Increased Intracranial Arterial Pulsatility and Microvascular Brain Damage in Pseudoxanthoma Elasticum

BACKGROUND AND PURPOSE: Carotid siphon calcification might contribute to the high prevalence of cerebrovascular disease in pseudoxanthoma elasticum through increased arterial flow pulsatility. This study aimed to compare intracranial artery flow pulsatility, brain volumes, and small-vessel disease markers between patients with pseudoxanthoma elasticum and controls and the association between arterial calcification and pulsatility in pseudoxanthoma elasticum. MATERIALS AND METHODS: Fifty patients with pseudoxanthoma elasticum and 40 age- and sex-matched controls underwent 3T MR imaging, including 2D phase-contrast acquisitions for flow pulsatility in the assessment of ICA and MCA and FLAIR acquisitions for brain volumes, white matter lesions, and infarctions. All patients with pseudoxanthoma elasticum underwent CT scanning to measure siphon calcification. Flow pulsatility (2D phase-contrast), brain volumes, white matter lesions, and infarctions (3D T1 and 3D T2 FLAIR) were compared between patients and controls. The association between siphon calcification and pulsatility in pseudoxanthoma elasticum was tested with linear regression models. RESULTS: Patients with pseudoxanthoma elasticum (mean age, 57 [SD, 12] years; 24 men) had significantly higher pulsatility indexes (1.05; range, 0.94-1.21 versus 0.94; range, 0.82-1.04; P = .02), lower mean GM volumes (597 [SD, 53] mL versus 632 [SD, 53] mL; P, .01), more white matter lesions (2.6; range, 0.5-7.5 versus 1.1; range, 0.5-2.4) mL; P = .05), and more lacunar infarctions (64 versus 8, P = .04) than controls (mean age, 58 [SD, 11] years; 20 men). Carotid siphon calcification was associated with higher pulsatility indexes in patients with pseudoxanthoma elasticum (b = 0.10; 95% CI, 0.01-0.18). CONCLUSIONS: Patients with pseudoxanthoma elasticum have increased intracranial artery flow pulsatility and measures of small-vessel disease. Carotid siphon calcification might underlie the high prevalence of cerebrovascular disease in pseudoxanthoma elasticum

Trajectories of health-related quality of life and symptom burden in patients with advanced cancer towards the end of life: Longitudinal results from the eQuiPe study

Background: Support for health-related quality of life (HRQOL) is an essential part of cancer care in the final stages of life, yet empirical guidance regarding HRQOL and symptom trajectories is lacking. Aim: To assess the change in HRQOL and symptom burden in the last year of life in patients with advanced cancer and its association with health care–related factors, cancer-specific treatment, and comorbidity. Methods: A prospective, multicenter, observational study in patients with advanced cancer (eQuiPe). Three monthly questionnaires included European Organization for Research and Treatment of Cancer Quality of Life-C30 and reported continuity of care. Multivariable mixed-effects analysis was used to assess the association between HRQOL and health care–related factors. Results: A total of 762 deceased patients were included with a mean age of 66 (SD, 10) years and 52% were male. The most common primary tumors were lung (29%), colorectal (20%), and breast cancer (13%). Mean overall HRQOL decreased in the last 9 months of life, with the greatest decrease in the last 3 months (β –16.2). Fatigue, pain, appetite loss, dyspnea, constipation, and nausea worsened significantly in the last year of life. Multimorbidity (β –7.5) and a better reported continuity of care (β 0.7) were both significantly associated with the trajectory of HRQOL. Conclusion: Mean overall HRQOL begins to decline 9 months before death, highlighting the need for early identification and (re)assessment of different symptoms as aspects of HRQOL follow different trajectories. Multimorbidity and reported continuity of care may be associated with the trajectory of HRQOL

Impact of reduced antibiotic treatment duration on antimicrobial resistance in critically ill patients in the randomized controlled SAPS-trial

Background: In the previously reported SAPS trial (https://clinicaltrials.gov/ct2/show/NCT01139489), procalcitonin-guidance safely reduced the duration of antibiotic treatment in critically ill patients. We assessed the impact of shorter antibiotic treatment on antimicrobial resistance development in SAPS patients. Materials and methods: Cultures were assessed for the presence of multi-drug resistant (MDR) or highly resistant organisms (HRMO) and compared between PCT-guided and control patients. Baseline isolates from 30 days before to 5 days after randomization were compared with those from 5 to 30 days post-randomization. The primary endpoint was the incidence of new MDR/HRMO positive patients. Results: In total, 8,113 cultures with 96,515 antibiotic test results were evaluated for 439 and 482 patients randomized to the PCT and control groups, respectively. Disease severity at admission was similar for both groups. Median (IQR) durations of the first course of antibiotics were 6 days (4–10) and 7 days (5–11), respectively (p = 0.0001). Antibiotic-free days were 7 days (IQR 0–14) and 6 days (0–13; p = 0.05). Of all isolates assessed, 13% were MDR/HRMO positive and at baseline 186 (20%) patients were MDR/HMRO-positive. The incidence of new MDR/HRMO was 39 (8.9%) and 45 (9.3%) in PCT and control patients, respectively (p = 0.82). The time courses for MDR/HRMO development were also similar for both groups (p = 0.33). Conclusions: In the 921 randomized patients studied, the small but statistically significant reduction in antibiotic treatment in the PCT-group did not translate into a detectable change in antimicrobial resistance. Studies with larger differences in antibiotic treatment duration, larger study populations or populations with higher MDR/HRMO incidences might detect such differences

