Influence of different data-averaging methods on mean values of selected variables derived from preoperative cardiopulmonary exercise testing in patients scheduled for colorectal surgery

Patients with a low cardiorespiratory fitness (CRF) undergoing colorectal cancer surgery have a high risk for postoperative complications. Cardiopulmonary exercise testing (CPET) to assess CRF is the gold standard for preoperative risk assessment. To aid interpretation of raw breath-by-breath data, different methods of data-Averaging can be applied. This study aimed to investigate the influence of different data-Averaging intervals on CPET variables used for preoperative risk assessment, as well as to evaluate whether different dataaveraging intervals influence preoperative risk assessment. Methods A total of 21 preoperative CPETs were interpreted by two exercise physiologists using stationary time-based data-Averaging intervals of 10, 20, and 30 seconds and rolling average intervals of 3 and 7 breaths. Mean values of CPET variables between different data averaging intervals were compared using repeated measures ANOVA. The variables of interest were oxygen uptake at peak exercise (VO2peak), oxygen uptake at the ventilatory anaerobic threshold (VO2VAT), oxygen uptake efficiency slope (OUES), the ventilatory equivalent for carbon dioxide at the ventilatory anaerobic threshold (VE/VCO2VAT), and the slope of the relationship between the minute ventilation and carbon dioxide production (VE/VCO2-slope). Results Between data-Averaging intervals, no statistically significant differences were found in the mean values of CPET variables except for the ventilatory equivalent for carbon dioxide at the ventilatory anaerobic threshold (P = 0.001). No statistically significant differences were found in the proportion of patients classified as high or low risk regardless of the used dataaveraging interval. Conclusion There appears to be no significant or clinically relevant influence of the evaluated data-Averaging intervals on the mean values of CPET outcomes used for preoperative risk assessment. Clinicians may choose a data-Averaging interval that is appropriate for optimal interpretation and data visualization of the preoperative CPET. Nevertheless, caution should be taken as the chosen data-Averaging interval might lead to substantial within-patient variation for individual patients

Impact of the COVID-19 pandemic on breast cancer incidence and tumor stage in the Netherlands and Norway:A population-based study

BACKGROUND: Comparing the impact of the COVID-19 pandemic on the incidence of newly diagnosed breast tumors and their tumor stage between the Netherlands and Norway will help us understand the effect of differences in governmental and social reactions towards the pandemic.METHODS: Women newly diagnosed with breast cancer in 2017-2021 were selected from the Netherlands Cancer Registry and the Cancer Registry of Norway. The crude breast cancer incidence rate (tumors per 100,000 women) during the first (March-September 2020), second (October 2020-April 2021), and Delta COVID-19 wave (May-December 2021) was compared with the incidence rate in the corresponding periods in 2017, 2018, and 2019. Incidence rates were stratified by age group, method of detection, and clinical tumor stage.RESULTS: During the first wave breast cancer incidence declined to a larger extent in the Netherlands than in Norway (27.7% vs. 17.2% decrease, respectively). In both countries, incidence decreased in women eligible for screening. In the Netherlands, incidence also decreased in women not eligible for screening. During the second wave an increase in the incidence of stage IV tumors in women aged 50-69 years was seen in the Netherlands. During the Delta wave an increase in overall incidence and incidence of stage I tumors was seen in Norway.CONCLUSION: Alterations in breast cancer incidence and tumor stage seem related to a combined effect of the suspension of the screening program, health care avoidance due to the severity of the pandemic, and other unknown factors.</p

Ribosomal Protein Mutations Induce Autophagy through S6 Kinase Inhibition of the Insulin Pathway

Mutations affecting the ribosome lead to several diseases known as ribosomopathies, with phenotypes that include growth defects, cytopenia, and bone marrow failure. Diamond-Blackfan anemia (DBA), for example, is a pure red cell aplasia linked to the mutation of ribosomal protein (RP) genes. Here we show the knock-down of the DBA-linked RPS19 gene induces the cellular self-digestion process of autophagy, a pathway critical for proper hematopoiesis. We also observe an increase of autophagy in cells derived from DBA patients, in CD34+ erythrocyte progenitor cells with RPS19 knock down, in the red blood cells of zebrafish embryos with RP-deficiency, and in cells from patients with Shwachman-Diamond syndrome (SDS). The loss of RPs in all these models results in a marked increase in S6 kinase phosphorylation that we find is triggered by an increase in reactive oxygen species (ROS). We show that this increase in S6 kinase phosphorylation inhibits the insulin pathway and AKT phosphorylation activity through a mechanism reminiscent of insulin resistance. While stimulating RP-deficient cells with insulin reduces autophagy, antioxidant treatment reduces S6 kinase phosphorylation, autophagy, and stabilization of the p53 tumor suppressor. Our data suggest that RP loss promotes the aberrant activation of both S6 kinase and p53 by increasing intracellular ROS levels. The deregulation of these signaling pathways is likely playing a major role in the pathophysiology of ribosomopathies

