Publications by authors named "Randall E Brand"

188 Publications

Timeline of development of pancreatic cancer and implications for successful early detection in high-risk individuals.

Gastroenterology 2021 Oct 19. Epub 2021 Oct 19.

Division of Gastroenterology, Johns Hopkins University School of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Baltimore, Maryland, United States of America.

Background And Aims: To successfully implement imaging-based pancreatic cancer (PC) surveillance, it is key to understand the timeline and morphological features of neoplastic progression. We aimed to investigate the progression to neoplasia from serial prediagnostic pancreatic imaging tests in high-risk individuals, and identify factors associated with successful early detection.

Methods: We retrospectively examined the development of pancreatic abnormalities in high-risk individuals who were diagnosed with PC and/or underwent pancreatic surgery in 16 international surveillance programs.

Results: Of 2552 high-risk individuals under surveillance, 28 (1%) developed neoplastic progression to PC or high-grade dysplasia during follow-up (median 29 months after baseline, IQR 40). 46% (13/28) presented with a new lesion (median size 15 mm, range 7-57), a median of 11 months (IQR 8, range 3-17) after a prior examination, by which time 77% (10/13) had progressed beyond the pancreas. The other 54% (15/28) had neoplastic progression in a previously detected lesion (12 originally cystic, 2 indeterminate, 1 solid); 11 (73%) had PC progressed beyond the pancreas. The 12 patients with cysts had been followed for 21 months (IQR 15) and had a median growth of 5 mm/year (IQR 8). Successful early detection (as high-grade dysplasia or PC confined to the pancreas) was associated with resection of cystic lesions (versus solid or indeterminate lesions, OR 5.388, 95%CI 1.525-19.029) and small lesions (OR 0.890/mm, 95%CI 0.812-0.976).

Conclusion: Nearly half of high-risk individuals developing high-grade dysplasia or PC have no prior lesions detected by imaging, yet present at an advanced stage. Progression can occur before the next scheduled annual examination. More sensitive diagnostic tools or a different management strategy for rapidly-growing cysts are needed.
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http://dx.doi.org/10.1053/j.gastro.2021.10.014DOI Listing
October 2021

Composite Score of Healthy Lifestyle Factors and the Risk of Pancreatic Cancer in a Prospective Cohort Study.

Cancer Prev Res (Phila) 2021 Oct 12. Epub 2021 Oct 12.

Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center.

While the associations between individual lifestyle factors and risk of pancreatic cancer were studied extensively, their combined impact has not been examined. We evaluated the association of a composite score of healthy lifestyle factors, including body mass index, cigarette smoking, the Alternative Healthy Eating Index-2010 (AHEI-2010), sleep duration, and physical activity with pancreatic cancer risk in the Singapore Chinese Health Study, an on-going prospective cohort study of 63,257 Chinese aged 45-74 at enrollment in 1993-1998 with up to 25 years of follow-up. Cox proportional hazard regression method was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) with adjustment for multiple potential confounders. We identified 316 incident pancreatic cancer cases among the cohort participants after a mean 17 years of follow-up. Individuals with higher composite scores representing healthier lifestyle were at significantly lower risk of pancreatic cancer. The multivariate-adjusted HRs (95% CIs) of pancreatic cancer incidence for the composite scores 2, 3, 4, 5, 6-7 were 0.60 (0.50-0.91), 0.48 (0.32-0.71), 0.45 (0.31-0.67), 0.41 (0.27-0.62) and 0.38 (0.24-0.62), respectively, compared with the scores 0-1 (Ptrend<0.0001). The inverse association was more apparent among participants without diabetes history and was robust in men and women as well as in alcohol drinkers and non-drinkers. In summary, the association for pancreatic cancer risk was stronger for the aggregated than individual healthy lifestyle factors. These findings suggest that a more comprehensive lifestyle modification strategy would be more effective for prevention of pancreatic cancer than the change of a single lifestyle factor.
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http://dx.doi.org/10.1158/1940-6207.CAPR-21-0205DOI Listing
October 2021

Serum biomarkers for chronic pancreatitis pain patterns.

