Peripheral blood monocyte counts are elevated in the pre-diagnostic phase of pancreatic cancer: A population based study.

BACKGROUND: Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with improved outcomes. A biomarker with incremental change in the pre-diagnostic phase of the disease would be valuable for early detection. In our clinical experience, we have observed elevated peripheral blood monocyte (PBM) counts in PDAC patients at diagnosis. In this study, we aimed to compare PBM counts in PDAC cases and healthy controls at diagnosis and in the 2-year pre-diagnostic period. METHODS: Using the Rochester Epidemiology Project database, we identified all patients diagnosed with PDAC between 2000 and 2015 (n = 219) and age-and gender-matched disease-free controls (n = 438). PBM counts and temporal trends were analyzed over a 24 month period before PDAC diagnosis. The groups were compared using Fisher's exact test and t-test. RESULTS: At diagnosis, compared to controls PDAC cases more often had monocytosis (23% vs 8%; p < 0.001) and higher mean PBM count (x109/L) (0.73 vs 0.59; p < 0.001). In the 2-year pre-diagnostic period, mean PBM counts were significantly higher in PDAC cases in the interval from 6 months to diagnosis (0.69 vs 0.61; p = 0.03). PDAC cases with monocytosis at diagnosis had a significantly lower median survival (1.9 months vs. 7.6 months; p = 0.001). CONCLUSION: Monocytosis is more prevalent in PDAC patients at diagnosis compared to controls and is associated with lower median survival. In a subset of patients, PBM count elevation precedes PDAC diagnosis by 6 months. This novel observation can possibly augment strategies for early diagnosis of PDAC but needs further study.

A Rare Cause of Abdominal Pain: Erdheim-Chester Disease.

A 65-year-old man presented with hematuria, night sweats, nausea, intermittent nonbloody diarrhea, and abdominal pain. Computed tomography angiogram with enterography showed retroperitoneal fibrosis surrounding both kidneys and ureters without any evidence of vascular obstruction or hydronephrosis. Laparoscopic biopsy demonstrated fibroadipose tissue involved by a subtle histiocytic infiltrate in a background of marked fibrosis, scattered lymphocytes, and plasma cells. The histiocytes strongly expressed CD163, Factor XIIIa, and BRAF V600E. He was diagnosed with Erdheim-Chester disease, a rare histiocytic neoplasm uncommonly presenting with gastroenterological manifestations.

Long-Term Outcomes and Risk of Pancreatic Cancer in Intraductal Papillary Mucinous Neoplasms.

Importance: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that can give rise to pancreatic cancer (PC). Limited population data exist on their prevalence, natural history, or risk of malignant transformation (IPMN-PC). Objective: To fill knowledge gaps in epidemiology of IPMNs and associated PC risk by estimating population prevalence of IPMNs, associated PC risk, and proportion of IPMN-PC. Design, Setting, and Participants: : This retrospective cohort study was conducted in Olmsted County, Minnesota. Using the Rochester Epidemiology Project (REP), patients aged 50 years and older with abdominal computed tomography (CT) scans between 2000 and 2015 were randomly selected (CT cohort). All patients from the REP with PC between 2000 and 2019 were also selected (PC cohort). Data were analyzed from November 2021 through August 2023. Main outcomes and Measures: CIs for PC incidence estimates were calculated using exact methods with the Poisson distribution. Cox models were used to estimate age, sex, and stage-adjusted hazard ratios for time-to-event end points. Results: The CT cohort included 2114 patients (1140 females [53.9%]; mean [SD] age, 68.6 [12.1] years). IPMNs were identified in 231 patients (10.9%; 95% CI, 9.7%-12.3%), most of which were branch duct (210 branch-duct [90.9%], 16 main-duct [6.9%], and 5 mixed [2.2%] IPMNs). There were 5 Fukuoka high-risk (F-HR) IPMNs (2.2%), 39 worrisome (F-W) IPMNs (16.9%), and 187 negative (F-N) IPMNs (81.0%). After a median (IQR) follow-up of 12.0 (8.1-15.3) years, 4 patients developed PC (2 patients in F-HR and 2 patients in F-N groups). The PC incidence rate per 100 person years for F-HR IPMNs was 34.06 incidents (95% CI, 4.12-123.02 incidents) and not significantly different for patients with F-N IPMNs compared with patients without IPMNs (0.16 patients; 95% CI, 0.02-0.57 patients vs 0.11 patients; 95% CI, 0.06-0.17 patients; P = .62). The PC cohort included 320 patients (155 females [48.4%]; mean [SD] age, 72.0 [12.3] years), and 9.8% (95% CI, 7.0%-13.7%) had IPMN-PC. Compared with 284 patients with non-IPMN PC, 31 patients with IPMN-PC were older (mean [SD] age, 76.9 [9.2] vs 71.3 [12.5] years; P = .02) and more likely to undergo surgical resection (14 patients [45.2%] vs 60 patients [21.1%]; P = .003) and more-frequently had nonmetastatic PC at diagnosis (20 patients [64.5%] vs 130 patients [46.8%]; P = .047). Patients with IPMN-PC had better survival (adjusted hazard ratio, 0.62; 95% CI, 0.40-0.94; P = .03) than patients with non-IPMN PC. Conclusions and Relevance: In this study, CTs identified IPMNs in approximately 10% of patients aged 50 years or older. PC risk in patients with F-N IPMNs was low and not different compared with patients without IPMNs; approximately 10% of patients with PC had IPMN-PC, and they had better survival compared with patients with non-IPMN PC.

