Prognosticators of survival in patients with metastatic pancreatic cancer and ascites.

BACKGROUND: Identification of factors associated with survival after ascites diagnosis in metastatic pancreatic cancer (mPC) patients may guide treatment decisions and help to maintain quality of life in this highly symptomatic patient collective. PATIENTS AND METHODS: All patients treated for mPC at the Medical University of Vienna between 2010 and 2019 developing ascites throughout their course of disease were identified by retrospective chart review. General risk factors, metastatic sites, systemic inflammation and liver function parameters, as well as type of treatment after ascites diagnosis were investigated for associations with survival. RESULTS: One hundred and seventeen mPC patients with ascites were included in this study. Median time from mPC to ascites diagnosis was 8.9 months (range 0-99 months) and median overall survival (OS) after ascites diagnosis was 27.4 days (range 21.3-42.6 days). Identified prognostic factors at ascites diagnosis independently associated with an impaired OS were presence of liver metastases [hazard ratio (HR): 2.07, 95% confidence interval (CI) 1.13-3.79, P = 0.018), peritoneal carcinomatosis (HR: 1.74, 95% CI 1.11-2.71, P = 0.015), and portal vein obstruction (HR: 2.52, 95% CI 1.29-4.90, P = 0.007). Compared with best supportive care, continuation of systemic therapy after ascites diagnosis was independently associated with survival (HR: 0.35, 95% CI 0.20-0.61, P < 0.001) with a median OS of 62 days (95% CI 51-129 days, P < 0.001) versus 16 days (95% CI 11-24 days), respectively. CONCLUSIONS: Liver and peritoneal metastases as well as portal vein obstruction were found to be prognostic factors after ascites diagnosis in mPC patients. Continuation of systemic therapy after ascites diagnosis was associated with a longer OS, which needs to be evaluated in larger clinical trials including quality-of-life assessment.

Timely course of SARS-CoV-2 infections and vaccinations in patients with hemato-oncological diseases: analysis of a real-life cohort.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has particularly impacted patients with hemato-oncological malignancies, as they showed not only a higher propensity for severe courses but also weaker immune responses after vaccination. Still, data on the influence of pandemic waves and vaccinations on outcomes are rare. This study aimed to analyze the timely course of infections and vaccinations in a real-life cohort of patients with hemato-oncological diseases. METHODS: In this cohort study, 1817 patients with hemato-oncological diseases from 1 February 2020 to 15 December 2022 at the 'Franz Tappeiner' Hospital in Merano/Meran, Italy, were followed for SARS-CoV-2 infections and vaccinations. RESULTS: Of 1817 patients with hemato-oncological malignancies, 735 (40.5%) were infected at least once with SARS-CoV-2, and 1614 (88.8%) received one or more doses of the approved vaccinations. Patients receiving antineoplastic treatment had a lower SARS-CoV-2 infection rate [35.1% versus 41.0%; odds ratio (OR) 0.78, 95% confidence interval (CI) 0.64-0.95], but higher risk of hospitalization (13.4% versus 6.9%; OR 2.11, 95% CI 1.25-3.69) compared with untreated patients. Overall, the case fatality rate (CFR) was 3.4%. Unvaccinated patients were more prone to severe coronavirus disease 2019 (COVID-19) courses requiring hospitalization (OR 2.34, 95% CI 1.25-4.36) and had a higher CFR (7.3% versus 1.6%; OR 4.98, 95% CI 2.16-12.98) than their vaccinated counterparts. In the Delta wave, patients with two vaccinations had a lower infection risk (OR 0.18, 95% CI 0.10-0.35) and tendentially lower hospitalization rates (OR 0.25, 95% CI 0.05-1.29) than unvaccinated patients. In the Omicron wave, 345/1198 (28.8%) patients with three or more vaccinations had breakthrough infections, resulting in a similar risk for infection (OR 0.88, 95% CI 0.60-1.30) but numerically lower risk for hospitalization (24/345, 7.0%) than unvaccinated individuals (4/40, 10.0%). Scheduled visits were postponed in 128/335 (38.2%) patients due to COVID-19, and deferrals correlated with pandemic wave (P = 0.002) and vaccination status (P < 0.001). CONCLUSIONS: SARS-CoV-2 infections and outcomes differ between distinct phases of the pandemic. Vaccination with variant-specific vaccines should be prioritized as general protective measures are increasingly lifted.

Clinical risk factors for ascites in metastatic pancreatic cancer.