Pancreatology 2021 Sep 30. Epub 2021 Sep 30.

Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Pittsburgh, PA, USA.

Objectives: Chronic pancreatitis (CP) is associated with debilitating refractory pain. Distinct subtypes of CP pain have been previously characterized based on severity (none, mild-moderate, severe) and temporal (none, intermittent, constant) nature of pain, but no mechanism-based tools are available to guide pain management. This exploratory study was designed to determine if potential pain biomarkers could be detected in patient serum and whether they associate with specific pain patterns.

Methods: Cytokines, chemokines, and peptides associated with nociception and pain were measured in legacy serum samples from CP patients (N = 99) enrolled in the North American Pancreatitis Studies. The unsupervised hierarchical cluster analysis was applied to cluster CP patients based on their biomarker profile. Classification and regression tree was used to assess whether these biomarkers can predict pain outcomes.

Results: The hierarchical cluster analysis revealed a subset of patients with predominantly constant, mild-moderate pain exhibited elevated interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP1) whereas patients with higher interleukin-4 (IL-4), interleukin-8 (IL-8) and calcitonin gene related peptide (CGRP) were more likely to have severe pain. Interestingly, analyses of each individual biomarker revealed that patients with constant pain had reduced circulating TNFα and fractalkine. Patients with severe pain exhibited a significant reduction in TNFα as well as trends towards lower levels of IL-6 and substance P.

Discussion: The observations from this study indicate that unique pain experiences within the chronic pancreatitis population can be associated with distinct biochemical signatures. These data indicate that further hypothesis-driven analyses combining biochemical measurements and detailed pain phenotyping could be used to develop precision approaches for pain management in patients with chronic pancreatitis.
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http://dx.doi.org/10.1016/j.pan.2021.09.016DOI Listing
September 2021

Quality Diet Index and Risk of Pancreatic Cancer: Findings from the Singapore Chinese Health Study.

Cancer Epidemiol Biomarkers Prev 2021 Aug 26. Epub 2021 Aug 26.

UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.

Background: Limited research has been conducted on the effect of quality diet index (QDI), which represents a comprehensive assessment of healthy diet quality and quantity, on pancreatic cancer risk in Asian populations.

Methods: Using data from the Singapore Chinese Health Study, a prospective cohort of 63,257 middle-aged or older Chinese men and women, four QDI scores: the Alternative Health Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED), the Dietary Approaches to Stop Hypertension (DASH), and the Heathy Diet Indicator (HDI), at baseline were calculated. After 25 years of follow-up, 311 cohort participants developed pancreatic cancer. Cox proportional hazard regression method was used to estimate HR and 95% confidence interval (CI) for pancreatic cancer associated with higher QDI scores.

Results: Higher scores of AHEI-2010, aMED, and DASH were significantly associated with lower pancreatic cancer risk (all < 0.05). Compared with the lowest quartile, HRs (95% CIs) of pancreatic cancer for the highest quartiles of AHEI-2010, aMED, and DASH scores were 0.65 (0.46-0.90), 0.57 (0.38-0.85), and 0.66 (0.46-0.95), respectively. These associations were more apparent among men. Overall, there was no statistically significant difference in the QDI-pancreatic cancer risk association between subgroups stratified by levels of body mass index, history of diabetes, and smoking status.

Conclusions: Higher QDI scores were significantly associated with reduced risk of pancreatic cancer.

Impact: The consistent results across multiple QDIs shows that adherence to a healthy diet may lower pancreatic cancer risk, suggesting that dietary modification may be a promising approach for primary prevention of pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0033DOI Listing
August 2021

Threshold Analysis of the Cost-effectiveness of Endoscopic Ultrasound in Patients at High Risk for Pancreatic Ductal Adenocarcinoma.

Pancreas 2021 07;50(6):807-814

Division of Digestive and Liver Diseases, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY.

