A National Audit of Pancreatic Enzyme Prescribing in Pancreatic Cancer from 2015 to 2023 in England Using OpenSAFELY-TPP.

OBJECTIVES: Cancer treatments were variably disrupted during the coronavirus disease 2019 (COVID-19) pandemic. UK guidelines recommend pancreatic enzyme replacement therapy (PERT) to all people with unresectable pancreatic cancer. The aim was to investigate the impact of the COVID-19 pandemic on PERT prescribing to people with unresectable pancreatic cancer and to investigate the national and regional rates from January 2015 to January 2023. DATA SOURCES: With the approval of NHS England, we conducted this study using 24 million electronic health records of people within the OpenSAFELY-TPP research platform. There were 22,860 people diagnosed with pancreatic cancer in the study cohort. We visualized the trends over time and modeled the effect of the COVID-19 pandemic with the interrupted time-series analysis. CONCLUSION: In contrast to many other treatments, prescribing of PERT was not affected during the pandemic. Overall, since 2015, the rates increased steadily over time by 1% every year. The national rates ranged from 41% in 2015 to 48% in early 2023. There was substantial regional variation, with the highest rates of 50% to 60% in West Midlands. IMPLICATIONS FOR NURSING PRACTICE: In pancreatic cancer, if PERT is prescribed, it is usually initiated in hospitals by clinical nurse specialists and continued after discharge by primary care practitioners. At just under 50% in early 2023, the rates were still below the recommended 100% standard. More research is needed to understand barriers to prescribing of PERT and geographic variation to improve quality of care. Prior work relied on manual audits. With OpenSAFELY, we developed an automated audit that allows for regular updates (https://doi.org/10.53764/rpt.a0b1b51c7a).

The impact of the COVID-19 pandemic upon pancreatic cancer treatment (CONTACT Study): a UK national observational cohort study.

INTRODUCTION: CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: The treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic ('COVID' cohort, 16/03/2020-10/05/2020), with 12-month follow-up. RESULTS: Among 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, p = 0.004) or received palliative anti-cancer therapy (20.5% vs. 26.5%, p = 0.045). Ultimately, fewer patients in the COVID cohort underwent surgical resection (6.4% vs. 9.3%, p = 0.036), whilst more patients received no anti-cancer treatment (69.3% vs. 59.2% p = 0.009). Despite these differences, there was no difference in median overall survival between the COVID and pre-COVID cohorts, (3.5 (IQR 2.8-4.1) vs. 4.4 (IQR 3.6-5.2) months, p = 0.093). CONCLUSION: Pathways for patients with PDAC were significantly disrupted during the first wave of the COVID-19 pandemic, with fewer patients receiving standard treatments. However, no significant impact on survival was discerned.

A Modified Regimen of 21-day Nab-Paclitaxel Plus Gemcitabine in Locally Advanced or Metastatic Pancreatic Cancer: A Retrospective Real-World Study.

BACKGROUND: It is 1 of the standard treatment options for metastasis pancreatic cancer to receive nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1, 8 and 15 every 28 days. Some patients showed intolerance and inconvenience to this therapeutic regimen. Thus, we conducted this retrospective real-world study to determine the efficacy and tolerability of a modified 21-day nab-paclitaxel plus gemcitabine (nab-P/Gem) regimen for the first-line treatment of locally advanced or metastatic pancreatic cancer. METHODS: Patients with locally advanced and metastatic pancreatic cancer treated with nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 every 21-day at West China Hospital and Shang Jin Hospital of Sichuan University from Mar 2018 to Dec 2021 were reviewed retrospectively. Clinical characteristics of patients were collected. The progression-free survival, overall survival, objective response rate, disease control rate, and toxicity were evaluated. RESULTS: A total of 113 patients who received the modified regimen of 21-day nab-P/Gem chemotherapy were included. The median overall survival was 9.3 months and the median progression-free survival was 4.4 months. The objective response rate and disease control rate were 18.6% and 56.7%, respectively. The median relative dose intensity for this modified regimen was 65%. The adverse events were mild to moderate, and the most common grade 3 or 4 treatment-related adverse events were neutropenia (21%) and leukopenia (16%). CONCLUSIONS: Our study showed that this modified regimen of 21-day nab-P/Gem for locally advanced and metastatic pancreatic cancer had comparable efficacy and tolerable toxicity. This treatment may provide a considerable option for pancreatic cancer patients who desire a modified schedule. The modified regimen of 21-day nab-P/Gem is also an option worth considering during the coronavirus disease 2019 pandemic for minimizing the number of visits and limiting the risk of exposure.

