UCHL1-dependent control of Hypoxia-Inducible Factor Transcriptional Activity during Liver Fibrosis.

Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in most  chronic liver diseases.  At the cellular level, liver fibrosis is associated with the activation of hepatic stellate cells (HSCs) which transdifferentiate into a myofibroblast-like phenotype that is contractile, proliferative and profibrogenic.  HSC transdifferentiation induces genome-wide changes in gene expression that enable the cell to adopt its profibrogenic functions. We have previously identified that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is highly induced following HSC activation, however, the cellular targets of its deubiquitinating activity are poorly defined.     Here we describe a role for UCHL1 in regulating the levels and activity of hypoxia-inducible factor 1 (HIF1), an oxygen-sensitive transcription factor, during HSC activation and liver fibrosis.  HIF1 is elevated during HSC activation and promotes the expression of profibrotic mediator HIF target genes. Increased HIF1α expression correlated with induction of UCHL1 mRNA and protein with HSC activation. Genetic deletion or chemical inhibition of UCHL1 impaired HIF activity through reduction of HIF1α levels. Furthermore, our mechanistic studies have shown that UCHL1 elevates HIF activity through specific cleavage of degradative ubiquitin chains, elevates levels of pro-fibrotic gene expression and increases proliferation rates. As we also show that UCHL1 inhibition blunts fibrogenesis in a pre-clinical 3D human liver slice model of fibrosis, these results demonstrate how small molecule inhibitors of DUBs can exert therapeutic effects through modulation of HIF transcription factors in liver disease.  Furthermore, inhibition of HIF activity using UCHL1 inhibitors may represent a therapeutic opportunity with other HIF-related pathologies.

The Association Between Metformin Use and New-Onset ICD Coding of Geographic Atrophy.

Purpose: Metformin has been suggested to protect against the development of age-related macular degeneration (AMD) in multiple observational studies. However, the association between metformin and geographic atrophy (GA), a debilitating subtype of AMD, has not been analyzed. Methods: We conducted a case-control study of patients ages 60 years and older with new-onset International Classification of Diseases (ICD) coding of GA in the Merative MarketScan Commercial and Medicare Databases between 2017 and 2021. Cases were matched with propensity scores estimated by age, region, hypertension, and Charlson Comorbidity Index to a control without GA of the same year. Exposure to metformin was assessed for cases and controls in the year prior to their index visit. Conditional multivariable logistic regression, adjusting for AMD risk factors, was used to calculate odd ratios and 95% confidence intervals (CIs). This study design and analysis were repeated in a sample of patients without diabetes. Results: In the full sample, we identified 10,505 cases with GA and 10,502 matched controls without GA. In total, 1149 (10.9%) cases and 1277 (12.2%) controls were exposed to metformin, and in multivariable regression, metformin decreased the odds of new-onset ICD coding of GA by 12% (95% CI, 0.79-0.99). In the sample of patients without diabetes, we identified 7611 cases with GA and 7608 matched controls without GA. Twenty-nine (0.4%) cases and 63 (0.8%) controls were exposed to metformin, and in multivariable regression, metformin decreased the odds of new-onset ICD coding of GA by 47% (95% CI, 0.33-0.83). Conclusions: Metformin may hold promise as a noninvasive, alternative agent to prevent the development of GA. This finding is notable due to shortcomings in recently approved therapeutics for GA and metformin's overall ease of use and few adverse effects. Additional studies are required to explore our findings further and motivate a clinical trial.

Racial Differences in Choroidal Vascularity Index in Healthy Patients: Novel Insights.

BACKGROUND AND OBJECTIVE: Choroidal vascularity index (CVI) measures the ratio of blood vessels in the choroid to the total choroidal area. We aimed to compare CVI between young Black and White patients without a history of ocular or systemic disease. PATIENTS AND METHODS: We used a previously validated algorithm for shadow compensation and choroidal vessel binarization to measure CVI across the Early Treatment of Diabetic Retinopathy Study grid. RESULTS: Black patients had a lower CVI (ß = -0.05, P < 0.001) compared to White patients. Choroidal volume or luminal volume did not significantly differ with respect to race, whereas there was a trend for Black patients to have a greater stromal volume (ß = 3.08, P = 0.01). CONCLUSIONS: Black patients have a lower CVI than do White patients, likely due to a greater proportion of stromal volume. Further study of this parameter is warranted to validate the findings of this exploratory study. [Ophthalmic Surg Lasers Imaging Retina 2024;55:30-38.].