Survival of MUTYH-Associated Polyposis Patients With Colorectal Cancer and Matched Control Colorectal Cancer Patients

Background: MUTYH-associated polyposis is a recessively inherited disorder characterized by a lifetime risk of colorectal cancer that is up to 100%. Because specific histological and molecular genetic features of MUTYH-associated polyposis colorectal cancers might influence tumor behavior and patient survival, we compared survival between patients with MUTYH-associated polyposis colorectal cancer and matched control patients with colorectal cancer from the general population. Method:s In this retrospective multicenter cohort study from Europe, 147 patients with MUTYH-associated polyposis colorectal cancer were compared with 272 population-based control patients with colorectal cancer who were matched for country, age at diagnosis, year of diagnosis, stage, and subsite of colorectal cancer. Kaplan–Meier survival and Cox regression analyses were used to compare survival between patients with MUTYH-associated polyposis colorectal cancer and control patients with colorectal cancer. All statistical tests were two-sided. Results: Five-year survival for patients with MUTYH-associated polyposis colorectal cancer was 78% (95% confidence interval [CI] = 70% to 84%) and for control patients was 63% (95% CI = 56% to 69%) (log-rank test, P = .002). After adjustment for differences in age, stage, sex, subsite, country, and year of diagnosis, survival remained better for MUTYH-associated polyposis colorectal cancer patients than for control patients (hazard ratio of death = 0.48, 95% CI = 0.32 to 0.72). Conclusions: In a European study cohort, we found statistically significantly better survival for patients with MUTYH-associated polyposis colorectal cancer than for matched control patients with colorectal cancer

The cumulative risk of lung cancer among current, ex- and never-smokers in European men

Recent analyses based on UK data indicate that people who stop smoking, even well into middle age, avoid most of their subsequent risk of lung cancer. We investigated whether similar absolute risks of lung cancer in men are found in other European countries with different smoking patterns and at different stages of their lung cancer epidemic. Using data for men from a multicentre case-control study of lung cancer in the UK, Germany, Italy and Sweden, and including 6523 lung cancer cases and 9468 controls, we combined odds ratio estimates with estimates of national lung cancer incidence rates to calculate the cumulative risk of lung cancer among men by age 75. Lung cancer cumulative risks by age 75 among continuing smokers were similar for the UK, Germany and Italy at 15.7, 14.3 and 13.8% respectively, whereas the cumulative risk among Swedish male smokers was 6.6%. The proportion of the risk of lung cancer avoided by quitting smoking before the age of 40 was comparable between the four countries, at 80% in Italy and 91% in the UK, Germany and Sweden. Similarly, the proportion of the excess risk avoided by quitting before the age of 50 ranged from 57% in Italy to 69% in Germany. Our results support the important conclusion that for long-term smokers, giving up smoking in middle age avoids most of the subsequent risk of lung cancer, and that lung cancer mortality in European men over the next three decades will be determined by the extent to which current smokers can successfully quit smoking

Impact of age on outcome after colorectal cancer surgery in the elderly - a developing country perspective

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer (CRC) is a major source of morbidity and mortality in the elderly population and surgery is often the only definitive management option. The suitability of surgical candidates based on age alone has traditionally been a source of controversy. Surgical resection may be considered detrimental in the elderly solely on the basis of advanced age. Based on recent evidence suggesting that age alone is not a predictor of outcomes, Western societies are increasingly performing definitive procedures on the elderly. Such evidence is not available from our region. We aimed to determine whether age has an independent effect on complications after surgery for colorectal cancer in our population.</p> <p>Methods</p> <p>A retrospective review of all patients who underwent surgery for pathologically confirmed colorectal cancer at Aga Khan University Hospital, Karachi between January 1999 and December 2008 was conducted. Using a cut-off of 70 years, patients were divided into two groups. Patient demographics, tumor characteristics and postoperative complications and 30-day mortality were compared. Multivariate logistic regression analysis was performed with clinically relevant variables to determine whether age had an independent and significant association with the outcome.</p> <p>Results</p> <p>A total of 271 files were reviewed, of which 56 belonged to elderly patients (≥ 70 years). The gender ratio was equal in both groups. Elderly patients had a significantly higher comorbidity status, Charlson score and American society of anesthesiologists (ASA) class (all p < 0.001). Upon multivariate analysis, factors associated with more complications were ASA status (95% CI = 1.30-6.25), preoperative perforation (95% CI = 1.94-48.0) and rectal tumors (95% CI = 1.21-5.34). Old age was significantly associated with systemic complications upon univariate analysis (p = 0.05), however, this association vanished upon multivariate analysis (p = 0.36).</p> <p>Conclusion</p> <p>Older patients have more co-morbid conditions and higher ASA scores, but increasing age itself is not independently associated with complications after surgery for CRC. Therefore patient selection should focus on the clinical status and ASA class of the patient rather than age.</p

Flow cytometric mepacrine fluorescence can be used for the exclusion of platelet dense granule deficiency