Objectives: Data from the International Cancer of the Pancreas Screening Consortium studies have demonstrated that screening for pancreatic ductal adenocarcinoma can be effective and that surveillance improves survival in high-risk individuals. Endoscopic ultrasound (EUS) and cross-sectional imaging are both used, although there is some suggestion that EUS is superior. Demonstration of the cost-effectiveness of screening is important to implement screening in high-risk groups.

Methods: Results from centers with EUS-predominant screening were pooled to evaluate efficacy of index EUS in screening. A decision analysis model simulated the outcome of high-risk patients who undergo screening and evaluated the parameters that would make screening cost-effective at a US $100,000 per quality-adjusted life-year willingness to pay.

Results: One-time index EUS has a sensitivity of 71.25% and specificity of 99.82% to detection to detect high-risk lesions. Screening with index EUS was cost-effective, particularly at lifetime pancreatic cancer probabilities of greater than 10.8%, or at lower probabilities if life expectancy after resection of a lesion that was at least 16 years, and if missed, lesion rates on index EUS are 5% or less.

Conclusions: Pancreatic cancer screening can be cost-effective through index EUS, particularly for those individuals at high-lifetime risk of cancer.
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http://dx.doi.org/10.1097/MPA.0000000000001835DOI Listing
July 2021

Lifetime smoking history and cohort-based smoking prevalence in chronic pancreatitis.

Pancreatology 2021 May 29. Epub 2021 May 29.

Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Background/objective: Smoking prevalence in patients with chronic pancreatitis [CP] is high. We aimed to understand lifetime history of smoking and cohort trends in CP patients to inform effective strategies for smoking cessation.

Method: Data on 317 CP patients from the North American Pancreatitis Study 2 [NAPS2] Continuation and Validation Study and the NAPS2 Ancillary Study were analyzed. Smoking history was assessed for each phase of life from the onset of smoking to study enrollment. Data on second-hand smoke and drinking history were also collected. We compared demographic factors, drinking history, pain level and pancreas morphology by smoking status at age 25 (non-smoking, <1 pack per day [PPD], ≥1 PPD). We compared smoking prevalence by birth cohorts: 1930-1949, 1950-1969, 1970-1989.

Result: Fifty-one percent of CP patients reported smoking at the time of enrollment. Those who smoked ≥1 PPD at age 25 smoked a cumulative total of 30.3 pack-years of cigarettes over a lifetime. Smoking at age 25 was associated with greater lifetime drinking and greater exposure to second-hand smoke at home and at workplace. Pancreatic atrophy and pseudocysts were more common among smokers. Pancreatic pain was more severe among smokers, and 12-13% of smokers reported smoking to alleviate pain. Male CP patients born in 1950-1969 reported the highest peak prevalence of smoking, and female CP patients born in 1970-1989 reported highest peak prevalence of smoking.

Conclusion: CP patients exhibit intense and sustained smoking behavior once established in the 20s. Regardless, cohort analyses demonstrate that the behaviors could potentially be altered by policy changes.
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http://dx.doi.org/10.1016/j.pan.2021.05.302DOI Listing
May 2021

COVID-19 related pancreatic cancer surveillance disruptions amongst high-risk individuals.

Pancreatology 2021 Apr 20. Epub 2021 Apr 20.

The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA. Electronic address:

Background: COVID-19 pandemic-related disruptions to EUS-based pancreatic cancer surveillance in high-risk individuals remain uncertain.

Methods: Analysis of enrolled participants in the CAPS5 Study, a prospective multicenter study of pancreatic cancer surveillance in high-risk individuals.

Results: Amongst 693 enrolled high-risk individuals under active surveillance, 108 (16%) had an EUS scheduled during the COVID-19 pandemic-related shutdown (median length of 78 days) in the spring of 2020, with 97% of these procedures being canceled. Of these canceled surveillance EUSs, 83% were rescheduled in a median of 4.1 months, however 17% were not rescheduled after 6 months follow-up. Prior history of cancer was associated with increased likelihood of rescheduling. To date no pancreatic cancer has been diagnosed among those whose surveillance was delayed.