Chronic Pancreatitis Is a Risk Factor for Pancreatic Cancer, and Incidence Increases With Duration of Disease: A Systematic Review and Meta-analysis.

INTRODUCTION: Observational studies have suggested an increased risk of pancreatic ductal adenocarcinoma (PDAC) in patients with acute and chronic pancreatitis. We conducted a systematic review and meta-analysis to evaluate the magnitude of this association and summarize the published epidemiological evidence. METHODS: We searched electronic databases (MEDLINE, Embase, Web of Science, Cochrane, and Scopus) and reference lists until January 18, 2021. Studies reporting quantitative association between pancreatitis and PDAC were included and assessed for eligibility, data abstraction, and risk of bias. Standardized incidence ratios (SIRs) were pooled using the random-effects model. RESULTS: Twenty-five cohort and case-control studies met inclusion criteria. Meta-analysis of 12 chronic pancreatitis (CP) studies demonstrated an increased risk of PDAC in patients with CP (SIR: 22.61, 95% confidence interval [CI]: 14.42-35.44). This elevated risk persisted in subgroup analysis of studies that excluded patients diagnosed with PDAC within 2 years of CP diagnosis (SIR: 21.77, 95% CI: 14.43-32.720). The risk was higher in hereditary pancreatitis (SIR: 63.36, 95% CI: 45.39-88.46). The cumulative incidence rates of PDAC in CP increased with follow-up duration. Limited evidence in acute pancreatitis indicates higher PDAC risk in the subset of patients eventually diagnosed with CP. PDAC seems to be uncommon in patients with autoimmune pancreatitis, with 8 reported cases in 358 patients with autoimmune pancreatitis across 4 studies. DISCUSSION: There is an increased risk of PDAC in patients with CP, and incidence rates increase with CP disease duration. Our results indicate that PDAC surveillance may be considered in individuals with long-standing CP.

Cardiac Masses (from a 15-Year Experience With 389 Surgical Cases).

Cardiac masses are highly heterogeneous and vary widely in their clinical presentation, imaging features, and survival outcomes. Our understanding is limited by their rarity and the fact that few are confirmed based on surgical pathology. We set out to provide a comprehensive analysis of all cardiac masses resected at our institution from 1999 to 2015, including imaging methods and histopathologic findings. We found papillary fibroelastomas (PFEs) to be the most commonly resected benign cardiac masses, followed by myxomas. Patients with PFEs most frequently presented with cerebrovascular accidents and transient ischemic attacks, whereas those with myxomas were more likely to present with arrhythmias and palpitations. In contrast, primary malignant cardiac masses were much rarer; angiosarcoma was the predominant subtype with a poor prognosis. Renal cell carcinomas were the most commonly discovered primary cancer for metastatic cardiac masses, and calcified amorphous tumors were the most prevalent non-neoplastic masses. For the detection of cardiac masses, transthoracic echocardiography was the most frequently used but least sensitive of the imaging methods analyzed. Transesophageal echocardiography (TEE) was the most sensitive imaging method. Fluorodeoxyglucose Positron Emission Tomography had similar sensitivity to TEE but was the least frequently used imaging method. Computed tomography and magnetic resonance imaging performed well in detecting most masses; PFEs, for which TEE was the most sensitive, was the exception. In conclusion, we found that PFEs were the most commonly resected benign cardiac masses, and TEE was the most accurate imaging method for the detection of all surgically removed masses at our institution.

