One-year trajectories of physical and mental health-related quality of life, fatigue and dyspnoea in COVID-19 survivors.

PURPOSE: A substantial number of people experience a persisting impact on health-related quality of life (HRQoL) after COVID-19. The current study aims to identify different trajectories of physical and mental HRQoL, fatigue severity, and dyspnoea severity following hospitalisation with COVID-19, and associated factors of these trajectories. METHODS: 500 patients with COVID-19 were followed for one year in a longitudinal cohort study. Self-reported outcomes were measured at 3, 6, 9, and 12 months after hospitalisation. Distinct trajectories were characterised using Growth Mixture Modelling. Sociodemographic and clinical correlates of trajectories were investigated using multivariable (multinomial) logistic regression analyses. RESULTS: Three trajectories ('stable high' (16%), 'improving' (40%), and 'stable low' (44%)) were found for physical HRQoL, and four ('stable high' (43%), 'improving' (14%), 'middle declining' (17%), and 'low' (26%)) for mental HRQoL. Older age, overweight and obesity, lower education, and comorbidities were associated with 'low' physical HRQoL. Younger age was associated with 'low' mental HRQoL. Four fatigue trajectories ('no fatigue' (15%), 'improving' (40%), 'low-severe' (27%), and 'high-severe' (18%)) were found. Participants either experienced almost never ('no dyspnoea', 75%) or almost always ('severe', 25%) dyspnoea. High co-occurrences between low HRQoL and severe fatigue and dyspnoea symptom trajectories were found. CONCLUSION: A substantial number of COVID-19 survivors continue to struggle with reduced HRQoL over time. However, large variations in these physical and mental HRQoL trajectories exist, and trajectories are associated with persisting COVID-19-related symptoms or pre-hospitalised health status. Regular measurement of HRQoL and post-COVID symptoms may help identify those that may benefit from timely interventions.

Dual Stromal Targeting Sensitizes Pancreatic Adenocarcinoma for Anti-Programmed Cell Death Protein 1 Therapy.

BACKGROUND & AIMS: The stroma in pancreatic ductal adenocarcinoma (PDAC) contributes to its immunosuppressive nature and therapeutic resistance. Herein we sought to modify signaling and enhance immunotherapy efficacy by targeting multiple stromal components through both intracellular and extracellular mechanisms. METHODS: A murine liver metastasis syngeneic model of PDAC was treated with focal adhesion kinase inhibitor (FAKi), anti-programmed cell death protein 1 (PD-1) antibody, and stromal hyaluronan (HA) degradation by PEGylated recombinant human hyaluronidase (PEGPH20) to assess immune and stromal modulating effects of these agents and their combinations. RESULTS: The results showed that HA degradation by PEGPH20 and reduction in phosphorylated FAK expression by FAKi leads to improved survival in PDAC-bearing mice treated with anti-PD-1 antibody. HA degradation in combination with FAKi and anti-PD-1 antibody increases T-cell infiltration and alters T-cell phenotype toward effector memory T cells. FAKi alters the expression of T-cell modulating cytokines and leads to changes in T-cell metabolism and increases in effector T-cell signatures. HA degradation in combination with anti-PD-1 antibody and FAKi treatments reduces granulocytes, including granulocytic- myeloid-derived suppressor cells and decreases C-X-C chemokine receptor type 4 (CXCR4)-expressing myeloid cells, particularly the CXCR4-expressing granulocytes. Anti-CXCR4 antibody combined with FAKi and anti-PD-1 antibody significantly decreases metastatic rates in the PDAC liver metastasis model. CONCLUSIONS: This represents the first preclinical study to identify synergistic effects of targeting both intracellular and extracellular components within the PDAC stroma and supports testing anti-CXCR4 antibody in combination with FAKi as a PDAC treatment strategy.

Early Application of Next-Generation Sequencing Identifies Pancreatic Mass as Metastasis From an EGFR-Mutated Lung Adenocarcinoma.