Relationship between quality of life and survival in patients with pancreatic and periampullary cancer: A multicenter cohort analysis

Patient-reported outcome measures (PROMs) are used increasingly in clinical practice to assess patients’ quality of life (QoL). Addressing QoL is important for patients with a short life expectancy, such as those with pancreatic and periampullary carcinoma, which has a median overall survival of 4 to 6 months.1 Different types of treatment that may improve survival in patients with pancreatic cancer may also impact QoL. Pancreatic resection has been found to be associated with a temporary deterioration in QoL, which usually returns to baseline values after 3 to 6 months.2,3 Moreover, chemotherapy has been found to improve QoL in randomized studies in the adjuvant and palliative setting.4,5 QoL may also be used to predict survival. Previous studies with other types of cancer (eg, breast, lung, esophageal, liver) consistently found a correlation between QoL and survival.6–11 Previous studies combined patients with different types of cancer, including a limited number (∼6%) of those with pancreatic cancer.9,10 Most of the data were acquired from randomized trials that included patients who were relatively fit. Only 1 case series of 55 patients with advanced pancreatic cancer suggested a prognostic relationship between the physical functioning scale scores of the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) and survival.12 In the Netherlands, the Dutch Pancreatic Cancer Project (PACAP) was established in 2013. This is a multicenter cohort of patients with pancreatic and periampullary carcinoma for whom clinical data and PROMs are collected.13 We used this cohort to investigate the relationship between QoL and survival in daily clinical practice. The aim of this study was to examine which domains of QoL are predictive of survival in patients with pancreatic and periampullary cancer

Relationship Between Quality of Life and Survival in Patients With Pancreatic and Periampullary Cancer:A Multicenter Cohort Analysis

Patient-reported outcome measures (PROMs) are used increasingly in clinical practice to assess patients’ quality of life (QoL). Addressing QoL is important for patients with a short life expectancy, such as those with pancreatic and periampullary carcinoma, which has a median overall survival of 4 to 6 months.1 Different types of treatment that may improve survival in patients with pancreatic cancer may also impact QoL. Pancreatic resection has been found to be associated with a temporary deterioration in QoL, which usually returns to baseline values after 3 to 6 months.2,3 Moreover, chemotherapy has been found to improve QoL in randomized studies in the adjuvant and palliative setting.4,5 QoL may also be used to predict survival. Previous studies with other types of cancer (eg, breast, lung, esophageal, liver) consistently found a correlation between QoL and survival.6–11 Previous studies combined patients with different types of cancer, including a limited number (∼6%) of those with pancreatic cancer.9,10 Most of the data were acquired from randomized trials that included patients who were relatively fit. Only 1 case series of 55 patients with advanced pancreatic cancer suggested a prognostic relationship between the physical functioning scale scores of the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) and survival.12 In the Netherlands, the Dutch Pancreatic Cancer Project (PACAP) was established in 2013. This is a multicenter cohort of patients with pancreatic and periampullary carcinoma for whom clinical data and PROMs are collected.13 We used this cohort to investigate the relationship between QoL and survival in daily clinical practice. The aim of this study was to examine which domains of QoL are predictive of survival in patients with pancreatic and periampullary cancer

A population-based study on incidence, treatment, and survival in ampullary cancer in the Netherlands