Pancreatic Cancer is More Frequently Early Stage at Diagnosis in Surgically Resected Intraductal Papillary Mucinous Neoplasms With Preoperative Surveillance.

Background and Aims: Management of intraductal papillary mucinous neoplasms (IPMNs) relies on clinical and imaging features to select patients for either pancreatectomy or periodic image-based surveillance. We aimed to compare outcomes in patients with IPMNs who underwent surgery at diagnosis with those who underwent surgery after a period of surveillance and identify preoperative clinical and imaging features associated with advanced neoplasia. Methods: Patients with surgically resected IPMN (n = 450) were divided into 2 groups: "immediate surgery": resection within 6 months of IPMN detection, and "surveillance surgery": resection after surveillance >6 months. Survival was analyzed with Kaplan-Meier estimates and Cox proportional hazard models. Results: Pancreatic cancers in the surveillance surgery group (n = 135) was more frequently stage I compared with the immediate surgery group (9/13, 69.2% vs 41/110, 37.3%; P = .027). Among Fukuoka "worrisome features," only main pancreatic duct dilation 5-9 mm (odds ratio [OR] = 3.12, 95% confidence interval [CI]: 1.72-5.68; P < .001) and serum CA 19-9≥ 35 U/mL (OR = 2.82, 95% CI: 1.31-6.06; P = .008) were significantly associated with advanced neoplasia. In addition, smoking history was associated with increased risk of advanced neoplasia (OR = 2.05, 95% CI: 1.23-3.43). Occurrence of future cancer was 16-fold higher in IPMN with high-grade dysplasia when compared with low-grade dysplasia (hazard ratio: 16.5; 95% CI: 4.19-64.7). Conclusion: Surveillance-detected pancreatic cancers in patients with IPMNs are more frequently stage I, and IPMN-HGD on surgical pathology is associated with significant risk of future pancreatic cancer. In addition to known "high-risk" features, main pancreatic duct dilation 5-9 mm, CA 19-9 elevation, and smoking history are significantly associated with advanced neoplasia.

Discovery and Validation of Methylated DNA Markers From Pancreatic Neuroendocrine Tumors.

Background and Aims: Methylated DNA markers (MDMs) accurately identify several different cancer types, but there are limited data for pancreatic neuroendocrine tumors (pNETs). We aimed to identify MDM candidates in tissue that differentiate pNETs from normal pancreas. Methods: wUsing DNA from frozen normal pancreas (13) and pNET (51) tissues, we performed reduced representation bisulfite sequencing for MDM discovery. Validation in independent formalin fixed paraffin embedded tissues used pNET cases (67; solid = 50, cystic = 17), normal pancreas (24), and buffy coat (36) controls. Primary pNET MDM distributions were compared with lung (36), small bowel (36) NETs, and metastatic pNET (25) tissues. The discrimination accuracy was summarized as the area under the receiver operator characteristic curve (AUC) with corresponding 95% confidence intervals (CIs). Fisher's linear discriminant analysis was performed to estimate a linear discriminate score (LDS) differentiating normal from pNET tissue and applied to all patient groups; discrimination accuracy of the LDS was summarized as the bootstrap cross-validated AUC. Results: Median AUC for distinguishing normal pancreas from pNET tissue was 0.91 (interquartile range: 0.80-0.93). The cross-validated AUC for the LDS discriminating normal pancreatic tissue from primary and metastatic pNETs was 0.957 (95% CI 0.858-1.0, P < .0001) and 0.963 (95% CI 0.865-1.0, P < .0001), respectively. The LDS for the MDM panel was significantly higher for primary pNET, metastatic pNET, lung NET, and small bowel NET, each compared with normal pancreas tissue (P < .0001). There was no statistical difference between primary pNET and metastatic pNET (P = .1947). Conclusion: In independent tissue validation, MDMs accurately discriminate pNETs from normal pancreas. These results provide scientific rationale for exploration of these tissue MDMs in a plasma-based assay for clinical application.

High Detection Rates of Pancreatic Cancer Across Stages by Plasma Assay of Novel Methylated DNA Markers and CA19-9.