Pancreatic metastasis of primary lung adenocarcinoma is a rare occurrence, accounting for <0.3% of all pancreatic malignancies. Given that the prognosis and treatment options for primary pancreatic cancer differ greatly from pancreatic metastases from a primary site, an accurate diagnosis is critical. This report presents a unique case of a 65-year-old man who was admitted with significant unintentional weight loss, fatigue, abdominal pain, and jaundice, and found to have a pancreatic mass initially thought to be primary pancreatic adenocarcinoma and subsequently diagnosed as an EGFR-mutated lung adenocarcinoma with metastases to the pancreas via early application of next-generation sequencing (NGS). The use of NGS early in the patient's clinical course not only changed the treatment strategy but also drastically altered the prognosis. Although metastatic pancreatic adenocarcinoma has a poor prognosis and survival rate, treatment of EGFR-mutated non-small cell lung cancer with EGFR tyrosine kinase inhibitors is associated with high response rates. Importantly, our case demonstrates that timely application of NGS very early in the disease course is paramount to the diagnosis, management, and prognosis of solid malignancies.

The effect of corticosteroids, antibiotics, and anticoagulants on the development of post-COVID-19 syndrome in COVID-19 hospitalized patients 6 months after discharge: a retrospective follow up study.

To assess the effect of pharmacotherapeutic interventions commonly employed in the management of COVID-19 hospitalized patients on the development of post-COVID-19 syndrome. This study employed two distinct databases, the Medisch Spectrum Twente (MST) clinical database comprising electronic health records of COVID-19 patients hospitalized at MST, and the Post-COVID cohort database which contains follow-up information on the same patients. These databases were integrated to establish the potential relationship between the administration of corticosteroids, antibiotics, or anticoagulants during hospitalization and the occurrence of post-COVID-19 syndrome after a 6-month interval following discharge. A total of 123 patients who were hospitalized due to COVID-19 infection were included in this study. Among these patients, 33 (26.8%) developed post-COVID-19 syndrome which persisted even 6 months after hospital discharge. Multivariate analysis revealed that patients who received treatment with corticosteroids had a significantly lower likelihood (OR 0.32, 95% CI 0.11-0.90) of developing post-COVID-19 syndrome, while no significant association was observed for treatment with antibiotics (OR 1.26, 95% CI 0.47-3.39) or anticoagulants (OR 0.55, 95% CI 0.18-1.71). The findings of this study indicate that corticosteroids exert a significant protective effect against the development of post-COVID-19 syndrome in patients who were hospitalized due to COVID-19 infection. Although a trend towards a protective effect of anticoagulants was observed, it did not reach statistical significance. On the contrary, patients treated with antibiotics were shown to have increased chances of developing post-COVID-19 syndrome, although this effect was also not statistically significant.

Combination L-Glutamine with Gemcitabine and Nab-Paclitaxel in Treatment-Naïve Advanced Pancreatic Cancer: The Phase I GlutaPanc Study Protocol.

Advanced pancreatic cancer is underscored by progressive therapeutic resistance and a dismal 5-year survival rate of 3%. Preclinical data demonstrated glutamine supplementation, not deprivation, elicited antitumor effects against pancreatic ductal adenocarcinoma (PDAC) alone and in combination with gemcitabine in a dose-dependent manner. The GlutaPanc phase I trial is a single-arm, open-label clinical trial investigating the safety of combination L-glutamine, gemcitabine, and nab-paclitaxel in subjects (n = 16) with untreated, locally advanced unresectable or metastatic pancreatic cancer. Following a 7-day lead-in phase with L-glutamine, the dose-finding phase via Bayesian design begins with treatment cycles lasting 28 days until disease progression, intolerance, or withdrawal. The primary objective is to establish the recommended phase II dose (RP2D) of combination L-glutamine, gemcitabine, and nab-paclitaxel. Secondary objectives include safety of the combination across all dose levels and preliminary evidence of antitumor activity. Exploratory objectives include evaluating changes in plasma metabolites across multiple time points and changes in the stool microbiome pre and post L-glutamine supplementation. If this phase I clinical trial demonstrates the feasibility of L-glutamine in combination with nab-paclitaxel and gemcitabine, we would advance the development of this combination as a first-line systemic option in subjects with metastatic pancreatic cancer, a high-risk subgroup desperately in need of additional therapies.