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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 (RB+) if CA19-9 ≥ 500 U/mL and favorable (RB−) otherwise. ECOG ≥ 2 was considered conditionally unfavorable (RC+) and favorable otherwise (RC−). 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 RB+C+ patients (3%; HR 1.61, 95% CI 0.86–2.70), 13 months (95% CI 11–15) in 156 RB+C− patients (23%; HR 1.86, 95% CI 1.50–2.31), and 21 months (95% CI 12–41) in 47 RB−C+ patients (7%; HR 1.14, 95% CI 0.80–1.62) compared with 24 months (95% CI 22–27) in 465 patients with RB−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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article focuses on a multicenter prospective patient preference trial named "Timing of start of systemic treatment in patients with asymptomatic metastasized pancreatic cancer (TIMEPAN)." Topics include the lack of evidence on treatment initiation timing, the potential benefits and risks of immediate versus delayed systemic treatment, and the trial's methodology, including patient eligibility criteria and study design alteration due to recruitment challenges.

Simple Summary: The use of imaging, in general and during follow-up after resection of pancreatic cancer, is increasing. Consequently, the number of asymptomatic patients diagnosed with metastatic pancreatic cancer (mPDAC), both at initial diagnosis and during the diagnosis of recurrent disease, is increasing. In these patients, palliative systemic therapy is the only (tumor-directed) therapy and, hence, is often immediately initiated. However, delaying therapy until symptoms occur may preserve quality of life and avoid therapy-related toxicity, but the impact on survival of this approach is unknown. Using an online survey sent to all first and last authors of published trials on mPDAC and to medical oncologists of the Dutch Pancreatic Cancer group, this study aimed to gain insight into the current perspectives and clinical decision-making of experts. Overall, 78 of 291 (27%) medical oncologists from 15 countries responded. Two-thirds of respondents (63%) preferred an immediate initiation of chemotherapy following diagnosis. In 3/9 case-vignettes, delayed treatment was favored in specific clinical contexts (i.e., patient with only one small lung metastasis, significant comorbidities, and higher age). Respondents from the Netherlands, as well as medical oncologists with fewer years of experience, more often favored delayed treatment. Although the response rate was limited, in this increasing group of asymptomatic patients with mPDAC, immediate treatment is most often preferred, although in specific clinical contexts (i.e., limited metastatic disease, more comorbidities, and higher age), delaying treatment until symptoms occur is considered. Background: The use of imaging, in general, and during follow-up after resection of pancreatic cancer, is increasing. Consequently, the number of asymptomatic patients diagnosed with metastatic pancreatic cancer (mPDAC) is increasing. In these patients, palliative systemic therapy is the only tumor-directed treatment option; hence, it is often immediately initiated. However, delaying therapy in asymptomatic palliative patients may preserve quality of life and avoid therapy-related toxicity, but the impact on survival is unknown. This study aimed to gain insight into the current perspectives and clinical decision=making of experts regarding the timing of treatment initiation of patients with asymptomatic mPDAC. Methods: An online survey (13 questions, 9 case-vignettes) was sent to all first and last authors of published clinical trials on mPDAC over the past 10 years and medical oncologists of the Dutch Pancreatic Cancer Group. Inter-rater variability was determined using the Kappa Light test. Differences in the preferred timing of treatment initiation among countries, continents, and years of experience were analyzed using Fisher's exact test. Results: Overall, 78 of 291 (27%) medical oncologists from 15 countries responded (62% from Europe, 23% from North America, and 15% from Asia–Pacific). The majority of respondents (63%) preferred the immediate initiation of chemotherapy following diagnosis. In 3/9 case-vignettes, delayed treatment was favored in specific clinical contexts (i.e., patient with only one small lung metastasis, significant comorbidities, and higher age). A significant degree of inter-rater variability was present within 7/9 case-vignettes. The recommended timing of treatment initiation differed between continents for 2/9 case-vignettes (22%), in 7/9 (77.9%) comparing the Netherlands with other countries, and based on years of experience for 5/9 (56%). Conclusions: Although the response rate was limited, in asymptomatic patients with mPDAC, immediate treatment is most often preferred. Delaying treatment until symptoms occur is considered in patients with limited metastatic disease, more comorbidities, and higher age. [ABSTRACT FROM AUTHOR]

Background: In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile. Patients and methods: Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses. Results: Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB. Conclusion: Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. Trial registration: Clinical trial registration: NCT02925234. First registration date: 05/10/2016. [ABSTRACT FROM AUTHOR]