Metformin Use and Age-Related Macular Degeneration in Patients Without Diabetes.

Importance: Metformin use may protect against the development of age-related macular degeneration (AMD) based on results from observational studies. However, its potential effectiveness among patients without diabetes remains unclear. Objective: To assess the association between metformin use and the development of AMD in patients without diabetes. Design, Setting, and Participants: This case-control study used data from 2006 to 2017 in the Merative MarketScan Research Database, a nationwide insurance claims database that includes between 27 and 57 million patients in the US with primary or Medicare supplemental health insurance. Cases with AMD and controls without AMD aged 55 years or older were matched 1:1 by year, age, anemia, hypertension, region, and Charlson Comorbidity Index score. Then, cases and matched controls without a diagnosis of diabetes were selected. In subgroup analyses, cases with dry AMD and their matched controls were identified to explore the association between metformin use and AMD staging in patients without diabetes. Data were analyzed between March and September 2023. Exposures: Exposure to metformin in the 2 years prior to the index date (ie, date of AMD diagnosis in cases and date of a randomly selected eye examination for controls) was assessed from the claims database and categorized into quartiles based on cumulative dose (1-270, 271-600, 601-1080, and >1080 g/2 y). Exposure to other antidiabetic medications was also noted. Main Outcomes and Measures: Odds of new-onset AMD development as assessed by multivariable conditional logistic regression after adjusting for known risk factors for AMD, including female sex, hyperlipidemia, smoking, and exposures to other antidiabetic medications. Asymptotic Cochran-Armitage tests for trend were also performed. Results: We identified 231 142 patients with any AMD (mean [SD] age, 75.1 [10.4] years; 140 172 females [60.6%]) and 232 879 matched controls without AMD (mean [SD] age, 74.9 [10.5] years; 133 670 females [57.4%]), none of whom had a diagnosis of diabetes. The sample included 144 147 cases with dry AMD that were matched to 144 530 controls. In all, 2268 (1.0%) cases and 3087 controls (1.3%) were exposed to metformin in the 2 years before their index visit. After data adjustment, exposure to any metformin was associated with reduced odds of any AMD development (adjusted odds ratio [AOR], 0.83; 95% CI, 0.74-0.87), specifically in the dosing quartiles of 1 to 270, 271 to 600, and 601 to 1080 g/2 y. Any metformin use was also associated with a reduced odds of developing dry AMD (AOR, 0.85; 95% CI, 0.79-0.92), specifically in the dosing quartiles of 1 to 270 and 271 to 600 g/2 y. Adjusted odds ratios for any AMD and dry AMD development did not differ across the dosing quartiles. Asymptotic Cochran-Armitage tests for trend revealed 2-sided P = .51 and P = .66 for the any and dry AMD samples, respectively. Conclusions and Relevance: In this case-control study of a population without a diagnosis of diabetes, metformin use was associated with reduced odds of developing AMD. This association does not appear to be dose dependent. These findings provide further impetus to study metformin's usefulness in protecting against AMD in prospective clinical trials.

Calcium channel blockers are associated with improved survival in pancreatic cancer patients undergoing neoadjuvant chemotherapy and resection.

BACKGROUND: Repurposing existing drugs for use in oncology is more efficient, cost-effective and safe than novel drug discovery. Calcium signalling is increasingly recognised to have a key role in chemoresistance. This study assessed the impact of calcium channel blockers (CCB) in pancreatic cancer. METHODS: Retrospective population study of patients undergoing resection (curative intent) of pancreatic ductal adenocarcinoma (SEER-Medicare, 2007-2017). Cox models were built to assess the impact on overall survival. As laboratory studies suggest a chemosensitising effect, the impact of CCB was assessed separately in patients receiving neoadjuvant chemotherapy. RESULTS: 6,223 patients were included, of whom 660 were prescribed CCB. In total, 591 received neoadjuvant chemotherapy; in this cohort CCB prescription was associated with improved overall survival when adjusting for multiple prognostic factors (aHR = 0.715, 0.514-0.996, P = 0.047). This effect was not observed in patients not receiving neoadjuvant chemotherapy (aHR = 1.082, 0.982-1.191, P = 0.112). CONCLUSION: CCB prescription was associated with improved overall survival in patients receiving neoadjuvant chemotherapy prior to pancreatic cancer resection. The association was specific to the group of patients receiving neoadjuvant chemotherapy, mirroring the chemosensitising effect in laboratory studies. This defines patients receiving neoadjuvant chemotherapy as a target population for prospective clinical trials of CCB in pancreatic cancer.

