Preoperative predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma

BACKGROUND: This study aimed to identify predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) resection with and without neoadjuvant therapy. METHODS: Included were patients who underwent PDAC resection (2014-2016). Multivariable multinomial regression was performed to identify preoperative predictors for manifestation of recurrence within 3, 6 and 12 months after PDAC resection. RESULTS: 836 patients with a median follow-up of 37 (interquartile range [IQR] 30-48) months and overall survival of 18 (IQR 10-32) months were analyzed. 670 patients (80%) developed recurrence: 82 patients (10%) <3 months, 96 patients (11%) within 3-6 months and 226 patients (27%) within 6-12 months. LogCA 19-9 (OR 1.25 [95% CI 1.10-1.41]; P < 0.001) and neoadjuvant treatment (OR 0.09 [95% CI 0.01-0.68]; P = 0.02) were associated with recurrence <3 months. LogCA 19-9 (OR 1.23 [95% CI 1.10-1.38]; P < 0.001) and 0-90° venous involvement on CT imaging (OR 2.93 [95% CI 1.60-5.37]; P < 0.001) were associated with recurrence within 3-6 months. A Charlson Age Comorbidity Index ≥4 (OR 1.53 [95% CI 1.09-2.16]; P = 0.02) and logCA 19-9 (OR 1.24 [95% CI 1.14-1.35]; P < 0.001) were related to recurrence within 6-12 months. CONCLUSION: This study demonstrates preoperative predictors that are associated with the manifestation of early and very early recurrence after PDAC resection. Knowledge of these predictors can be used to guide individualized surveillance and treatment strategies

Detection, Treatment, and Survival of Pancreatic Cancer Recurrence in the Netherlands A Nationwide Analysis

OBJECTIVE: To evaluate whether detection of recurrent pancreatic ductal adenocarcinoma (PDAC) in an early, asymptomatic stage increases the number of patients receiving additional treatment, subsequently improving survival. SUMMARY OF BACKGROUND DATA: International guidelines disagree on the value of standardized postoperative surveillance for early detection and treatment of PDAC recurrence. METHODS: A nationwide, observational cohort study was performed including all patients who underwent PDAC resection (2014-2016). Prospective baseline and perioperative data were retrieved from the Dutch Pancreatic Cancer Audit. Data on follow-up, treatment, and survival were collected retrospectively. Overall survival (OS) was evaluated using multivariable Cox regression analysis, before and after propensity-score matching, stratified for patients with symptomatic and asymptomatic recurrence. RESULTS: Eight hundred thirty-six patients with a median follow-up of 37 months (interquartile range 30-48) were analyzed. Of those, 670 patients (80%) developed PDAC recurrence after a median follow-up of 10 months (interquartile range 5-17). Additional treatment was performed in 159/511 patients (31%) with symptomatic recurrence versus 77/159 (48%) asymptomatic patients (P < 0.001). After propensity-score matching on lymph node ratio, adjuvant therapy, disease-free survival, and recurrence site, additional treatment was independently associated with improved OS for both symptomatic patients [hazard ratio 0.53 (95% confidence interval 0.42-0.67); P < 0.001] and asymptomatic patients [hazard ratio 0.45 (95% confidence interval 0.29-0.70); P < 0.001]. CONCLUSIONS: Additional treatment of PDAC recurrence was independently associated with improved OS, with asymptomatic patients having a higher probability to receive recurrence treatment. Therefore, standardized postoperative surveillance aiming to detect PDAC recurrence before the onset of symptoms has the potential to improve survival. This provides a rationale for prospective studies on standardized surveillance after PDAC resection

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor

Objective: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. Methods: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. Results: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. Interpretation: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023

Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response

BACKGROUND: The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies. METHODS: We optimized drug screen methods on 5-11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient's response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness. RESULTS: Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU & oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU & oxaliplatin was screened in a ratio, and 5-FU & SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n = 6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n = 10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n = 11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9 months, p = 0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p = 0.003). CONCLUSIONS: Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens

The Value of Biological and Conditional Factors for Staging of Patients with Resectable Pancreatic Cancer Undergoing Upfront Resection: A Nationwide Analysis

BACKGROUND: Novel definitions suggest that resectability status for pancreatic ductal adenocarcinoma (PDAC) should be assessed beyond anatomical criteria, considering both biological and conditional factors. This has, however, yet to be validated on a nationwide scale. This study evaluated the prognostic value of biological and conditional factors for staging of patients with resectable PDAC. PATIENTS AND METHODS: A nationwide observational cohort study was performed, including all consecutive patients who underwent upfront resection of National Comprehensive Cancer Network resectable PDAC in the Netherlands (2014-2019) with complete information on preoperative carbohydrate antigen (CA) 19-9 and Eastern Cooperative Oncology Group (ECOG) performance status. PDAC was considered biologically unfavorable (R B+) if CA19-9 ≥ 500 U/mL and favorable (R B-) otherwise. ECOG ≥ 2 was considered conditionally unfavorable (R C+) and favorable otherwise (R C-). Overall survival (OS) was assessed using Kaplan-Meier and Cox-proportional hazard analysis, presented as hazard ratios (HRs) with 95% confidence interval (CI). RESULTS: Overall, 688 patients were analyzed with a median overall survival (OS) of 20 months (95% CI 19-23). OS was 14 months (95% CI 10 months-median not reached) in 20 R B+C+ patients (3%; HR 1.61, 95% CI 0.86-2.70), 13 months (95% CI 11-15) in 156 R B+C- patients (23%; HR 1.86, 95% CI 1.50-2.31), and 21 months (95% CI 12-41) in 47 R B-C+ patients (7%; HR 1.14, 95% CI 0.80-1.62) compared with 24 months (95% CI 22-27) in 465 patients with R B-C- PDAC (68%; reference). CONCLUSIONS: Survival after upfront resection of anatomically resectable PDAC is worse in patients with CA19-9 ≥ 500 U/mL, while performance status had no impact. This supports consideration of CA19-9 in preoperative staging of resectable PDAC

Dutch Oncology COVID-19 consortium:Outcome of COVID-19 in patients with cancer in a nationwide cohort study

Aim of the study: Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19. Methods: This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible. Results: Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years). Conclusion: The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered

Cluster headache genome-wide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor.

OBJECTIVE: Aggregating data for the first genome-wide association study meta-analysis of cluster headache, to identify genetic risk variants and gain biological insights. METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from ten European and one East Asian cohorts. We first performed an inverse-variance genome-wide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by five complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis and Mendelian randomization were part of the downstream analyses. RESULTS: The estimated SNP-based heritability of cluster headache was 14.5%. We identified nine independent signals in seven genome-wide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, ADHD, depression and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. INTERPRETATION: This first genome-wide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. This article is protected by copyright. All rights reserved