BACKGROUND: Malignant ascites is common in metastatic pancreatic cancer (mPC) and its management still remains a clinical challenge. Early identification of patients at risk for ascites development may support and guide treatment decisions. MATERIALS AND METHODS: Data of patients treated for mPC at the Medical University of Vienna between 2010 and 2019 were collected by retrospective chart review. Ascites was defined as clinically relevant accumulation of intraperitoneal fluid diagnosed by ultrasound or computer tomography scan of the abdomen. We investigated the association between general risk factors, metastatic sites, liver function, systemic inflammation as well as portal vein obstruction (PVO) and ascites development. RESULTS: Among 581 patients with mPC included in this study, 122 (21.0%) developed ascites after a median of 8.7 months after diagnosis of metastatic disease. The occurrence of ascites led to an 8.9-fold increased risk of death [confidence interval (CI) 7.2-11, P < 0.001] with a median overall survival of 1 month thereafter. Clinical risk factors for ascites were male sex [hazard ratio (HR) 1.71, CI 1.00-2.90, P = 0.048], peritoneal carcinomatosis (HR 6.79, CI 4.09-11.3, P < 0.001), liver metastases (HR 2.16, CI 1.19-3.91, P = 0.011), an albumin-bilirubin (ALBI) score grade 3 (HR 6.79, CI 2.11-21.8, P = 0.001), PVO (HR 2.28, CI 1.15-4.52, P = 0.019), and an elevated C-reactive protein (CRP) (HR 4.19, CI 1.58-11.1, P = 0.004). CONCLUSIONS: Survival after diagnosis of ascites is very limited in mPC patients. Male sex, liver and peritoneal metastases, impaired liver function, PVO, as well as systemic inflammation were identified as independent risk factors for ascites development in this uniquely large real-life patient cohort.

New Magnetic Resonance Imaging Index for Renal Fibrosis Assessment: A Comparison between Diffusion-Weighted Imaging and T1 Mapping with Histological Validation.

A need exists to noninvasively assess renal interstitial fibrosis, a common process to all kidney diseases and predictive of renal prognosis. In this translational study, Magnetic Resonance Imaging (MRI) T1 mapping and a new segmented Diffusion-Weighted Imaging (DWI) technique, for Apparent Diffusion Coefficient (ADC), were first compared to renal fibrosis in two well-controlled animal models to assess detection limits. Validation against biopsy was then performed in 33 kidney allograft recipients (KARs). Predictive MRI indices, ΔT1 and ΔADC (defined as the cortico-medullary differences), were compared to histology. In rats, both T1 and ADC correlated well with fibrosis and inflammation showing a difference between normal and diseased kidneys. In KARs, MRI indices were not sensitive to interstitial inflammation. By contrast, ΔADC outperformed ΔT1 with a stronger negative correlation to fibrosis (R(2) = 0.64 against R(2) = 0.29 p < 0.001). ΔADC tends to negative values in KARs harboring cortical fibrosis of more than 40%. Using a discriminant analysis method, the ΔADC, as a marker to detect such level of fibrosis or higher, led to a specificity and sensitivity of 100% and 71%, respectively. This new index has potential for noninvasive assessment of fibrosis in the clinical setting.

Cytokines and Pancreatic ß-Cell Apoptosis.

The discovery 30 years ago that inflammatory cytokines cause a concentration, activity, and time-dependent bimodal response in pancreatic ß-cell function and viability has been a game-changer in the fields of research directed at understanding inflammatory regulation of ß-cell function and survival and the causes of ß-cell failure and destruction in diabetes. Having until then been confined to the use of pathophysiologically irrelevant ß-cell toxic chemicals as a model of ß-cell death, researchers could now mimic endocrine and paracrine effects of the cytokine response in vitro by titrating concentrations in the low to the high picomolar-femtomolar range and vary exposure time for up to 14-16h to reproduce the acute regulatory effects of systemic inflammation on ß-cell secretory responses, with a shift to inhibition at high picomolar concentrations or more than 16h of exposure to illustrate adverse effects of local, chronic islet inflammation. Since then, numerous studies have clarified how these bimodal responses depend on discrete signaling pathways. Most interest has been devoted to the proapoptotic response dependent upon mainly nuclear factor κ B and mitogen-activated protein kinase activation, leading to gene expressional changes, endoplasmic reticulum stress, and triggering of mitochondrial dysfunction. Preclinical studies have shown preventive effects of cytokine antagonism in animal models of diabetes, and clinical trials demonstrating proof of concept are emerging. The full clinical potential of anticytokine therapies has yet to be shown by testing the incremental effects of appropriate dosing, timing, and combinations of treatments. Due to the considerable translational importance of enhancing the precision, specificity, and safety of antiinflammatory treatments of diabetes, we review here the cellular, preclinical, and clinical evidence of which of the death pathways recently proposed in the Nomenclature Committee on Cell Death 2012 Recommendations are activated by inflammatory cytokines in the pancreatic ß-cell to guide the identification of antidiabetic targets. Although there are still scarce human data, the cellular and preclinical studies point to the caspase-dependent intrinsic apoptosis pathway as the prime effector of inflammatory ß-cell apoptosis.