Associations Between Autoimmune Disease and the Development of Age-Related Macular Degeneration.

Purpose: The pathogenesis of age-related macular degeneration (AMD) likely implicates the dysregulation of immune response pathways. Several studies demonstrate that the pathogenic elements of AMD resemble those of autoimmune diseases, yet the association between AMD development and most autoimmune diseases remain unexplored. Methods: We conducted a case-control analysis of patients ages 55 and older with new-onset International Classification of Diseases (ICD) coding of dry, wet, or unspecified AMD between 2005 and 2019 in the Merative MarketScan Commercial and Medicare Databases. The diagnosis of an autoimmune disease was defined by an outpatient or inpatient claim with a relevant ICD code in the 12 months before the index visit. Conditional multivariable logistic regression, adjusted for AMD risk factors, was used to calculate odd ratios and 95% confidence intervals. Results: We identified 415,027 cases with new-onset ICD coding for AMD matched with propensity scores to 414,853 controls. In total, 16.1% of cases and 15.9% of controls were diagnosed with any autoimmune disease. The diagnosis of any autoimmune disease did not affect the odds of new-onset ICD coding for AMD in multivariable regression (OR = 1.01; 95% CI, 0.999-1.02). Discoid lupus erythematosus (OR = 1.29; 95% CI, 1.12-1.48), systemic lupus erythematosus (SLE) (OR = 1.21; 95% CI, 1.15-1.27), giant cell arteritis (OR = 1.19; 95% CI, 1.09-1.30), Sjogren's syndrome (OR = 1.17; 95% CI, 1.09-1.26), and Crohn's disease (OR = 1.13; 95% CI, 1.06-1.22) increased the odds of a new-onset ICD coding for AMD. Conclusions: Most autoimmune diseases do not affect the odds of developing AMD but several common autoimmune disorders such as SLE and Crohn's disease were associated with modestly increased odds of AMD. Further studies are needed to validate and investigate the underlying mechanisms of these associations.

Is aggressive intravenous fluid prescription the answer to reduce mortality in severe pancreatitis? The FLIP study: Fluid resuscitation in pancreatitis.

Backgrounds/Aims: Acute pancreatitis is an emergency presentation, which can range from mild to life threatening. Intravenous fluids are the cornerstone of management. Although the WATERFALL trial described the optimal fluid rate in mild/moderate pancreatitis, this trial excluded patients with moderate-severe/severe pancreatitis. The aim of this study was to establish clinical practice regarding intravenous fluid administration in acute pancreatitis and assess its effect on mortality. Methods: Prospective multi-centre audit of patients with acute pancreatitis was conducted. Data were collected regarding intravenous fluid administration within 72 hours of admission. The primary outcome was 30-day mortality. Multivariable logistic regression was used to identify predictors of 30-day mortality. Results: Those with severe pancreatitis received more fluid; median 5.7 L versus 4 L in 72 hours (p = 0.003). Participants with severe pancreatitis who died within 30 days received a median of 2,750 mL in the first 24 hours, compared to 4,000 mL in those who survived. The following factors were significant predictors of 30-day mortality: age, Glasgow score, C-reactive protein, ischaemic heart disease, and pancreatitis aetiology. Overall, volume of intravenous fluid was not associated with mortality. However, the effect of intravenous fluid volume on mortality differed significantly depending on pancreatitis severity. In severe pancreatitis, increased volume of intravenous fluid was associated with significant reductions in mortality (odds ratio = 0.655; 0.459-0.936; p = 0.020). Conclusions: In severe pancreatitis, more aggressive fluid prescription was associated with decreased mortality; however, this was not the case in milder disease. Further prospective trials guiding fluid resuscitation in severe pancreatitis are needed, as the impact of fluid on this population appears to differ from that in those with milder disease.

