unusual specificity of the androgen receptor in the human prostate tumor cell line LNCaP: High affinity for progestagenic and estrogenic steroids

Abstract LNCaP tumor cells, derived from a metastatic lesion of a human prostatic carcinoma, are androgen-sensitive in cell culture. Although increase in growth rate is observed with low doses of progestagens or estradiol, these cells contain exclusively androgen receptors. In the present study the binding affinity of different ligands for both non-DNA- and DNA-binding (transformed) forms of the androgen receptor were analyzed. The cytosolic (non-transformed) form of the receptor displayed an abnormal high affinity for progestagens and estradiol when compared with the cytosolic androgen receptor from other sources. Subsequently the non-transformed forms of the androgen receptor obtained from LNCaP cell nuclei was studied. A high binding affinity was found not only for dihydrotestosterone, but also for progesterone and the synthetic progestagen R5020 (relative binding affinity 42% and 10% of dihydrotestosterone). The binding characteristics of the transformed androgen receptor were examined in intact cells at 37°C. LNCaP cells were compared in this respect with COS cells containing the cloned human androgen receptor, normal human skin fibroblasts and PC3 (prostate) and NHIK (cervix) human tumor cell lines. The affinity of the transformed androgen receptors for the progestagen R5020 in LNCaP cells was significantly higher than in the other cell systems, although the differences were less pronounced than for the non-transformed receptor form. In conclusion: the LNCaP tumor cells contain an androgen receptor with an abnormal binding site. This might be due to a mutation and/or a post-transcriptional effect

Trends of cutaneous melanoma in the Netherlands: increasing incidence rates among all Breslow thickness categories and rising mortality rates since 1989

Abstract: Background: It has been debated that the epidemic of melanoma is largely due to overdiagnosis, since increases in incidence were mainly among thin melanomas and mortality rates remained stable. Our objective was to examine this controversy in the Netherlands. Patients and Methods: Information on newly diagnosed melanoma patients was obtained from the Netherlands Cancer Registry (NCR). European Standardised Rates (ESR) and Estimated Annual Percentage Change (EAPC) were calculated for the period 1989-2008.Cohort-based, period-based and multivariate survival analyses were performed. Results: The incidence rate of melanoma increased with 4.1% (95% CI: 3.6-4.5) annually. Incidence rates of both thin melanomas (. 1mm) and thick melanomas (> 4 mm) increased since 1989. Mortality rates increased mainly in older patients (>65 years). Ten-year relative survival of males improved significantly from 70% in 1989-1993 to 77% in 2004-2008 (p < 0.001) and for females the 10-year relative survival increased from 85% to 88% (p < 0.01). Recently diagnosed patients had a better prognosis even after adjusting for all known prognostic factors. Conclusion: Since incidence of melanomas among all Breslow thickness categories increased as well as the mortality rates, the melanoma epidemic in the Netherlands seems to be real and not only due to overdiagnosis

Objective allergy markers and risk of cancer mortality and hospitalization in a large population-based cohort

PURPOSE: There are indications that a history of allergy may offer some protection against cancer. We studied the relation of three objectively determined allergy markers with cancer mortality and hospitalization risk. METHODS: Associations between three allergy markers (number of peripheral blood eosinophil counts, skin test positivity, and serum total IgE) with mortality and hospitalization from any type and four common types of cancer (lung, colorectal, prostate, and breast cancer) were assessed in the Vlagtwedde-Vlaardingen cohort (1965-1990), with follow-up of mortality until 31 December 2008. Hospitalization data were available since 1 January 1995. RESULTS: There were no significant associations between objective allergy markers and cancer mortality or hospitalization. We found several associations in specific subgroups. A higher number of eosinophils was associated with a decreased risk of colorectal cancer mortality in ever smokers HR (95 % CI) = 0.61 (0.45-0.83) and in males 0.59 (0.42-0.83); however, no overall association was observed 0.84 (0.64-1.09). Skin test positivity was associated with a decreased risk of any cancer mortality only among females 0.59 (0.38-0.91) and showed no overall association 0.83 (0.67-1.04). Serum total IgE levels were associated with an increased risk of lung cancer mortality among females 4.64 (1.04-20.70), but with a decreased risk of cancer hospitalization in ever smokers 0.77 (0.61-0.97) and males 0.72 (0.55-0.93); however, no overall associations were observed [mortality 0.99 (0.79-1.25), and hospitalization 0.86 (0.71-1.04)]. CONCLUSIONS: We found no associations between objective allergy markers and cancer in the total population. However, skin test positivity and a high number of eosinophils were associated with a reduced risk to die of cancer in specific subgroups. Hence, it seems important to study specific subgroups defined by gender and smoking habits in order to identify allergy markers of predictive value for cancer mortality

Radiolabeled Monoclonal Antibody Against Colony-Stimulating Factor 1 Receptor Specifically Distributes to the Spleen and Liver in Immunocompetent Mice

Macrophages can promote tumor development. Preclinically, targeting macrophages by colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R) monoclonal antibodies (mAbs) enhances conventional therapeutics in combination treatments. The physiological distribution and tumor uptake of CSF1R mAbs are unknown. Therefore, we radiolabeled a murine CSF1R mAb and preclinically visualized its biodistribution by PET. CSF1R mAb was conjugated to N-succinyl-desferrioxamine (N-suc-DFO) and subsequently radiolabeled with zirconium-89 ((89)Zr). Optimal protein antibody dose was first determined in non-tumor-bearing mice to assess physiological distribution. Next, biodistribution of optimal protein dose and (89)Zr-labeled isotype control was compared with PET and ex vivo biodistribution after 24 and 72 h in mammary tumor-bearing mice. Tissue autoradiography and immunohistochemistry determined radioactivity distribution and tissue macrophage presence, respectively. [(89)Zr]Zr-DFO-N-suc-CSF1R-mAb optimal protein dose was 10 mg/kg, with blood pool levels of 10 ± 2% injected dose per gram tissue (ID/g) and spleen and liver uptake of 17 ± 4 and 11 ± 4%ID/g at 72 h. In contrast, 0.4 mg/kg of [(89)Zr]Zr-DFO-N-suc-CSF1R mAb was eliminated from circulation within 24 h; spleen and liver uptake was 126 ± 44% and 34 ± 7%ID/g, respectively. Tumor-bearing mice showed higher uptake of [(89)Zr]Zr-DFO-N-suc-CSF1R-mAb in the liver, lymphoid tissues, duodenum, and ileum, but not in the tumor than did (89)Zr-labeled control at 72 h. Immunohistochemistry and autoradiography showed that (89)Zr was localized to macrophages within lymphoid tissues. Following [(89)Zr]Zr-DFO-N-suc-CSF1R-mAb administration, tumor macrophages were almost absent, whereas isotype-group tumors contained over 500 cells/mm(2). We hypothesize that intratumoral macrophage depletion by [(89)Zr]Zr-DFO-N-suc-CSF1R-mAb precluded tumor uptake higher than (89)Zr-labeled control. Translation of molecular imaging of macrophage-targeting therapeutics to humans may support macrophage-directed therapeutic development