Faculty Bibliography

Purpose of Review Advances in medical therapy have resulted in a growing population of older adults with advanced heart failure. Frailty is a clinical syndrome that increases in prevalence with age and is highly prevalent in patients with heart failure. This paper reviews the complex relationship between frailty and advanced systolic heart failure in older adults, including the potential for reversal of frailty following advanced cardiac interventions. Recent Findings Frailty is predictive of adverse outcomes, including rehospitalization and mortality, in heart failure patients. Several small studies have shown that mechanical circulatory support can modify, and possibly reverse, functional impairments and the pathophysiologic changes associated with heart failure-related frailty. Summary Frailty is highly prevalent in patients with advanced heart failure and is a powerful prognostic marker. Routine frailty assessment could allow clinicians to define optimal patient-centered care strategies for older adult patients with advanced heart failure.

High-grade atrioventricular block (HAVB) is historically considered a marker of worse outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, the predictors and prognostic impact of HAVB in the primary percutaneous coronary intervention (PCI) era remain poorly understood. We sought to describe the characteristics and predictors of HAVB in patients undergoing primary PCI in STEMI and to assess the prognostic significance of HAVB in the contemporary reperfusion era. The present analysis includes 3,115 patients presenting with STEMI from the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial who underwent primary PCI. Outcomes were examined according to the presence of HAVB on a presenting electrocardiogram, as interpreted by an independent electrocardiography core laboratory. HAVB (second-degree Mobitz II or third-degree atrioventricular block) was present at baseline in 46 patients (1.5%). Independent predictors of HAVB included increased age, diabetes mellitus, right coronary artery occlusion, sum of ST-segment deviation, and baseline Thrombolysis In Myocardial Infarction flow 0/1. Thrombolysis In Myocardial Infarction flow 3 was restored in 83.7% and 91.5% of patients with versus without baseline HAVB respectively (p = 0.06). Mortality rate was significantly higher in patients with versus without HAVB at 30-day, 1-, and 3-year follow-ups (unadjusted hazard ratio [HR] 3.83, 95% CI 1.40 to 10.48; unadjusted HR 4.37, 95% CI 2.09 to 9.38 and unadjusted HR 2.78, 95% CI 1.31 to 5.91, respectively). After covariate adjustment, mortality rate was significantly higher in patients with HAVB at 1 year (adjusted HR 2.45, 95% CI 1.09 to 5.50, p = 0.03) but not at 30 days (adjusted HR 1.70, 95% CI 0.58 to 5.01, p = 0.33) or 3 years (adjusted HR 0.71 to 3.41, p = 0.27). In conclusion, HAVB is a rare complication of STEMI but remains associated with increased mortality, even after primary PCI.