The Association of Antibiotic Use and the Odds of a New-Onset ICD Code Diagnosis of Age-Related Macular Degeneration: A Large National Case-Control Study.

Purpose: The widespread use of antibiotics has many well-documented impacts on the human microbiome, which may be associated with the development of various inflammatory diseases. Despite age-related macular degeneration (AMD) featuring an inflammatory pathogenesis, the relationship between antibiotics and AMD has remained unexplored. We conducted the first study to determine the association between antibiotic exposure and a new-onset International Classification of Diseases (ICD) diagnosis of AMD. Methods: We performed a case-control analysis of patients aged 55 and older with new-onset AMD between 2008 and 2017 from a nationwide commercial health insurance claims database. Exposure to antibiotics in the two years before the index date was determined for cases and controls matched one-to-one by age, year, region, anemia, hypertension, and a comorbidity index. Conditional multivariable logistic regression, adjusted for AMD risk factors, was performed to calculate odd ratios (OR) and 95% confidence intervals (CI). Results: Among the antibiotic classes, exposure to aminoglycosides (OR = 1.24; 95% CI, 1.22-1.26) and fluoroquinolones (OR = 1.13; 95% CI, 1.12-1.14) was associated with the greatest odds of a new-onset ICD code diagnosis of AMD. Broad-spectrum antibiotics were associated with nearly three times greater odds of a new-onset ICD code diagnosis of AMD (OR = 1.15; 95% CI, 1.13-1.16) compared to narrow-spectrum antibiotics (OR = 1.05; 95% CI, 1.03-1.07). We also identified a frequency- and duration-dependent association, with a greater cumulative number of antibiotic prescriptions or day supply of antibiotics conferring increased odds of a new-onset ICD code diagnosis of AMD. Conclusions: Greater cumulative exposure to antibiotics, particularly fluoroquinolones, aminoglycosides, and those with broader-spectrum coverage, may be associated with the development of AMD, a finding that requires further investigation using prospective studies.

Clinical characteristics and long-term outcomes following pancreatic injury - An international multicenter cohort study.

Background: Trauma to the pancreas is rare but associated with significant morbidity. Currently available management guidelines are based on low-quality evidence and data on long-term outcomes is lacking. This study aimed to evaluate clinical characteristics and patient-reported long-term outcomes for pancreatic injury. Methods: A retrospective cohort study evaluating treatment for pancreatic injury in 11 centers across 5 European nations over >10 years was performed. Data relating to pancreatic injury and treatment were collected from hospital records. Patients reported quality of life (QoL), changes to employment and new or ongoing therapy due to index injury. Results: In all, 165 patients were included. The majority were male (70.9%), median age was 27 years (range: 6-93) and mechanism of injury predominantly blunt (87.9%). A quarter of cases were treated conservatively; higher injury severity score (ISS) and American Association for the Surgery of Trauma (AAST) pancreatic injury scores increased the likelihood for surgical, endoscopic and/or radiologic intervention. Isolated, blunt pancreatic injury was associated with younger age and pancreatic duct involvement; this cohort appeared to benefit from non-operative management. In the long term (median follow-up 93; range 8-214 months), exocrine and endocrine pancreatic insufficiency were reported by 9.3% of respondents. Long-term analgesic use also affected 9.3% of respondents, with many reported quality of life problems (QoL) potentially attributable to side-effects of opiate therapy. Overall, impaired QoL correlated with higher ISS scores, surgical therapy and opioid analgesia on discharge. Conclusions: Pancreatic trauma is rare but can lead to substantial short- and long-term morbidity. Near complete recovery of QoL indicators and pancreatic function can occur despite significant injury, especially in isolated, blunt pancreatic injury managed conservatively and when early weaning off opiate analgesia is achieved.

Repurposing medications for treatment of age-related macular degeneration: Insights from novel approaches to data mining.