PURPOSE: We have previously identified tissue methylated DNA markers (MDMs) associated with pancreatic ductal adenocarcinoma (PDAC). In this case-control study, we aimed to assess the diagnostic performance of plasma MDMs for PDAC. EXPERIMENTAL DESIGN: Thirteen MDMs (GRIN2D, CD1D, ZNF781, FER1L4, RYR2, CLEC11A, AK055957, LRRC4, GH05J042948, HOXA1, PRKCB, SHISA9, and NTRK3) were identified on the basis of selection criteria applied to results of prior tissue experiments and assays were optimized in plasma. Next, 340 plasma samples (170 PDAC cases and 170 controls) were assayed using target enrichment long-probe quantitative amplified signal method. Initially, 120 advanced-stage PDAC cases and 120 healthy controls were used to train a prediction algorithm at 97.5% specificity using random forest modeling. Subsequently, the locked algorithm derived from the training set was applied to an independent blinded test set of 50 early-stage PDAC cases and 50 controls. Finally, data from all 340 patients were combined, and cross-validated. RESULTS: The cross-validated area under the receiver operating characteristic curve (AUC) for the training set was 0.93 (0.89-0.96) for the MDM panel alone, 0.91 (95% confidence interval, 0.87-0.96) for carbohydrate antigen 19-9 (CA19-9) alone, and 0.99 (0.98-1) for the combined MDM-CA19-9 panel. In the test set of early-stage PDAC, the AUC for MDMs alone was 0.84 (0.76-0.92), CA19-9 alone was 0.87 (0.79-0.94), and combined MDM-CA19-9 panel was 0.90 (0.84-0.97) significantly better compared with either MDMs alone or CA19-9 alone (P = 0.0382 and 0.0490, respectively). At a preset specificity of 97.5%, the sensitivity for the combined panel in the test set was 80% (28%-99%) for stage I disease and 82% (68%-92%) for stage II disease. Using the combined datasets, the cross-validated AUC was 0.9 (0.86-0.94) for the MDM panel alone and 0.89 for CA19-9 alone (0.84-0.93) versus 0.97 (0.94-0.99) for the combined MDM-CA19-9 panel (P ≤ 0.0001). Overall, cross-validated sensitivity of MDM-CA19-9 panel was 92% (83%-98%), with an observed specificity of 92% at the preset specificity of 97.5%. CONCLUSIONS: Plasma MDMs in combination with CA19-9 detect PDAC with significantly higher accuracy compared with either biomarker individually.

Molecular Diagnostics and Testing for Pancreatic Cysts.

PURPOSE OF REVIEW: In current clinical practice, the diagnosis and management of pancreatic cystic lesions (PCLs) are based on guidelines that combine clinical and imaging findings. These guidelines usefully identify a large category of low-risk PCLs that do not require treatment. However, they have limited accuracy for diagnosis of advanced neoplasia in worrisome and high-risk PCLs. Novel molecular markers that can accurately detect advanced neoplasia in PCLs can transform the care of patients with PCLs. We reviewed the recent medical literature on molecular diagnostics of PCLs and summarized molecular biomarkers assayed in cyst fluid, pancreatic juice, and blood. RECENT FINDINGS: Several studies have been recently published describing promising early results in genetic, epigenetic, and protein biomarkers from cyst fluid to help in both histologic diagnosis and detection of advanced neoplasia. The majority of studies have been completed using opportunistically collected archival cyst fluid and few report validation in independent sample sets. Results of ongoing multicenter prospective validation studies are awaited and will help define the best combination of cyst fluid molecular markers. In multifocal PCLs communicating with the pancreatic ductal system, a pancreatic juice biomarker is likely to be less invasive and more informative. Novel biomarkers in pancreatic juice and blood are in early phases of study. SUMMARY: The field of molecular diagnostic biomarkers for PCLs is rapidly evolving with several promising candidate markers being prospectively evaluated. In the near future, these novel molecular markers, combined with advances in imaging technology, will transform clinical decision-making in the management of PCLs and improve patient outcomes.

Echocardiography in centenarians: characteristics, utility and follow-up.