Background: The number of elderly patients with pancreatic cancer is growing, however clinical data on the short-term outcomes, rate of adjuvant chemotherapy, and survival in these patients are limited and we therefore performed a nationwide analysis. Methods: Data from the prospective Dutch Pancreatic Cancer Audit were analyzed, including all patients undergoing pancreatic cancer resection between January 2014 and December 2016. Patients were classified into two age groups: <75 and ≥75 years. Major complications (Clavien–Dindo grade 3 or higher), 90-day mortality, rates of adjuvant chemotherapy, and survival were compared between age groups. Factors associated with start of adjuvant chemotherapy and survival were evaluated with logistic regression and multivariable Cox regression analysis. Results: Of 836 patients, 198 were aged ≥75 years (24%) and 638 were aged <75 years (76%). Median follow-up was 38 months (interquartile range [IQR] 31–47). Major complications (31% vs. 28%; p = 0.43) and 90-day mortality (8% vs. 5%; p = 0.18) did not differ. Adjuvant chemotherapy was started in 37% of patients aged ≥75 years versus 69% of patients aged <75 years (p < 0.001). Median overall survival (OS) was 15 months (95% confidence interval [CI] 14–18) versus 21 months (95% CI 19–24; p < 0.001). Age ≥75 years was not independently associated with OS (hazard ratio 0.96, 95% CI 0.79–1.17; p = 0.71), but was associated with a lower rate of adjuvant chemotherapy (odds ratio 0.27, 95% CI 0.18–0.40; p < 0.001). Conclusions: The rate of major complications and 90-day mortality after pancreatic resection did not differ between elderly and younger patients; however, elderly patients were less often treated with adjuvant chemotherapy and their OS was shorter. [ABSTRACT FROM AUTHOR]

Background: Biological sex, gender and age have an impact on the incidence and outcome in patients with metastatic pancreatic cancer. The aim of this study is to investigate whether biological sex, gender and age are associated with treatment allocation and overall survival (OS) of patients with metastatic pancreatic cancer in a nationwide cohort. Methods: Patients with synchronous metastatic pancreatic cancer diagnosed between 2015 and 2019 were selected from the Netherlands Cancer Registry (NCR). The association between biological sex and the probability of receiving systemic treatment were examined with multivariable logistic regression analyses. Kaplan Meier analyses with log-rank test were used to describe OS. Results: A total of 7470 patients with metastatic pancreatic cancer were included in this study. Fourty-eight percent of patients were women. Women received less often systemic treatment (26% vs. 28%, P=0.03), as compared to men. Multivariable logistic regression analyses with adjustment for confounders showed that women ≤55 years of age, received more often systemic treatment (OR 1.82, 95% CI 1.24-2.68) compared to men of the same age group. In contrast, women at >55 years of age had a comparable probability to receive systemic treatment compared to men of the same age groups. After adjustment for confounders, women had longer OS compared to men (HR 0.89, 95% CI 0.84-0.93). Conclusion: This study found that women in general had a lower probability of receiving systemic treatment compared to men, but this can mainly be explained by age differences. Women had better OS compared to men after adjustment for confounders. [ABSTRACT FROM AUTHOR]

In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance. Molecular landscapes of metastatic colorectal cancers (mCRC) have often been restricted to coding regions or low numbers of patients. Here the authors present a whole-genome landscape of 429 mCRC patients, revealing the mutational impact of prior therapies and potential actionable targets. [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy-resistance remains a major obstacle to effective anti-cancer treatment. We previously showed that platinum analogs cause the release of two fatty acids. These platinum-induced fatty acids (PIFAs) induced complete chemoresistance in mice, whereas co-administration of a COX-1 inhibitor, indomethacin, prevented PIFA release and significantly enhanced chemosensitivity. To assess the safety of combining indomethacin with platinum-based chemotherapy, and to explore its efficacy and associated PIFA levels, a multi-center phase I trial was conducted.Methods: The study was comprised of two arms: oxaliplatin plus capecitabine (CAPOX, arm I) and cisplatin plus gemcitabine, capecitabine or 5FU (arm II) in patients for whom these regimens were indicated as standard care. Indomethacin was escalated from 25 to 75 mg TID, using a standard 3 × 3 design per arm, and was administered orally 8 days around chemo-infusion from cycle two onwards. PIFA levels were measured before and after treatment initiation, with and without indomethacin.Results: Thirteen patients were enrolled, of which ten were evaluable for safety analyses. In arm I, no dose-limiting toxicities were observed, and all indomethacin dose levels were well-tolerated. Partial responses were observed in three patients (30%). Indomethacin lowered plasma levels of 12-S-hydroxy-5,8,10-heptadecatrienoic acid (12-S-HHT), whereas 4,7,10,13-hexadecatetraenoic acid (16:4(n-3)) levels were not affected. Only one patient was included in arm II; renal toxicity led to closure of this cohort.Conclusions: Combined indomethacin and CAPOX treatment is safe and reduces the concentrations of 12-S-HHT, which may be associated with improved chemosensitivity. The recommended phase II dose is 75 mg indomethacin TID given 8 days surrounding standard dosed CAPOX. [ABSTRACT FROM AUTHOR]