The economic and visual burdens associated with age-related macular degeneration (AMD) are expected to significantly increase in the coming years. As of now, interventions to delay or prevent AMD are limited. Hence, there is an urgent and unmet need to expand our therapeutic tools for AMD in a manner, that is, both efficient and cost-effective. In this review, we consider the idea of drug repurposing, in which existing medications with other indications can be re-imagined for treating AMD. We detail the results of several population-level studies that have shown associations between several candidates and decreased risk of AMD development or progression. Such candidates include the more extensively studied metformin and statins, in addition to recently identified candidates fluoxetine and l-DOPA (levodopa) that show promise. We then briefly explore results from an advanced bioinformatics study, which provides further evidence that existing medications are associated with AMD risk genes. Many of these candidates warrant further study in prospective, clinical trials, where their potential causal relationships with AMD can be thoroughly assessed.

Racial differences in quantitative optical coherence tomography angiography findings between older non-diabetics with co-morbidities.

This cross-sectional study compared optical coherence tomography angiography (OCTA) parameters between older Black and White adults with systemic comorbidities in an effort to further understand racial differences in the retinal microvasculature. We analyzed vessel density at the superficial (SCP), intermediate (ICP), and deep capillary plexuses (DCP), foveal avascular zone (FAZ) parameters, and blood flow area (BFA) at the choriocapillaris. We used a mixed-effects linear regression model, controlling for hypertension and two eyes from the same subject, to compare OCTA parameters. Black subjects had lower foveal vessel density at the SCP and ICP, while no differences were observed at the parafovea or 3x3 mm macular area of any capillary layer. Black subjects had greater FAZ area, perimeter, and FD-300, a measurement of vessel density in a 300 µm wide ring around the FAZ. Black subjects also had lower BFA at the choriocapillaris. Within a cohort of subjects without hypertension, these differences remained statistically significant, with the exception of foveal vessel density at the SCP and foveal BFA of the choriocapillaris. These findings suggest that normative databases of OCTA parameters must strive to be diverse in nature to adequately capture differences across patient populations. Further study is required to understand if baseline differences in OCTA parameters contribute to epidemiological disparities in ocular diseases.

Levodopa Is Associated with Reduced Development of Neovascular Age-Related Macular Degeneration.

OBJECTIVE: To determine whether levodopa (L-DOPA) is associated with a reduced likelihood of developing neovascular age-related macular degeneration (AMD). DESIGN: Three studies were performed: retrospective analyses in the Vestrum Health Retina Database (#1-2) and case-control analysis in the Merative MarketScan Research Databases (#3). PARTICIPANTS: Eyes with neovascular AMD and 2 years of follow-up (#1). Eyes with non-neovascular AMD and 1 to 5 years of follow-up (#2). Patients aged ≥ 55 years with newly diagnosed neovascular AMD matched to controls without neovascular AMD (#3). METHODS: Eyes were divided into 2 groups (#1-2): exposed to L-DOPA before or on the date of neovascular (#1) or nonneovascular (#2) AMD diagnosis, and eyes not exposed to L-DOPA. We extracted AMD risk factors, number of intravitreal injections (#1), and conversion rate to neovascular AMD (#2). We calculated the percentage of newly diagnosed neovascular AMD cases and matched controls exposed to any L-DOPA and determined the cumulative 2-year dose in grams by tertiles (< 100 mg, approximately 100-300 mg, and approximately > 300 mg per day, #3). MAIN OUTCOME MEASURES: Number of intravitreal injections (#1) and detection of new-onset neovascular AMD (#2-3) after adjusting for AMD risk factors. RESULTS: In the Vestrum database, eyes with neovascular AMD that were exposed to L-DOPA underwent 1 fewer intravitreal injection over 2 years (N = 84 088 control vs. 530 L-DOPA eyes, P = 0.006). In eyes with nonneovascular AMD (N = 42 081-203 155 control vs. 314-1525 L-DOPA eyes), L-DOPA exposure was associated with a reduced risk of conversion to neovascular AMD by 21% at year 2 (P = 0.029), 35% at years 3 to 4 (P < 0.001), and 28% at year 5 (P = 0.024). In the MarketScan databases (N = 86 900 per group), cumulative 2-year doses of L-DOPA between approximately 100 to 300 mg per day and approximately > 300 mg were associated with decreased odds of developing neovascular AMD by 15% (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.75-0.97) and 23% (OR, 0.77; 95% CI, 0.67-0.87), respectively. CONCLUSIONS: Levodopa use was associated with reduced detection of new-onset neovascular AMD. A prospective, randomized clinical trial should be considered to investigate whether low-dose L-DOPA reduces neovascular AMD conversion. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Clinical variations of polypoidal choroidal vasculopathy: A cohort study from Japan and the USA.