Efficacy, Safety, and Impact on Patient Survival of PDL1/PD-1 Inhibitors versus FOLFIRINOX Regimens for Advanced Pancreatic Cancer.

Background: Over the last few years, the role of PDL1/PD-1 in pancreatic cancer development has received increasing attention, and this article is aimed at opening up new ideas for the medicine-based treatment of pancreatic cancer. Aims: To investigate the efficacy and safety of PDL1/PD-1 inhibitors versus FOLFIRINOX regimen in the treatment of advanced pancreatic cancer and its impact on patient survival and to provide a reference basis for clinical treatment of pancreatic cancer. Materials and Methods: The 116 pancreatic cancer patients treated in our hospital from September 2019 to September 2021 were selected and divided into 58 cases each in the (instance of watching, noticing, or making a statement) group and the comparison group according to the method based on random number table. The comparison group was treated with FOLFIRINOX, and the group was treated with PDL1/PD-1 stopper. The effectiveness, safety, and hit/effect on survival of the patients in the two groups were compared. Results: The median chemotherapy cycle for all patients was 4 (1-6), and the combined objective remission rate (0RR) was 36% and the disease control rate (DCR) was 80% after no chemotherapy in 116 patients, with 37.5% 0RR and 81.3% DCR in the observation group and 33.3% 0RR and 77.8% DCR in the comparison group. The greatest number of all patients reached SD, 44%; in the observation group, 43.8%; and in the comparison group, 44.5%. The rate of adverse reactions such as hematological toxicity, neutropenia, anemia, thrombocytopenia, nonhematological toxicity, vomiting, fatigue, infection, diarrhea, intestinal obstruction, and peripheral neuropathy was lower in 10.3% of patients in the observation group than in 25.8% of patients in the comparison group, which was significantly different by χ 2 test (P < 0.05). The median progression-free survival curve of the two groups was 19 months in the comparison group and 22 months in the observation group. The progression-free survival in the observation group was significantly higher than that in the comparison group, and there was a statistically significant difference between the two groups (P < 0.05). Conclusion: PDL1/PD-1 inhibitors in combination with FOLFIRINOX regimens have shown longer survival than treatment with FOLFIRINOX regimens for pancreatic cancer patients, with reliable clinical efficacy, tolerable adverse effects, and a high safety profile for patients.

In Silico Studies, Biological Activities, and Anti-human Pancreatic Cancer Potential of 6-Hydroxy-4-methylcoumarin and 2,5-Dihydroxyacetophenone as Flavonoid Compounds.

Coronavirus is one of the RNA viruses with the largest genome; It is a group of viruses known to infect humans very little until the end of the 20th century, generally causing infection in animals (bird, cat, pig, mouse, horse, bat). It is the causative agent of 15-30% of seasonal lower and upper respiratory tract infections, and may rarely cause gastrointestinal and nervous system infections. We have obtained results for the collagenase and elastase enzymes were at the micromolar level. We obtained IC50 results for the collagenase enzyme for 6-hydroxy-4-methylcoumarin 257.22 ± 34.07 µM and for 2,5-dihydroxyacetophenone 74.46 ± 8.61 µM. 6-Hydroxy-4-methylcoumarin and 2,5-dihydroxyacetophenone were considered good inhibitors for elastase enzyme. Additionally, these compounds significantly decreased human pancreatic cancer cell viability from low doses. In addition, 100 µM dose of all compounds caused significant reductions in human pancreatic cancer cell viability. IC50 results (IC50: 10-50 µM) were better than control. In the otherwords, the docking results suggest that both compounds tend to have lower efficacy on the main protease targets of SARS-CoV-2 than standard compounds, (NL-1 and NL-2). The reason for this is that the standard compounds interact strongly and more frequently with the target proteins, and the surface areas they cover on the active surface are much larger than the small ligand molecules studied.

Reversibility of valve regurgitation due to cancer-related non-bacterial thrombotic endocarditis after switching direct oral anticoagulation for heparin.

Non-bacterial thrombotic endocarditis (NBTE) is a rare condition related to a state of hypercoagulability in advanced neoplastic disease. Most of the time, arterial thromboembolic event precedes the diagnosis of NBTE. We report here a case of NBTE responsible for multiple ischaemic strokes, which leads to the diagnosis of metastatic pancreatic adenocarcinoma. Aortic and mitral valvular regurgitations secondary to NBTE appeared within 6 weeks despite therapeutic anticoagulation with direct oral anticoagulant (DOAC) in stroke prevention of paroxysmal atrial fibrillation. Bivalvular regurgitations resolved 8 weeks after therapeutic switch to low-molecular-weight heparin (LMWH) and chemotherapy. DOACs are a possible alternative to LMWH for the prevention of venous thromboembolism in patients with active neoplasia. There is a lack of evidence for a clinical efficiency for the prevention of arterial thromboembolism in NBTE. We propose here a short review of the efficacy of anticoagulant therapy for the prevention of arterial thromboembolism in NBTE.