Background and Study Aims: Fluorescent in-situ hybridization (FISH) performed on brush specimens is one of the most accurate and widely used second line diagnostic modalities. Our goal was to compare the diagnostic accuracy of FISH in the detection of malignancy compared with other standard diagnostic modalities, including brush cytology and biopsy specimens over a ten year period of prospective data collection. Patients and methods: We conducted a review of a prospectively maintained database of biliary strictures between 2006 and 2016. Patients with a final pathologic diagnosis or a conclusive follow-up were included. Cytology and biopsy results were considered positive for malignancy when suspicious or malignant cells were identified. We evaluated the performance of FISH polysomy (CEP 3, 7, and 17) and 9p21 deletion. Statistical analysis was performed with the Chi square and Fisher exact tests. Results: Of 382 who underwent evaluation for biliary strictures, 277 met inclusion criteria. 119 patients (42.8%) were found to have malignancy (58.0% pancreatic cancer, 37.0% cholangiocarcinoma, 5.0% other malignancies). Benign etiology included inflammatory strictures (63.9%), PSC (19.6%), post-operative (6.3%) or other benign etiologies (10.2%). The sensitivities for FISH and cytology were found to be 55.4% and 39.0%. Both cytology and FISH showed a very high specificity of 99.4%. The accuracy and AUC of FISH polysomy and cytology (AUC=.789) was significantly higher than cytology alone (AUC=.688; p<0.05). The addition of detection of 9p21 deletion led to no additional false positives but an additional diagnosis of 11/119 (9.2%) malignant cases, however there was a nonsignificant difference in the accuracy and AUC of FISH polysomy versus FISH polysomy plus 9p21 deletion. The combination of brush cytology, FISH polysomy and 9p21 deletion and any additional sampling (i.e. biopsy) taken during ERCP showed a sensitivity of 70.0% that was not significantly higher than cytology plus FISH polysomy. There were 36 (30.3 %) patients who had malignancies that were undetected by any of the diagnostic modalities studied. Conclusion: This is the largest prospective cohort of patients with biliary strictures evaluated by FISH. The very high specificity of FISH polysomy and 9p21 deletion suggests that a positive result is sufficient for the diagnosis of biliary malignancy. A limitation of our data is the relatively small number of PSC patients where specificity may be lower. The significantly higher sensitivity of both FISH polysomy and polysomy or 9p21 deletion compared to cytology and the non-significant improvement in sensitivity when combing further sampling methods supports the use of FISH as first line in the evaluation of cytology negative strictures. (Table Presented)

BACKGROUND AND AIMS/OBJECTIVE:Preliminary single-institution data suggest that fluorescence in situ hybridization (FISH) may be useful for detecting high-grade dysplasia (HGD) and esophageal adenocarcinoma (EA) in patients with Barrett's esophagus (BE). This multicenter study aims to validate the measurement of polysomy (gain of at least two loci) by FISH as a way to discriminate degrees of dysplasia in BE specimens. METHODS:Tissue specimens were collected from four different hospitals and read by both the local pathology department ("Site diagnosis") and a single central pathologist ("Review diagnosis") at a separate institution. The specimens then underwent FISH analysis using probes 8q24 (MYC), 9p21 (CDKN2A), 17q12 (ERBB2), and 20q13 (ZNF217) for comparison. A total of 46 non-BE, 42 non-dysplastic specialized intestinal metaplasia (SIM), 23 indefinite-grade dysplasia (IGD), 10 low-grade dysplasia (LGD), 29 HGD, and 42 EA specimens were analyzed. RESULTS:We found that polysomy, as detected by FISH, was the predominant chromosomal abnormality present as dysplasia increased. Polysomy was also the best predictor for the presence of dysplasia or EA when comparing its area under the curve to that of other FISH abnormalities. We observed that if at least 10% of cells had polysomy within a specimen, the FISH probe was able to differentiate between EA/HGD and the remaining pathologies with a sensitivity of 80% and a specificity of 88%. CONCLUSIONS:This study demonstrates that using FISH to determine the percentage of cells with polysomy can accurately and objectively aid in the diagnosis of HGD/EA in BE specimens.

Peptide receptor radionuclide therapy (PRRT) with [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-DOTATATE) is a treatment with good results in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEPNETs). However, there are some pitfalls that should be taken into consideration when evaluating the treatment response after PRRT. 354 Dutch patients with GEPNETs who were treated with ¹⁷⁷Lu-DOTATATE between March 2000 and December 2011 were retrospectively selected. Liver function parameters and chromogranin A were measured before each therapy and in follow-up. Anatomical imaging was performed before therapy and in follow-up. An increase in aminotransferases by ≥20% compared to baseline was observed in 83 of 351 patients (24%). In patients with an objective response (OR) and stable disease (SD) this increase was observed in 71/297 (24%) and in patients with progressive disease (PD) it was observed in 12/54 patients (22%). An increase in chromogranin A by ≥20% compared to baseline was observed in 76 patients (29%). This was present in 34% of patients who eventually had PD and 27% of patients who had OR/SD. In 70% of patients this tumour marker returned to baseline levels after therapy. An increase in liver enzymes and chromogranin A is not uncommon after PRRT. In the vast majority of patients this will resolve in follow-up. Clinicians should be aware that these changes may occur due to radiation-induced inflammation or disease progression and that repeated measurements over time are necessary to differentiate between the two.