Background The discovery of novel biomarkers that predict treatment response in advanced cancer patients requires acquisition of high-quality tumor samples. As cancer evolves over time, tissue is ideally obtained before the start of each treatment. Preferably, samples are freshly frozen to allow analysis by next-generation DNA/RNA sequencing (NGS) but also for making other emerging systematic techniques such as proteomics and metabolomics possible. Here, we describe the first 469 image-guided biopsies collected in a large collaboration in The Netherlands (Center for Personalized Cancer Treatment) and show the utility of these specimens for NGS analysis. Patients and Methods Image-guided tumor biopsies were performed in advanced cancer patients. Samples were fresh frozen, vital tumor cellularity was estimated, and DNA was isolated after macrodissection of tumor-rich areas. Safety of the image-guided biopsy procedures was assessed by reporting of serious adverse events within 14 days after the biopsy procedure. Results Biopsy procedures were generally well tolerated. Major complications occurred in 2.1%, most frequently consisting of pain. In 7.3% of the percutaneous lung biopsies, pneumothorax requiring drainage occurred. The majority of samples (81%) contained a vital tumor percentage of at least 30%, from which at least 500 ng DNA could be isolated in 91%. Given our preset criteria, 74% of samples were of sufficient quality for biomarker discovery. The NGS results in this cohort were in line with those in other groups. Conclusion Image-guided biopsy procedures for biomarker discovery to enable personalized cancer treatment are safe and feasible and yield a highly valuable biobank. The Oncologist 2017;22:33-40 Implications for Practice: This study shows that it is safe to perform image-guided biopsy procedures to obtain fresh frozen tumor samples and that it is feasible to use these biopsies for biomarker discovery purposes in a Dutch multicenter collaboration. From the majority of the samples, sufficient DNA could be yielded to perform next-generation sequencing. These results indicate that the way is paved for consortia to prospectively collect fresh frozen tumor tissue. [ABSTRACT FROM AUTHOR]

BACKGROUND: Oral refeeding in patients recovering from acute pancreatitis may cause pain relapse. Patients with pain relapse may be ill for prolonged periods, thereby consuming additional health care resources. We aimed to determine the incidence and risk factors of pain relapse on the basis of reviewing all studies on oral refeeding in acute pancreatitis. METHODS: Relevant literature cited in three electronic databases (Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE) as well as the abstracts of major gastroenterological meetings was reviewed. Outcome measures studied were the incidence of pain relapse and length of hospital stay. RESULTS: A total of three studies met the inclusion criteria. Sixty of 274 patients (21.9%) experienced pain relapse during the course of acute pancreatitis. In 47 of 60 (78.3%) patients pain relapse occurred within 48 h after commencement of oral refeeding. Two studies showed a significantly higher Balthazar's CT score on hospital admission in patients with pain relapse, whereas all three studies found no difference in the severity scores between patients with and without pain relapse. All three studies found a significant increase in the length of hospital stay in patients with pain relapse. CONCLUSIONS: The incidence of pain relapse after oral refeeding in acute pancreatitis is relatively high. Thereby, the quest for new therapeutical modalities that can prevent pain relapse is of current importance. [ABSTRACT FROM AUTHOR]

Background: RDS involving inflammatory and oxidative processes may lead to increased production of carbon monoxide (CO). Aim: The relationship between end-tidal CO, corrected for inhaled CO (ETCOc), and RDS severity was investigated in preterm infants as well as the value of early ETCOc measurements to predict chronic lung disease. Methods: 78 infants (30 no RDS, 32 moderate RDS, 16 severe RDS) were included. ETCOc was measured using the CO-Stat™ End Tidal Breath Analyzer. Results: ETCOc was significantly higher in RDS compared to no RDS during the first week ( p Conclusion: During severe RDS, inflammation may contribute to increased lipid peroxidation leading to increased local CO production in the lung, indicated by increased ETCOc. Early ETCOc determinations may be helpful to exclude occurrence of chronic lung disease. [ABSTRACT FROM AUTHOR]

The original version of this Article contained an error in Table 4, in which the coefficients of the LASSO regression model of treatment response corresponded to a version that was performed without non-coding genes. The original version of this Article contained an error in the Methods, section "Whole-genome sequencing; identification of somatic changes", which incorrectly read 'GATK BQSR and Haplotype Caller v3.4.46 were used to call somatic mutations'. [Extracted from the article]