Conclusions: COVID-19 delayed pancreatic cancer surveillance with no adverse outcomes in efficiently rescheduled individuals. However, 1 in 6 high-risk individuals had not rescheduled surveillance, indicating the need for vigilance to ensure timely surveillance rescheduling.
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http://dx.doi.org/10.1016/j.pan.2021.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055495PMC
April 2021

Plasma miRNA Biomarkers in Limited Volume Samples for Detection of Early-stage Pancreatic Cancer.

Cancer Prev Res (Phila) 2021 Jul 23;14(7):729-740. Epub 2021 Apr 23.

Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Early detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes; however, PDAC is usually diagnosed late. Therefore, blood-based minimally invasive biomarker assays for limited volume clinical samples are urgently needed. A novel miRNA profiling platform (Abcam Fireplex-Oncology Panel) was used to investigate the feasibility of developing early detection miRNA biomarkers with 20 μL plasma from a training set (58 stage II PDAC cases and 30 controls) and two validation sets (34 stage II PDAC cases and 25 controls; 44 stage II PDAC cases and 18 controls). miR-34a-5p [AUC = 0.77; 95% confidence interval (CI), 0.66-0.87], miR-130a-3p (AUC = 0.74; 95% CI, 0.63-0.84), and miR-222-3p (AUC = 0.70; 95% CI, 0.58-0.81) were identified as significantly differentially abundant in plasma from stage II PDAC versus controls. Although none of the miRNAs individually outperformed the currently used serologic biomarker for PDAC, carbohydrate antigen 19-9 (CA19-9), combining the miRNAs with CA 19-9 improved AUCs from 0.89 (95% CI, 0.81-0.95) for CA 19-9 alone to 0.92 (95% CI, 0.86-0.97), 0.94 (95% CI, 0.89-0.98), and 0.92 (95% CI, 0.87-0.97), respectively. Gene set enrichment analyses of transcripts correlated with high and low expression of the three miRNAs in The Cancer Genome Atlas PDAC sample set. These miRNA biomarkers, assayed in limited volume plasma together with CA19-9, discriminate stage II PDAC from controls with good sensitivity and specificity. Unbiased profiling of larger cohorts should help develop an informative early detection biomarker assay for diagnostic settings. PREVENTION RELEVANCE: Development of minimally invasive biomarker assays for detection of premalignant disease and early-stage pancreatic cancer is key to improving patient survival. This study describes a limited volume plasma miRNA biomarker assay that can detect early-stage resectable pancreatic cancer in clinical samples necessary for effective prevention and clinical intervention.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0303DOI Listing
July 2021

DNA mismatch repair-deficient non-neoplastic endometrial glands are common in Lynch syndrome patients and are present at a higher density than in the colon.

Histopathology 2021 Oct 15;79(4):573-583. Epub 2021 Jun 15.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Aims: The hallmark of Lynch syndrome (LS) is DNA mismatch repair protein (MMR) deficiency. Recently, MMR deficiency in non-neoplastic colonic crypts has been identified as a novel indicator of LS. We aimed to determine whether MMR-deficient non-neoplastic endometrial glands can distinguish patients with and without LS, and to compare the level of MMR deficiency in the normal endometrium and colon in LS patients.

Methods And Results: We evaluated the immunohistochemical expression of MMR proteins in the normal endometrial mucosa from 64 patients, including 34 patients with confirmed LS (17 with endometrial cancer and 17 without cancer), 30 patients with endometrial cancer without LS (10 with tumours with MLH1 promoter hypermethylation and 20 with MMR-proficient tumours), and in the normal colonic mucosa from 30 LS patients. MMR-deficient non-neoplastic endometrial glands were identified in 47% of LS patients and in no patients without LS (P < 0.001). MMR-deficient non-neoplastic glands were more often identified in LS patients with endometrial cancer (65%) than in those without endometrial cancer (29%) (P = 0.04). In contrast to what was seen in the normal colon, MMR-deficient glands in the normal endometrium were seen as large, contiguous groups, ranging in number from two to 101 (87% versus 45%, P = 0.02). MMR-deficient glands were identified at a higher density in the endometrium than in the colon in LS patients (median number of MMR-deficient glands, 22 versus two, P = 0.02).