Limbic encephalitis presents as altered mood, memory loss and confusion. Clinical features may include psychiatric symptoms and seizures. In contrast to paraneoplastic disorders, non-paraneoplastic autoimmune encephalitis often responds to immunotherapy and sometimes with marked recovery. However, relapse can occur. An 82-year-old male presented with subacute episodes of memory loss over a few days. The patient was unable to recognize his own home and family members. Physical exam was unremarkable. Neuropsychological assessment revealed deficits in cognitive performance that could be consistent with moderate dementia or a more rapidly progressive encephalopathy. Agitated behavior and anxiety were also noted. Laboratory evaluation included hyponatremia, which was corrected with no symptom improvement. B12, TSH, and HIV were normal. CSF analysis revealed 10 WBCs/muL, Glucose-52 mg/dl, Protein-62 mg/dl and was negative for infectious, neoplastic causes, varicella, VDRL, viral cultures, NMDA receptor antibody, GAD 65 antibody and Anti-Hu antibody. Occult malignancy work up with CT scan of chest and abdomen and colonoscopy was normal. Serum for voltage-gated potassium channel antibodies was positive at 849 pmol/l (>88). EEG showed occasional focal left fronto-temporal slowing without epileptiform activity. MRI revealed focal enhancement of the medial left temporal lobe consistent with limbic encephalitis. The patient started high dose steroids with improvement in memory and complete resolution of focal abnormality within the left hippocampal/parahippocampal region suggestive of resolving encephalitis. At seven months after tapering steroids the patient presented with myoclonus and recurrent memory loss. MRI demonstrated recurrent encephalitis with gyral swelling and FLAIR hyperintensity in the left temporal lobe. The patient was restarted on high dose steroids with addition of Rituximab. This case illustrates that limbic encephalitis can present as a rapidly progressive dementia. Differential diagnosis should include more unusual forms of rapidly progressive dementia such as Jakob-Creutzfeldt disease if myoclonus is present, Lewy body dementia if waxing and waning memory, and Alzheimer's dementia with acute delirium if presenting over a period of months. In this patient, MRI changes were crucial to recognizing a potentially reversible limbic encephalitis. Early recognition and treatment may decrease relapse and reduce functional impairment

The cancer community understands the value of blood profiling measurements in assessing and monitoring cancer. We describe an effort among academic, government, biotechnology, diagnostic, and pharmaceutical companies called the Blood Profiling Atlas in Cancer (BloodPAC) Project. BloodPAC will aggregate, make freely available, and harmonize for further analyses, raw datasets, relevant associated clinical data (e.g., clinical diagnosis, treatment history, and outcomes), and sample preparation and handling protocols to accelerate the development of blood profiling assays.

BACKGROUND:Healthcare-associated infections (HAIs) are common and harmful to patients. Effective hand hygiene can help prevent HAIs, however, suboptimal healthcare worker hand hygiene remains problematic across the globe. This study analyses the impact of organisational changes on hand hygiene. METHODS:This observational study assessed hand hygiene by different professions before and after a merger of a recently combined infectious diseases (ID) unit coupled with a qualitative study about barriers to optimal hand hygiene. Direct observations were compared with previous data collected on both units before they merged. We also conducted focus groups with the doctors and nurses about hand hygiene. RESULTS:= 0.004). Data from the focus groups revealed a gap between doctor and nurses perceptions of education and goal adherence rates. CONCLUSIONS:Our findings underscore the important role played by effective unit leaders to prevent infection. We found long-term sustainability of hand hygiene practices among doctors. However, adherence among nurses was substantially lower.