Impact of the COVID-19 Pandemic on Management of Patients with Metastatic Pancreatic Ductal Adenocarcinoma in the United States.

BACKGROUND: The purpose of this study was to understand how the COVID-19 pandemic has affected health care patterns and outcomes for patients diagnosed with metastatic pancreatic ductal adenocarcinoma (mPDAC) in 2020 compared with those diagnosed with mPDAC in 2019. PATIENTS AND METHODS: We used the Flatiron Health database to identify adults diagnosed with mPDAC from March 1 to September 30, 2019 (pre-COVID-19 cohort) and March 1 to September 30, 2020 (post-COVID-19 cohort). Between-cohort comparisons included demographic and clinical characteristics and year-over-year data for diagnosis of mPDAC, newly treated patients, time to and types of first-line therapy, and adverse events (AEs) during first-line therapy. Overall survival (OS) and milestone survival rates were evaluated. Kaplan-Meier methods were used to assess OS. RESULTS: Pre-COVID-19 (n = 923) and post-COVID-19 (n = 796) cohorts had similar baseline demographic characteristics. A smaller proportion of patients in the pre-COVID-19 cohort were initially diagnosed with stage IV disease versus the post-COVID-19 cohort (62.2% vs 69.7%). Between 2019 and 2020, there was a 13.8% decrease in diagnosis of mPDAC and a 13.0% decrease in newly treated patients. Median (interquartile range) times to first-line treatment were similar (21 [13-40] and 19 [12-32] days). Median OS (months) was significantly longer in the pre-COVID-19 cohort (8·4 [95% CI: 7·5, 9·0]) versus the post-COVID-19 cohort (6·1 [95% CI: 5·4, 6·9]; P < .001). Survival rates were higher in the pre-COVID-19 versus post-COVID-19 cohorts. CONCLUSIONS: During the pandemic, patients were initially diagnosed with PDAC at more advanced stages. While patients in both cohorts appeared to receive similar care, survival outcomes were adversely affected.

Eicosanoid regulation of debris-stimulated metastasis.

Cancer therapy reduces tumor burden via tumor cell death ("debris"), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth.

Mechanistic Actions between Garcinia atroviridis Essential Oil and 2 Deoxy-d-glucose in Cultured PANC-1 Human Pancreatic Cancer Cells.

Pancreatic cancer is an aggressive disease that progresses in a relatively symptom-free manner; thus, is difficult to detect and treat. Essential oil is reported to exhibit pharmacological properties, besides its common and well-known function as aromatherapy. Therefore, this study herein aimed to investigate the anti-proliferative effect of essential oil extracted from leaves of Garcinia atroviridis (EO-L) against PANC-1 human pancreatic cancer cell line. The cell growth inhibitory concentration at 50% (IC50) and selective index (SI) values of EO-L analyses were determined as 78 µg/mL and 1.23, respectively. Combination index (CI) analysis revealed moderate synergism (CI values of 0.36 to 0.75) between EO-L and 2 deoxy-d-glucose (2-DG) treatments. The treatments of PANC-1 cells with EO-L, 2-DG and EOL+2DG showed evidence of depolarization of mitochondrial membrane potential, cell growth arrest and apoptosis. The molecular mechanism causing the anti-proliferative effect between EO-L and 2-DG is potentially through pronounced up-regulation of P53 (4.40-fold), HIF1α (1.92-fold), HK2 (2.88-fold) and down-regulation of CYP3A5 (0.11-fold), as supported by quantitative mRNA expression analysis. Collectively, the current data suggest that the combination of two anti-proliferative agents, EO-L and 2-DG, can potentially be explored as therapeutic treatments and as potentiating agents to conventional therapy against human pancreatic cancer.

Glycemic Profile of Intravenous Dexamethasone-Induced Hyperglycemia Using Continuous Glucose Monitoring.