We describe the clinical characteristics of treatment-naïve polypoidal choroidal vasculopathy (PCV) in three tertiary clinic settings in 2 cities (Chicago in the USA and Nishinomiya in Japan). This cohort study was a retrospective, multicenter, consecutive case series. A total of 126 patients with treatment-naïve PCV-46 in Chicago and 80 in Nishinomiya-were identified. The proportion of PCV in patients with neovascular age-related macular degeneration was lower in Chicago (10.8% vs. 36.9%). Patients in Chicago had a significantly higher prevalence of soft drusen (50.0% vs 25.0%, p = 0.006) and intra-retinal cyst (37.0% vs 15.0%, p = 0.008), and a significantly lower prevalence of pachyvessels (41.3% vs 62.5%, p = 0.03). At baseline, presenting vision for patients in Chicago was worse than in Nishinomiya (mean log MAR: 0.609 vs. 0.312, p < 0.001). Ninety-five eyes were followed for more than one year. The Nishinomiya group received a higher rate of combination therapy (61.0%) compared to the Chicago group (5.3%). Vision and central foveal thickness at month 12 were significantly improved from baseline in both Chicago (p = 0.009 and p = 0.01) and Nishinomiya groups (both p < 0.001). Our study highlights interesting differences in the proportion of PCV, clinical findings and treatment responses of PCV, that need to be further evaluated in larger, epidemiologic cohorts.

Use of OCT Angiography to Diagnose and Manage Atypical Presentations of Macular Telangiectasia Type 2.

Macular telangiectasia Type 2 (MacTel) is a bilateral acquired retinal disease characterized by both vascular changes and atrophy of the retina. The purpose of this case series is to highlight the use of optical coherence tomography angiography (OCTA) as a non-invasive imaging modality to distinguish atypical MacTel from other macular conditions with similar presentations. We performed a retrospective review of patients referred to our academic retinal practice with unconfirmed or misdiagnosed MacTel between July 2017 and July 2021. Patients' OCTA imaging findings were reviewed to guide the appropriate diagnosis and management of atypical MacTel. Fifteen eyes from eight patients were included in this study. Six patients were referred with previous diagnoses of either full-thickness macular hole, lamellar hole, vitreomacular traction (VMT), postoperative cystoid macular edema (CME), or diabetic macular edema (DME). Two patients were referred to us to confirm the diagnosis of MacTel. OCTA revealed telangiectatic vessels in the temporal parafovea of all 15 eyes. OCTA also highlighted previously undiagnosed subretinal neovascularization (SRNV) in seven eyes. OCTA imaging is a valuable imaging modality to distinguish MacTel from other macular conditions, whose treatment courses vary substantially. Due to its ease of use, it holds immense potential in the future as treatments for non-proliferative MacTel emerge.

Computerized Texture Analysis of Optical Coherence Tomography Angiography of Choriocapillaris in Normal Eyes of Young and Healthy Subjects.

Computerized texture analysis uses higher-order mathematics to identify patterns beyond what the naked eye can recognize. We tested its feasibility in optical coherence tomography angiography imaging of choriocapillaris. Our objective was to determine sets of parameters that provide coherent and consistent output when applied to a homogeneous, healthy group of patients. This observational cross-sectional study involved 19 eyes of 10 young and healthy Caucasian subjects. En-face macular optical coherence tomography angiography of superficial choriocapillaris was obtained by the RTVue-XR Avanti system. Various algorithms were used to extract texture features. The mean and standard deviation were used to assess the distribution and dispersion of data points in each metric among eyes, which included: average gray level, gray level yielding 70% threshold and 30% threshold, balance, skewness, energy, entropy, contrast, edge mean gradient, root-mean-square variation, and first moment of power spectrum, which was compared between images, showing a highly concordant homology between all eyes of participants. We conclude that computerized texture analysis for en-face optical coherence tomography angiography images of choriocapillaris is feasible and provides values that are coherent and tightly distributed around the mean in a homogenous, healthy group of patients. Homology of blob size among subjects may represent a "repeat pattern" in signal density and thus a perfusion in the superficial choriocapillaris of healthy young individuals of the same ethnic background.