Introduction: Ampullary cancer is rare and as a result epidemiological data are scarce. The aim of this population-based study was to determine the trends in incidence, treatment and overall survival (OS) in patients with ampullary adenocarcinoma in the Netherlands between 1989 and 2016. Methods: Patients diagnosed with ampullary adenocarcinoma were identified from the Netherlands Cancer Registry. Incidence rates were age-adjusted to the European standard population. Trends in treatment and OS were studied over (7 years) period of diagnosis, using Kaplan-Meier and Cox regression analyses for OS and stratified by the presence of metastatic disease. Results: In total, 3840 patients with ampullary adenocarcinoma were diagnosed of whom, 55.0% were male and 87.1% had non-metastatic disease. The incidence increased from 0.59 per 100,000 in 1989-1995 to 0.68 per 100,000in 2010-2016. In non-metastatic disease, the resection rate increased from 49.5% in 1989-1995 to 63.9% in 2010-2016 (p < 0.001). The rate of adjuvant therapy increased from 3.1% to 7.9%. In non-metastatic disease, five-year OS (95% CI) increased from 19.8% (16.9-22.8) in 1989-1995 to 29.1% (26.0-31.2) in 2010e2016 (logrank p < 0.001). In patients with metastatic disease, median OS did not significantly improve (from 4.4 months (3.6-5.0) to 5.9 months (4.7-7.1); logrank p = 0.06). Cancer treatment was an independent prognostic factor for OS among all patients. Conclusion: Both incidence and OS of ampullary cancer increased from 1989 to 2016 which is most likely related to the observed increased resection rates and use of adjuvant therapy. (C) 2021 The Authors. Published by Elsevier Ltd

PD-1+ T-Cells Correlate with Nerve Fiber Density as a Prognostic Biomarker in Patients with Resected Perihilar Cholangiocarcinoma

Background and Aims: Perihilar cholangiocarcinoma (pCCA) is a hepatobiliary malignancy, with a dismal prognosis. Nerve fiber density (NFD)—a novel prognostic biomarker—describes the density of small nerve fibers without cancer invasion and is categorized into high numbers and low numbers of small nerve fibers (high vs low NFD). NFD is different than perineural invasion (PNI), defined as nerve fiber trunks invaded by cancer cells. Here, we aim to explore differences in immune cell populations and survival between high and low NFD patients. Approach and Results: We applied multiplex immunofluorescence (mIF) on 47 pCCA patients and investigated immune cell composition in the tumor microenvironment (TME) of high and low NFD. Group comparison and oncological outcome analysis was performed. CD8+PD-1 expression was higher in the high NFD than in the low NFD group (12.24 × 10−6 vs. 1.38 × 10−6 positive cells by overall cell count, p = 0.017). High CD8+PD-1 expression was further identified as an independent predictor of overall (OS; Hazard ratio (HR) = 0.41; p = 0.031) and recurrence-free survival (RFS; HR = 0.40; p = 0.039). Correspondingly, the median OS was 83 months (95% confidence interval (CI): 18–48) in patients with high CD8+PD-1+ expression compared to 19 months (95% CI: 5–93) in patients with low CD8+PD-1+ expression (p = 0.018 log rank). Furthermore, RFS was significantly lower in patients with low CD8+PD-1+ expression (14 months (95% CI: 6–22)) compared to patients with high CD8+PD-1+ expression (83 months (95% CI: 17–149), p = 0.018 log rank). Conclusions: PD-1+ T-cells correlate with high NFD as a prognostic biomarker and predict good survival; the biological pathway needs to be investigated

Risk factors for adverse outcomes during mechanical ventilation of 1152 COVID-19 patients: a multicenter machine learning study with highly granular data from the Dutch Data Warehouse

Background: The identification of risk factors for adverse outcomes and prolonged intensive care unit (ICU) stay in COVID-19 patients is essential for prognostication, determining treatment intensity, and resource allocation. Previous studies have determined risk factors on admission only, and included a limited number of predictors. Therefore, using data from the highly granular and multicenter Dutch Data Warehouse, we developed machine learning models to identify risk factors for ICU mortality, ventilator-free days and ICU-free days during the course of invasive mechanical ventilation (IMV) in COVID-19 patients. Methods: The DDW is a growing electronic health record database of critically ill COVID-19 patients in the Netherlands. All adult ICU patients on IMV were eligible for inclusion. Transfers, patients admitted for less than 24 h, and patients still admitted at time of data extraction were excluded. Predictors were selected based on the literature, and included medication dosage and fluid balance. Multiple algorithms were trained and validated on up to three sets of observations per patient on day 1, 7, and 14 using fivefold nested cross-validation, keeping observations from an individual patient in the same split. Results: A total of 1152 patients were included in the model. XGBoost models performed best for all outcomes and were used to calculate predictor importance. Using Shapley additive explanations (SHAP), age was the most important demographic risk factor for the outcomes upon start of IMV and throughout its course. The relative probability of death across age values is visualized in Partial Dependence Plots (PDPs), with an increase starting at 54 years. Besides age, acidaemia, low P/F-ratios and high driving pressures demonstrated a higher probability of death. The PDP for driving pressure showed a relative probability increase starting at 12 cmH2O. Conclusion: Age is the most important demographic risk factor of ICU mortality, ICU-free days and ventilator-free days throughout the course of invasive mechanical ventilation in critically ill COVID-19 patients. pH, P/F ratio, and driving pressure should be monitored closely over the course of mechanical ventilation as risk factors predictive of these outcomes