BACKGROUND Intravenous (IV) dexamethasone is widely used in critical illness, chemotherapy, or severe COVID-19. Although glucocorticoid-induced hyperglycemia (GCIH) is well-known, there is no report describing the glycemic profile following a single dose of IV dexamethasone as captured on continuous glucose monitoring (CGM) in a patient with diabetes treated with insulin. CASE REPORT A 70-year-old woman with diabetes and pancreatic adenocarcinoma was treated with chemotherapy containing dexamethasone every other week. CGM data of 23 cycles revealed a reproducible triphasic glycemic pattern consisting of a constant hyperglycemia period, followed by a transient improvement, and ending with another hyperglycemic plateau. Given this recurrent pattern, basal insulin and correction insulin were adjusted with subsequent GCIH attenuation. CONCLUSIONS This is the first report of CGM glycemic profile following recurring doses of IV dexamethasone in a patient with diabetes treated with basal-bolus insulin. The understanding of triphasic glycemic pattern allows optimal glycemic management.

New Roles for Vitamin D Superagonists: From COVID to Cancer.

Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin D with particular reference to COVID-19 and pancreatic cancer. Utility as a therapeutic agent is limited by hypercalcemic effects and attempts to circumvent this problem have used vitamin D superagonists, with increased efficacy and reduced calcemic effect. A further caveat is that vitamin D mediates multiple diverse effects. Some of these (anti-fibrosis) are likely beneficial in patients with COVID-19 and pancreatic cancer, whereas others (reduced immunity), may be beneficial through attenuation of the cytokine storm in patients with advanced COVID-19, but detrimental in pancreatic cancer. Vitamin D superagonists represent an untapped resource for development of effective therapeutic agents. However, to be successful this approach will require agonists with high cell-tissue specificity.

Successful and Safe Reinstitution of Chemotherapy for Pancreatic Cancer after COVID-19.

Cancer patients are regarded as highly vulnerable to severe acute respiratory syndrome coronavirus (SARS-CoV)-2. However, little is known regarding how cancer treatments should be restarted for cancer patients after coronavirus disease (COVID)-19. We herein report a pancreatic cancer case in which chemotherapy was able to be reinstituted after COVID-19. The patient was a 67-year-old man diagnosed with pancreatic cancer. On day 7 after first chemotherapy, he was infected with COVID-19. A SARS-CoV-2 test was negative after one month of treatment, and we reinstituted chemotherapy. The patient has received three cycles of chemotherapy without recurrence of COVID-19. It may be feasible to reinstitute chemotherapy for cancer patients after a negative SARS-CoV-2 test.

Efficacy of chemotherapy combined with toripalimab in PD-L1-positive and high tumor mutation burden pancreatic acinar cell carcinoma: case report.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare tumor, accounting for about 1% of all pancreatic exocrine cancers. Consensus on the management of metastatic PACC remains unclear. CASE PRESENTATION: Starting from April 2019, a patient first received chemotherapy with two cycles of gemcitabine and nab-paclitaxel and two cycles of SOX regimen. After progression of disease evaluated based on RECIST 1.1, toripalimab and SOX regimen was administered because of PD-L1-positive expression, high tumor mutation burden (TMB), and somatic FANCA deletion in the tumor. Both the primary and metastatic tumor mass shrank significantly after two courses. The patient exhibited sustained partial response for at least six courses with well-controlled toxic effects. Then the treatment had to be stopped for 2 months because of the coronavirus disease 2019 pandemic. Computed tomography scan in March 2020 showed disease progression. Time from initiating treatment to tumor progression on toripalimab and SOX regimen treatment took up to at least 8 months. CONCLUSIONS: We present the first case report where a PD-L1 positive, high TMB, and FANCA-deleted pancreatic acinar cell carcinoma was treated using chemotherapy combined with immunotherapy, in which the patient exhibited satisfactory response and tolerance.

Considerations for the treatment of pancreatic cancer during the COVID-19 pandemic: the UK consensus position.

The coronavirus disease 2019 (COVID-19) pandemic epicentre has moved to the USA and Europe, where it is placing unprecedented demands on healthcare resources and staff availability. These service constraints, coupled with concerns relating to an increased incidence and severity of COVID-19 among patients with cancer, should lead to re-consideration of the risk-benefit balance for standard treatment pathways. This is of particular importance to pancreatic cancer, given that standard diagnostic modalities such as endoscopy may be restricted, and that disease biology precludes significant delays in treatment. In light of this, we sought consensus from UK clinicians with an interest in pancreatic cancer for management approaches that would minimise patient risk and accommodate for healthcare service restrictions. The outcomes are described here and include recommendations for treatment prioritisation, strategies to bridge to later surgical resection in resectable disease and factors that modify the risk-benefit balance for treatment in the resectable through to the metastatic settings. Priority is given to strategies that limit hospital visits, including through the use of hypofractionated precision radiotherapy and chemoradiotherapy treatment approaches.