SARS-CoV-2 infection in acute pancreatitis increases disease severity and 30-day mortality: COVID PAN collaborative study.

OBJECTIVE: There is emerging evidence that the pancreas may be a target organ of SARS-CoV-2 infection. This aim of this study was to investigate the outcome of patients with acute pancreatitis (AP) and coexistent SARS-CoV-2 infection. DESIGN: A prospective international multicentre cohort study including consecutive patients admitted with AP during the current pandemic was undertaken. Primary outcome measure was severity of AP. Secondary outcome measures were aetiology of AP, intensive care unit (ICU) admission, length of hospital stay, local complications, acute respiratory distress syndrome (ARDS), persistent organ failure and 30-day mortality. Multilevel logistic regression was used to compare the two groups. RESULTS: 1777 patients with AP were included during the study period from 1 March to 23 July 2020. 149 patients (8.3%) had concomitant SARS-CoV-2 infection. Overall, SARS-CoV-2-positive patients were older male patients and more likely to develop severe AP and ARDS (p<0.001). Unadjusted analysis showed that SARS-CoV-2-positive patients with AP were more likely to require ICU admission (OR 5.21, p<0.001), local complications (OR 2.91, p<0.001), persistent organ failure (OR 7.32, p<0.001), prolonged hospital stay (OR 1.89, p<0.001) and a higher 30-day mortality (OR 6.56, p<0.001). Adjusted analysis showed length of stay (OR 1.32, p<0.001), persistent organ failure (OR 2.77, p<0.003) and 30-day mortality (OR 2.41, p<0.04) were significantly higher in SARS-CoV-2 co-infection. CONCLUSION: Patients with AP and coexistent SARS-CoV-2 infection are at increased risk of severe AP, worse clinical outcomes, prolonged length of hospital stay and high 30-day mortality.

Surgical Management of Non-Metastatic Pancreatic Cancer in the United Kingdom: Results of a Nationwide Survey on Current Practice.

BACKGROUND: It is presently unclear what clinical pathways are followed for patients with non-metastatic PDAC in specialised centres for pancreatic surgery across the United Kingdom (UK). METHODS: Between August 2019 and August 2020 an electronic survey was conducted aiming at a national cohort of pancreatic surgeons in the UK. Participants replied to a list of standardised questions and clinical vignettes, and data were collected and analysed focusing on management preferences, resectability criteria, and contraindications to surgery. RESULTS: Within the study period, 65 pancreatic surgeons from 27 specialist centres in the UK (96%) completed the survey. Multidisciplinary team meetings are utilised universally for the management of patients with PDAC, however, different staging systems for resectability classification are being applied. In borderline resectable PDAC, most surgeons were keen to proceed with surgical exploration post NAT, but differences were noted in preferred chemotherapy regimens. Surgeons from standard volume institutions performed fewer vein resections annually and were more likely to deem patients with locally advanced PDAC as unresectable. Intra-institutional variability in patient management was also present and ranging between 20-80%. CONCLUSIONS: Significant variability in the surgical management of non-metastatic PDAC was identified both on inter- and intra-institutional level.

Therapeutic Strategies Toward Lactate Dehydrogenase Within the Tumor Microenvironment of Pancreatic Cancer.

OBJECTIVES: Pancreatic stellate cells (PSCs) play a key metabolic role within the tumor microenvironment (stroma) of pancreatic ductal adenocarcinoma (PDAC), being glycolytic and associated with protumorigenic acidification from excess lactate. This study investigates the clinical significance of glycolytic enzyme lactate dehydrogenase (LDH) and determines efficacy of the novel pan-LDH inhibitor Galloflavin. METHODS: An in vitro Transwell system was adopted for coculture of PSCs and 3 PDAC cell lines (MIA PaCa-2, PANC-1, and BxPC-3). Cells were treated with Galloflavin, and outcomes were analyzed regarding proliferation, apoptosis, lactate production, and glycolytic enzyme protein expression. Immunohistochemical staining for lactate dehydrogenase B (LDHB) was performed on 59 resected PDAC tumors annotated for clinical outcome. RESULTS: Galloflavin reduced PDAC proliferation in monoculture (P < 0.01); however, in co-culture with PSCs, an antiproliferative effect was only evident in PANC-1 (P = 0.001). An apoptotic effect was observed in MIA PaCa-2 and BxPC-3 in coculture (P < 0.05). A reduction in media lactate was observed in coculture (P < 0.01) with PSCs. Immunohistochemistry revealed stromal and tumoral LDHB expression had no impact on survival. CONCLUSIONS: Galloflavin has the potential to neutralize the acidic PDAC microenvironment and thereby reduce tumor invasiveness and metastasis. Patients with lower LDHB expression are more likely to be beneficial responders.

The quality of pain management in pancreatic cancer: A prospective multi-center study.

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with severe pain. Given the almost inevitably fatal nature of the disease, pain control is crucial. However, data on quality of pain management in PDAC is scarce. METHODS: This is a multi-center, prospective study to evaluate the quality of pain management in PDAC. Insufficient pain treatment (undertreatment) was prevalent if there was an incongruence between the patients level of pain and the potency of analgesic drug therapy. Determinants of pain and undertreatment were identified using multivariable logistic regression. RESULTS: 139 patients with histologically confirmed PDAC were analyzed. The prevalence of pain was 63%, with approximately one third of the patients grading their pain as moderate to severe. Palliative stage (OR: 3.37, 95%CI: 1.23-9.21, p = 0.018) and localization of the primary tumor in the body or tail (OR: 2.57, 95%CI: 1.05-6.31, p = 0.039) were independent determinants of pain. Of those reporting pain, 60% were undertreated and in 89% pain interfered with activities and emotions. Age ≥ 70 years (OR: 3.20, 95%CI: 1.09-9.41, p = 0.035) was an independent predictor of undertreatment. Patients with longer-known PDAC ( ≥ 30 days) showed improved pain management compared to new cases (OR: 0.19, 95%CI: 0.05-0.81, p = 0.025). Treatment by gastroenterologists (OR: 0.22, 95%CI: 0.05-0.89, p = 0.034) was associated with less undertreatment. CONCLUSIONS: The results show a high proportion of PDAC patients with pain, pain interference and undertreatment, whose characteristics could help to identify patients at risk in the future. Several changes in the management of cancer-related pain are necessary to overcome barriers to optimal treatment.

Neoadjuvant therapy in elderly patients receiving FOLFIRINOX or gemcitabine/nab-paclitaxel for borderline resectable or locally advanced pancreatic cancer is feasible and lead to a similar oncological outcome compared to non-aged patients - Results of the RESPECT-Study.

INTRODUCTION: The number of people aged 60 and above will rise from 46 million in 2015 to 157 in 2050 million, exceeding 30% of the population in many western countries. Consequently, the demand for oncological therapy for elderly patients will increase within the next decades. Currently, sufficient data on neoadjuvant therapy (NTx) of pancreatic cancer in elderly patients are lacking. METHODS: Data of a multinational, retrospective database were screened for patients having received preoperative FOLFIRINOX (FFx) or Gemcitabine/nab-paclitaxel (GNP) for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC) before June 2017. Data were included in an intention-to-treat-analysis and outcomes were compared between non-aged and elderly patients using a cut-off age of 63 (comparison 1) and 70 years (comparison 2). RESULTS: Of 165 patients receiving NTx, 76 and 33 were older than 63 and 70 years. Baseline characteristics revealed that elderly patients preferably undergo GNP (comparison 1: p = 0.063; comparison2: p = 0.005), with less cycles of NTx (comparison 1: p = 0.057). Whereas reductions of NTx dosage was more common in elderly patients in comparison 1 (p = 0.003), resection rates (p = 0.575; p = 1.000) and median survival (p = 0.406; p = 0.499) were not different. Whereas resected patients showed no differences in survival (p = 0.328; p = 0.132), patients aged >70 years showed a decreased progression-free survival (p = 0.019). CONCLUSION: Elderly patients treated with NTx show encouragingly high resection rates. If comorbidities allow for FFx or GNP, elderly patients with LAPC/BRPC can offered NTx with the prospect of survival comparable to younger patients.