BACKGROUND: Echocardiography has been shown to be a valuable resource in the diagnosis of many cardiac conditions, and can be used in all age groups, from the fetus to the oldest old. In the context of an increasingly aging population, the impact and utility of echocardiography in centenarians is largely unknown. This study is to determine whether echocardiography in centenarians aids in making clinical patient management decisions. METHODS: A retrospective review of echocardiograms from 1986 to 2014, at two affiliated tertiary centers, in individuals who were 100 years or older at the time of the examination. Patient and echocardiogram characteristics, management decisions based on echocardiography, and mortality were documented. RESULTS: 114 centenarians had echocardiograms, with ages ranging from 100 to 107 years (101 ± 1.4 years). In 82 of the centenarians evaluated (72%), no changes in management occurred as a consequence of the echocardiogram. From all management changes directly related to the echocardiogram, 81% (n = 26) of these corresponded to medication adjustments; interventional or surgical procedures followed the echocardiogram only in 4% (n = 5) of the total number of centenarians. Echocardiogram-based changes in management were only significant in patients that were referred for congestive heart failure (P = 0.02). After the echocardiogram was performed, 1-month and 1-year mortality were 15% and 47%, respectively. The median survival after the echocardiogram was obtained was 13 months (range 0.03 to 145 months), with no difference if there was a change or no change in management (P = 0.21). CONCLUSIONS: Among centenarians undergoing echocardiography, despite additional diagnostic information, echocardiograms in centenarians influence management in a minority of cases, most commonly in the form of medication changes for treatment of heart failure. A significant proportion of centenarians are deceased within a year of undergoing echocardiographic assessment. These findings may question the overall utility of echocardiography in these late survivors.

Phenotype and Clinical Course of Inflammatory Bowel Disease With Co-existent Celiac Disease.

BACKGROUND AND AIMS: Inflammatory bowel diseases, principally Crohn's disease and ulcerative colitis, and celiac disease are among the most common immune-mediated gastrointestinal diseases. We aim to elucidate the clinical course and outcomes of patients with concomitant inflammatory bowel disease and celiac disease, a unique population that remains scarcely studied to date. METHODS: A retrospective matched case-control study of adults with co-existent inflammatory bowel disease [IBD] and celiac disease was performed at a tertiary referral institution in North America. Logistic regression and Kaplan-Meier curves compared disease characteristics and clinical outcomes of the two groups. RESULTS: A total of 342 inflammatory bowel disease patients were included in this study, of whom 114 had co-existent celiac disease and 228 did not. Patients with co-existent inflammatory bowel disease and celiac disease had higher rates of primary sclerosing cholangitis [19.3% vs 5.7%; odds ratio, 4.4; 95% confidence interval, 2.1-9.4; p <0.001], extensive ulcerative colitis [78.1% vs 59.0%; odds ratio, 2.8; 95% confidence interval, 1.5-5.5; p =0.002], and family history of celiac disease [10.5% vs 3.5%; odds ratio 3.2; 95% confidence interval, 1.3-8.2; p =0.01], compared with patients without concomitant celiac disease. CONCLUSIONS: Patients with inflammatory bowel disease with concomitant celiac disease have unique phenotypic features compared with non-celiac inflammatory bowel disease, with higher risks for colitis-related hospitalisations, extensive colitis, and primary sclerosing cholangitis. Increased recognition of co-existent IBD and celiac disease can prompt clinicians to investigate for concomitant disease sooner, particularly in patients with seemingly refractory disease.

A Case Series of the Probability Density and Cumulative Distribution of Laryngeal Disease in a Tertiary Care Voice Center.

OBJECTIVE: To examine the distribution of clinic and operative pathology in a tertiary care laryngology practice. METHODS: Probability density and cumulative distribution analyses (Pareto analysis) was used to rank order laryngeal conditions seen in an outpatient tertiary care laryngology practice and those requiring surgical intervention during a 3-year period. RESULTS: Among 3783 new clinic consultations and 1380 operative procedures, voice disorders were the most common primary diagnostic category seen in clinic (n = 3223), followed by airway (n = 374) and swallowing (n = 186) disorders. Within the voice strata, the most common primary ICD-9 code used was dysphonia (41%), followed by unilateral vocal fold paralysis (UVFP) (9%) and cough (7%). Among new voice patients, 45% were found to have a structural abnormality. The most common surgical indications were laryngotracheal stenosis (37%), followed by recurrent respiratory papillomatosis (18%) and UVFP (17%). CONCLUSIONS: Nearly 55% of patients presenting to a tertiary referral laryngology practice did not have an identifiable structural abnormality in the larynx on direct or indirect examination. The distribution of ICD-9 codes requiring surgical intervention was disparate from that seen in clinic. Application of the Pareto principle may improve resource allocation in laryngology, but these initial results require confirmation across multiple institutions.