Background: δ-storage pool disease (δ-SPD) is a bleeding disorder characterized by a reduced number of platelet-dense granules. The diagnosis of δ-SPD depends on the measurement of platelet ADP content, but this test is time consuming and requires a relatively large blood volume. Flow cytometric analysis of platelet mepacrine uptake is a potential alternative, but this approach lacks validation, which precludes its use in a diagnostic setting. Objectives: To evaluate the performance of platelet mepacrine uptake as a diagnostic test for δ-SPD. Patients/Methods: Mepacrine fluorescence was determined with flow cytometry before and after platelet activation in 156 patients with a suspected platelet function disorder and compared with platelet ADP content as a reference test. Performance was analyzed with a receiver operating characteristic (ROC) curve. Results: Eleven of 156 patients had δ-SPD based on platelet ADP content. Mepacrine fluorescence was inferior to platelet ADP content in identifying patients with δ-SPD, but both mepacrine uptake (area under the ROC curve [AUC] 0.87) and mepacrine release after platelet activation (AUC 0.80) had good discriminative ability. In our tertiary reference center, mepacrine uptake showed high negative predicitive value (97%) with low positive predictive value (35%). Combined with a negative likelihood ratio of 0.1, these data indicate that mepacrine uptake can be used to exclude δ-SPD in patients with a bleeding tendency. Conclusion: Mepacrine fluorescence can be used as a screening tool to exclude δ-SPD in a large number of patients with a suspected platelet function disorder

Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer.

BACKGROUND: Invasive lobular breast cancer (ILC) is the second most common type of breast cancer after invasive breast cancer of no special type (NST), representing up to 15% of all breast cancers. DESIGN: Latest data on ILC are presented, focusing on diagnosis, molecular make-up according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) guidelines, treatment in the early and metastatic setting and ILC-focused clinical trials. RESULTS: At the imaging level, magnetic resonance imaging-based and novel positron emission tomography/computed tomography-based techniques can overcome the limitations of currently used imaging techniques for diagnosing ILC. At the pathology level, E-cadherin immunohistochemistry could help improving inter-pathologist agreement. The majority of patients with ILC do not seem to benefit as much from (neo-)adjuvant chemotherapy as patients with NST, although chemotherapy might be required in a subset of high-risk patients. No differences in treatment efficacy are seen for anti-human epidermal growth factor receptor 2 (HER2) therapies in the adjuvant setting and cyclin-dependent kinases 4 and 6 inhibitors in the metastatic setting. The clinical utility of the commercially available prognostic gene expression-based tests is unclear for patients with ILC. Several ESCAT alterations differ in frequency between ILC and NST. Germline BRCA1 and PALB2 alterations are less frequent in patients with ILC, while germline CDH1 (gene coding for E-cadherin) alterations are more frequent in patients with ILC. Somatic HER2 mutations are more frequent in ILC, especially in metastases (15% ILC versus 5% NST). A high tumour mutational burden, relevant for immune checkpoint inhibition, is more frequent in ILC metastases (16%) than in NST metastases (5%). Tumours with somatic inactivating CDH1 mutations may be vulnerable for treatment with ROS1 inhibitors, a concept currently investigated in early and metastatic ILC. CONCLUSION: ILC is a unique malignancy based on its pathological and biological features leading to differences in diagnosis as well as in treatment response, resistance and targets as compared to NST

Quality of Life in Oncological Patients with Oropharyngeal Dysphagia: Validity and Reliability of the Dutch Version of the MD Anderson Dysphagia Inventory and the Deglutition Handicap Index

Quality of life is an important outcome measurement in objectifying the current health status or therapy effects in patients with oropharyngeal dysphagia. In this study, the validity and reliability of the Dutch version of the Deglutition Handicap Index (DHI) and the MD Anderson Dysphagia Inventory (MDADI) have been determined for oncological patients with oropharyngeal dysphagia. At Maastricht University Medical Center, 76 consecutive patients were selected and asked to fill in three questionnaires on quality of life related to oropharyngeal dysphagia (the SWAL-QOL, the MDADI, and the DHI) as well as a simple one-item visual analog Dysphagia Severity Scale. None of the quality-of-life questionnaires showed any floor or ceiling effect. The test-retest reliability of the MDADI and the Dysphagia Severity Scale proved to be good. The test-retest reliability of the DHI could not be determined because of insufficient data, but the intraclass correlation coefficients were rather high. The internal consistency proved to be good. However, confirmatory factor analysis could not distinguish the underlying constructs as defined by the subscales per questionnaire. When assessing criterion validity, both the MDADI and the DHI showed satisfactory associations with the SWAL-QOL (reference or gold standard) after having removed the less relevant subscales of the SWAL-QOL. In conclusion, when assessing the validity and reliability of the Dutch version of the DHI or the MDADI, not all psychometric properties have been adequately met. In general, because of difficulties in the interpretation of study results when using questionnaires lacking sufficient psychometric quality, it is recommended that researchers strive to use questionnaires with the most optimal psychometric properties

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches