Morbidity and Outcomes After Distal Pancreatectomy for Primary Retroperitoneal Sarcoma: An Analysis by the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: Multi-visceral resection often is used in the treatment of retroperitoneal sarcoma (RPS). The morbidity after distal pancreatectomy for primary pancreatic cancer is well-documented, but the outcomes after distal pancreatectomy for primary RPS are not. This study aimed to evaluate morbidity and oncologic outcomes after distal pancreatectomy for primary RPS. METHODS: In this study, 26 sarcoma centers that are members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) retrospectively identified consecutive patients who underwent distal pancreatectomy for primary RPS from 2008 to 2017. The outcomes measured were 90-day severe complications (Clavien-Dindo ≥ 3), postoperative pancreatic fistula (POPF) rate, and oncologic outcomes. RESULTS: Between 2008 and 2017, 280 patients underwent distal pancreatectomy for primary RPS. The median tumor size was 25 cm, and the median number of organs resected, including the pancreas, was three. In 96% of the operations, R0/R1 resection was achieved. The 90-day severe complication rate was 40 %. The grades B and C POPF complication rates were respectively 19% and 5% and not associated with worse overall survival. Administration of preoperative radiation and factors to mitigate POPF did not have an impact on the risk for the development of a POPF. The RPS invaded the pancreas in 38% of the patients, and local recurrence was doubled for the patients who had a microscopic, positive pancreas margin (hazard ratio, 2.0; p = 0.042). CONCLUSION: Distal pancreatectomy for primary RPS has acceptable morbidity and oncologic outcomes and is a reasonable approach to facilitate complete tumor resection.

Incidence of Dementia in Patients With Open-angle Glaucoma: A Population-based Study.

PRECIS: In this population-based study of 509 open-angle glaucoma (OAG) patients over a 36-year period, we identified a decreased rate of developing dementia compared with the rate in the general population. PURPOSE: The aim was to determine the incidence of dementia and Alzheimer disease (AD) among patients with OAG. PATIENTS AND METHODS: Retrospective, population-based cohort study. All residents of Olmsted County, Minnesota (≥40 y) who were diagnosed with OAG between January 1, 1965 and December 31, 2000, were eligible for inclusion in this study. A total of 509 patients were included over the 36-year period. The cumulative probability of developing dementia was calculated and compared with the population risk of dementia. RESULTS: Of the 509 patients included, 300 (58.9%) were female, the median age was 67.5 years, and 278 patients (54.6%) had primary OAG. Other subgroups were pseudoexfoliation in 15.1%, treated ocular hypertension in 14.1%, normal tension glaucoma in 10.6%, and pigmentary glaucoma in 5.5% of the patients. Respectively, 118 (23.0%) and 99 (19.4%) patients developed dementia and AD. The 10-year cumulative probability of developing dementia and AD was 12.0% and 9.9%, with a 95% confidence interval of 9.3%-15.3% and 7.5%-13%, respectively. The observed 10-year incidence of dementia and AD were significantly lower than the expected population incidence (19.0% and 19.0%; P<0.001). Older age at diagnosis of glaucoma was a strong predictor for the development of dementia by multivariate analysis (hazard ratio: 3.31, 95% confidence interval: 2.61-4.20, P<0.001). CONCLUSION: The risk of developing dementia or AD was decreased in OAG patients compared with the general population. OAG with onset at a later age may present as a different etiopathogenetic entity compared with onset at a younger age, and represent the optic nerve findings of generalized neurodegenerative processes.

Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

Proton-pump-inhibitor use associated with lower short-term rebleeding and mortality in patients receiving esophageal variceal band ligation: a retrospective cohort study.

BACKGROUND: The impact of proton-pump inhibitor (PPI) therapy on subsequent hemorrhage and mortality after variceal hemorrhage is unclear. AIM: Evaluate the associations of PPI use with upper gastrointestinal bleeding (UGIB) and death within 30 days of undergoing esophageal variceal band ligation (EBL) separately in inpatient and outpatient settings. METHODS: Retrospective review of cirrhotic patients with variceal hemorrhage who underwent EBL between 2005 and 2018. Endoscopic findings, PPI use at admission (inpatients only), PPI use at discharge (inpatients and outpatients), and adverse outcomes data (liver transplant, UGIB, transjugular intrahepatic portosystemic shunt, and death within 30 days of discharge or death during hospitalization) were reviewed. RESULTS: A total of 446 patients (164 inpatients, 282 outpatients) were included. The most commonly observed outcomes were death within 30 days of discharge in inpatients (12.8%), UGIB within 30 days of discharge in inpatients (21.3%), and UGIB within 30 days of discharge in outpatients (8.5%). For inpatients, prescription of PPI at discharge was associated with a lower risk of bleeding within 30 days (odds ratio: 0.30, P = 0.025) and death within 30 days (odds ratio = 0.16, P = 0.002). No other significant associations of PPI with death or UGIB were reported. CONCLUSION: Post-EBL PPI therapy is associated with reduced risk of bleeding and death within 30 days after variceal hemorrhage in hospitalized patients.

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia.

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients.

OBJECTIVE: To provide an update on key safety metrics after transfusion of convalescent plasma in hospitalized coronavirus 2019 (COVID-19) patients, having previously demonstrated safety in 5000 hospitalized patients. PATIENTS AND METHODS: From April 3 to June 2, 2020, the US Food and Drug Administration Expanded Access Program for COVID-19 convalescent plasma transfused a convenience sample of 20,000 hospitalized patients with COVID-19 convalescent plasma. RESULTS: The incidence of all serious adverse events was low; these included transfusion reactions (n=78; <1%), thromboembolic or thrombotic events (n=113; <1%), and cardiac events (n=677, ~3%). Notably, the vast majority of the thromboembolic or thrombotic events (n=75) and cardiac events (n=597) were judged to be unrelated to the plasma transfusion per se. The 7-day mortality rate was 13.0% (12.5%, 13.4%), and was higher among more critically ill patients relative to less ill counterparts, including patients admitted to the intensive care unit versus those not admitted (15.6 vs 9.3%), mechanically ventilated versus not ventilated (18.3% vs 9.9%), and with septic shock or multiple organ dysfunction/failure versus those without dysfunction/failure (21.7% vs 11.5%). CONCLUSION: These updated data provide robust evidence that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19, and support the notion that earlier administration of plasma within the clinical course of COVID-19 is more likely to reduce mortality.

Etiology of Papilledema in Patients in the Eye Clinic Setting.

Importance: The study of health conditions associated with papilledema will augment the clinical judgment of eye care professionals treating patients with optic disc edema in determining the urgency of additional evaluation and counseling patients accordingly. Objectives: To determine the incidence, demographic characteristics, and etiologies of papilledema based on a unique records-linkage research platform; and to describe the demographic and clinical differences between patients with idiopathic intracranial hypertension (IIH) and other causes of papilledema. Design, Setting, and Participants: Retrospective population-based cross-sectional study of patients treated for papilledema at outpatient eye clinics in Olmsted County, Minnesota, using the Rochester Epidemiology Project. Data were collected from January 1990 to December 2014 and analyzed from September 2018 to April 2019. Main Outcomes and Measures: Etiologies of papilledema, body mass index, incidence of headache, or localizing neurologic signs. Results: Eighty-six patients were diagnosed with papilledema during the 24-year period, providing an age- and sex-adjusted incidence of 2.5 individuals per 100 000 per year; 68 patients (79%) were women, 73 (85%) were white patients, and the median (range) age was 27.7 (6.2-64.2) years. Nineteen patients (22%) presented with a previously diagnosed attributable cause (eg, trauma or intracranial tumor). Among patients presenting with papilledema without a previously diagnosed attributable cause, 58 patients (87%) had IIH, and 9 patients (13%) were found to have a secondary cause of raised intracranial pressure, such as intracranial tumor, cerebral venous sinus thrombosis, or granulomatous meningitis. Patients with IIH had a higher median (range) body mass index (37.5 [20.4-55.7] vs 27.4 [16.6-40.1]; P = .003) and headache prevalence (54 of 58 patients [93%] vs 6 of 9 patients [67%]; P = .004) than patients with other causes of papilledema. Of 9 patients with papilledema but no IIH, 2 (22%) had localizing neurologic signs, such as gait abnormalities, hearing loss, focal weakness or numbness, visual field defects, or aphasia. Among 42 patients with demographic characteristics typically associated with IIH (female sex, with obesity, aged 15 to 45 years, and absent localizing neurologic signs or symptoms), 40 (95%) had papilledema that was associated with IIH. Conversely, among the 19 patients without these demographic characteristics, 7 (37%) had an alternative cause. Conclusions and Relevance: In this study, most patients who presented to the eye clinic with papilledema without a previously known cause were found to have IIH. These patients were more likely to present with headaches and had statistically higher body mass index. Clinicians should take these findings into account when determining the pretest probability of a patient having IIH or an alternative cause of papilledema.

Early safety indicators of COVID-19 convalescent plasma in 5000 patients.

BACKGROUNDConvalescent plasma is the only antibody-based therapy currently available for patients with coronavirus disease 2019 (COVID-19). It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19.METHODSThus, we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma in 5000 hospitalized adults with severe or life-threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA expanded access program for COVID-19 convalescent plasma.RESULTSThe incidence of all serious adverse events (SAEs), including mortality rate (0.3%), in the first 4 hours after transfusion was <1%. Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n = 4), transfusion-associated circulatory overload (n = 7), transfusion-related acute lung injury (n = 11), and severe allergic transfusion reactions (n = 3). However, only 2 of 36 SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The 7-day mortality rate was 14.9%.CONCLUSIONGiven the deadly nature of COVID-19 and the large population of critically ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19.TRIAL REGISTRATIONClinicalTrials.gov NCT04338360.FUNDINGMayo Clinic, Biomedical Advanced Research and Development Authority (75A50120C00096), National Center for Advancing Translational Sciences (UL1TR002377), National Heart, Lung, and Blood Institute (5R35HL139854 and R01 HL059842), National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK07352), Natural Sciences and Engineering Research Council of Canada (PDF-532926-2019), National Institute of Allergy and Infectious Disease (R21 AI145356, R21 AI152318, and AI152078), Schwab Charitable Fund, United Health Group, National Basketball Association, Millennium Pharmaceuticals, and Octapharma USA Inc.

Repeatability of Scheimpflug Tomography for Assessing Fuchs Endothelial Corneal Dystrophy.

PURPOSE: To determine if agreement between subjective interpretations of Scheimpflug tomography maps of corneas with Fuchs endothelial corneal dystrophy (FECD) is affected by daily and hourly changes in corneal edema. DESIGN: Reliability analysis. METHODS: Scheimpflug imaging pachymetry and posterior elevation maps of corneas with a range of severity of FECD were evaluated in a randomized manner for the presence of 3 tomographic features of edema. Agreement between interpretations of 1 masked observer was assessed (percentage, and κ-statistic with 95% confidence interval) for images taken within minutes on the same day, for images taken at a similar time on a different day, and for images taken over the course of a morning. Intra- and interobserver agreement was also assessed. RESULTS: Interpretations for individual tomographic features agreed for ≥88% of images (κ ≥ 0.75) taken within minutes on the same day; complete disagreement (ie, disagreement for all 3 tomographic features in an image) occurred in ≤3% of images. Interpretations agreed for ≥77% of images (κ ≥ 0.52) taken at a similar time on a different day; complete disagreement did not occur. Interpretations agreed for ≥81% of images (κ ≥ 0.61) taken over the course of a morning; complete disagreement occurred in ≤6% of images. Intraobserver agreement was ≥93% (κ ≥ 0.83) and interobserver agreement was ≥93% (κ ≥ 0.66); complete disagreement did not occur. CONCLUSIONS: Subjective interpretation of Scheimpflug images in FECD is highly repeatable for disease classification. Although small variations in interpretations resulted from pathophysiologic changes in corneal hydration and other factors, clinically significant disagreements in interpretation were uncommon and therefore unlikely to affect clinical decision-making.

Determinants of Sudden Cardiac Death in Adult Patients With Eisenmenger Syndrome.

Background Patients with Eisenmenger syndrome are known to have a high incidence of sudden cardiac death (SCD), yet the underlying causes are not well understood. We sought to define the predictors of SCD in this population. Methods and Results A retrospective analysis of all patients with Eisenmenger syndrome from 2 large tertiary referral centers was performed. ECGs, prolonged ambulatory recordings, echocardiograms, and clinical histories were reviewed; and the cause of death was identified. A total of 246 patients (85 [34.6%] men) with a mean age of 37.3 (±14.2) years were followed up for a median of 7 years. Over the study period, 136 patients died, with 40 experiencing SCD and 74 experiencing cardiac death (sudden and nonsudden). Age, atrial fibrillation, prolonged QRS duration, complete heart block, right atrial enlargement, right bundle branch block, increased right atrial pressure, impaired biventricular function, and the presence of a pacemaker were associated with increased risk of SCD, whereas advanced pulmonary hypertension therapies were protective. Atrial fibrillation (11.45-fold increased risk; P<0.001) and QRS duration ≥120 ms (2.06-fold increased risk; P=0.034) remained significant predictors of SCD in the multivariate analysis, whereas advanced pulmonary hypertension therapies were strongly protective against SCD (P<0.001). Conclusions Atrial arrhythmias, impaired ventricular function, and conduction system disease were associated with increased risk of SCD in this cohort of patients with Eisenmenger syndrome, providing an opportunity for early risk stratification and potential intervention. Clinical heart failure symptoms (New York Heart Association class ≥II) were predictive of increased mortality but not of SCD, suggesting a potential arrhythmic cause behind SCD.

Factors Predisposing to Catheter Reinsertion Following Holmium Laser Enucleation of the Prostate.

OBJECTIVE: To determine if preoperative catheter dependence or specimen weight is associated with failed trial without catheter (TWOC) following holmium laser enucleation of the prostate (HoLEP). MATERIAL AND METHODS: The study population consisted of 143 consecutive men who underwent HoLEP by a single surgeon over 10 months. Ten were excluded from analysis because they did not have a TWOC on the morning following surgery. Preoperative catheter dependence and specimen weight as well as catheter reinsertions were analyzed. RESULTS: Of 133 men included in analysis, 23 (17.3%) required catheter reinsertion. Of the 23 requiring catheter reinsertion, 6 were catheter dependent preoperatively and 17 were not. Men who were catheter dependent had a lower overall rate of failed TWOC compared to those who were not catheter dependent (15.0% vs 18.3%, P = .647). Mean specimen weight for men requiring catheter reinsertion was significantly lower than men who passed their TWOC (49.9 gm vs 73.1 gm, P = .013). CONCLUSION: Very few studies exist on factors associated with short-term catheter reinsertion following HoLEP or other prostatic hyperplasia procedures. We hypothesized that preoperative catheter dependence and small specimen weight would predispose to catheter reinsertion. Specimen weight was inversely related to risk of catheter reinsertion after HoLEP and preoperative catheter dependence was not associated with catheter reinsertion. In men with small prostates, consideration should be given to delayed TWOC to allow resolution of capsular edema and accumulation of clot in the prostatic fossa. Transition zone volume below which delayed TWOC should be considered is the subject of future studies.

Predicting the Prognosis of Fuchs Endothelial Corneal Dystrophy by Using Scheimpflug Tomography.

PURPOSE: To determine if Scheimpflug tomography pachymetry map and posterior elevation map patterns, central corneal thickness (CCT), and corneal backscatter can predict the prognosis of Fuchs endothelial corneal dystrophy (FECD). DESIGN: Cross-sectional study with follow-up of outcomes. PARTICIPANTS: Ninety-six eyes (56 subjects) with a range of severity of FECD. METHODS: Corneas were graded by cornea specialists according to the area and confluence of guttae and the presence of clinically definite edema. Masked and randomized Scheimpflug imaging pachymetry map and posterior elevation map patterns were assessed by 1 observer for loss of regular isopachs, displacement of the thinnest point of the cornea, and the presence of posterior surface depression. The prognosis of eyes over a 5-year (median) follow-up period was determined based on FECD progression (new onset of clinically definite edema or ≥5% increase in CCT) or intervention by endothelial keratoplasty. Cumulative probabilities of progression and intervention were estimated from survival analyses, with risk factors determined by using Cox proportional hazards models. MAIN OUTCOME MEASURES: Pachymetry map and posterior elevation map patterns, corneal backscatter, and CCT (ultrasonic pachymetry). RESULTS: In univariate analyses, loss of regular isopachs (hazard ratio [HR], 18.00) displacement of the thinnest point (HR, 11.53), focal posterior surface depression (HR, 10.21), and anterior corneal backscatter (HR, 1.22, per 1-grayscale unit increment), were risk factors for progression or intervention (P < 0.001), whereas CCT (HR, 1.30, per 25-µm increment) was not (P = 0.15). In multivariate analyses, loss of regular isopachs (HR, 11.57; P < 0.001) and displacement of the thinnest point (HR, 5.61; P = 0.02) were independent and clinically important risk factors for progression and intervention. The 5-year cumulative risk of disease progression and intervention was 7%, 48%, and 89% when none, 1 or 2, and all 3 pachymetry map and posterior elevation map parameters were present, respectively (P <0.001). The 4-year cumulative risk of disease progression and intervention after uncomplicated cataract surgery was 0%, 50%, and 75% when none, 1 or 2, and all 3 pachymetry map and posterior elevation map parameters were present, respectively (P < 0.001). CONCLUSIONS: Three Scheimpflug tomography pachymetry map and posterior elevation map patterns can predict FECD prognosis independent of CCT. The risk of FECD progression and intervention, including after uncomplicated cataract surgery, increases according to the number of parameters present.