Conclusions: Our findings indicate that MMR-deficient non-neoplastic endometrial glands constitute an indicator of LS, and that MMR-deficient glands in the endometrium are present in a pattern of contiguous large groups.
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http://dx.doi.org/10.1111/his.14386DOI Listing
October 2021

Natural course of pain in chronic pancreatitis is independent of disease duration.

Pancreatology 2021 Apr 2;21(3):649-657. Epub 2021 Feb 2.

Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address:

Objectives: Pain burn-out during the course of chronic pancreatitis (CP), proposed in the 1980s, remains controversial, and has clinical implications. We aimed to describe the natural course of pain in a well-characterized cohort.

Methods: We constructed the clinical course of 279 C P patients enrolled from 2000 to 2014 in the North American Pancreatitis Studies from UPMC by retrospectively reviewing their medical records (median observation period, 12.4 years). We assessed abdominal pain at different time points, characterized pain pattern (Type A [short-lived pain episodes] or B [persistent pain and/or clusters of recurrent severe pain]) and recorded information on relevant covariates.

Results: Pain at any time, at the end of follow-up, Type A pain pattern or B pain pattern was reported by 89.6%, 46.6%, 34% and 66% patients, respectively. In multivariable analyses, disease duration (time from first diagnosis of pancreatitis to end of observation) did not associate with pain - at last clinical contact (OR, 1.0, 95% CI 0.96-1.03), at NAPS2 enrollment (OR 1.02, 95% CI 0.96-1.07) or Type B pain pattern (OR 1.01, 95% CI 0.97-1.04). Patients needing endoscopic or surgical therapy (97.8 vs. 75.2%, p < 0.001) and those with alcohol etiology (94.7 vs. 84.9%, p = 0.007) had a higher prevalence of pain. In multivariable analyses, invasive therapy associated with Type B pain and pain at last clinical contact.

Conclusions: Only a subset of CP patients achieve durable pain relief. There is urgent need to develop new strategies to evaluate and manage pain, and to identify predictors of response to pain therapies for CP.
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http://dx.doi.org/10.1016/j.pan.2021.01.020DOI Listing
April 2021

Tofacitinib inhibits inflammatory cytokines from ulcerative colitis and healthy mucosal explants and is associated with pSTAT1/3 reduction in T-cells.

Am J Physiol Gastrointest Liver Physiol 2021 03 23;320(3):G396-G410. Epub 2020 Dec 23.

University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Poor translatability of animal disease models has hampered the development of new inflammatory bowel disorder (IBD) therapeutics. We describe a preclinical, ex vivo system using freshly obtained and well-characterized human colorectal tissue from patients with ulcerative colitis (UC) and healthy control (HC) participants to test potential therapeutics for efficacy and target engagement, using the JAK/STAT inhibitor tofacitinib (TOFA) as a model therapeutic. Colorectal biopsies from HC participants and patients with UC were cultured and stimulated with multiple mitogens ± TOFA. Soluble biomarkers were detected using a 29-analyte multiplex ELISA. Target engagement in CD3CD4 and CD3CD8 T-cells was determined by flow cytometry in peripheral blood mononuclear cells (PBMCs) and isolated mucosal mononuclear cells (MMCs) following the activation of STAT1/3 phosphorylation. Data were analyzed using linear mixed-effects modeling, test, and analysis of variance. Biomarker selection was performed using penalized and Bayesian logistic regression modeling, with results visualized using uniform manifold approximation and projection. Under baseline conditions, 27 of 29 biomarkers from patients with UC were increased versus HC participants. Explant stimulation increased biomarker release magnitude, expanding the dynamic range for efficacy and target engagement studies. Logistic regression analyses identified the most representative UC baseline and stimulated biomarkers. TOFA inhibited biomarkers dependent on JAK/STAT signaling. STAT1/3 phosphorylation in T-cells revealed compartmental differences between PBMCs and MMCs. Immunogen stimulation increases biomarker release in similar patterns for HC participants and patients with UC, while enhancing the dynamic range for pharmacological effects. This work demonstrates the power of ex vivo human colorectal tissue as preclinical tools for evaluating target engagement and downstream effects of new IBD therapeutic agents. Using colorectal biopsy material from healthy volunteers and patients with clinically defined IBD supports translational research by informing the evaluation of therapeutic efficacy and target engagement for the development of new therapeutic entities. Combining experimental readouts from intact and dissociated tissue enhances our understanding of the tissue-resident immune system that contribute to disease pathology. Bayesian logistic regression modeling is an effective tool for predicting ex vivo explant biomarker release patterns.
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http://dx.doi.org/10.1152/ajpgi.00383.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202239PMC
March 2021

Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma Exhibit Differential Growth and Metabolic Patterns in the Pre-Diagnostic Period: Implications for Early Detection.

Front Oncol 2020 2;10:596931. Epub 2020 Dec 2.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Background: Previously, we characterized subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed-tomography (CT) scans, whereby conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we hypothesized that these imaging-based subtypes would exhibit different growth-rates and distinctive metabolic effects in the period prior to PDAC diagnosis.

Materials And Methods: Retrospectively, we evaluated 55 patients who developed PDAC as a second primary cancer and underwent serial pre-diagnostic (T0) and diagnostic (T1) CT-scans. We scored the PDAC tumors into high and low delta on T1 and, serially, obtained the biaxial measurements of the pancreatic lesions (T0-T1). We used the Gompertz-function to model the growth-kinetics and estimate the tumor growth-rate constant (α) which was used for tumor binary classification, followed by cross-validation of the classifier accuracy. We used maximum-likelihood estimation to estimate initiation-time from a single cell (10 mm) to a 10 mm tumor mass. Finally, we serially quantified the subcutaneous-abdominal-fat (SAF), visceral-abdominal-fat (VAF), and muscles volumes (cm) on CT-scans, and recorded the change in blood glucose (BG) levels. T-test, likelihood-ratio, Cox proportional-hazards, and Kaplan-Meier were used for statistical analysis and p-value <0.05 was considered significant.

Results: Compared to high delta tumors, low delta tumors had significantly slower average growth-rate constants (0.024 month vs. 0.088 month, p<0.0001) and longer average initiation-times (14 years vs. 5 years, p<0.0001). α demonstrated high accuracy (area under the curve (AUC)=0.85) in classifying the tumors into high and low delta, with an optimal cut-off of 0.034 month. Leave-one-out-cross-validation showed 80% accuracy in predicting the delta-class (AUC=0.84). High delta tumors exhibited accelerated SAF, VAF, and muscle wasting (p <0.001), and BG disturbance (p<0.01) compared to low delta tumors. Patients with low delta tumors had better PDAC-specific progression-free survival (log-rank, p<0.0001), earlier stage tumors (p=0.005), and higher likelihood to receive resection after PDAC diagnosis (p=0.008), compared to those with high delta tumors.

Conclusion: Imaging-based subtypes of PDAC exhibit distinct growth, metabolic, and clinical profiles during the pre-diagnostic period. Our results suggest that heterogeneous disease biology may be an important consideration in early detection strategies for PDAC.
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http://dx.doi.org/10.3389/fonc.2020.596931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738633PMC
December 2020

Tumor Size Differences Between Preoperative Endoscopic Ultrasound and Postoperative Pathology for Neoadjuvant-Treated Pancreatic Ductal Adenocarcinoma Predict Patient Outcome.

Clin Gastroenterol Hepatol 2020 Dec 3. Epub 2020 Dec 3.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Background & Aims: The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response.

Methods: For 340 treatment-naïve and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis.

Results: Among treatment-naïve PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8 edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using a ≥47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥47% was an independent prognostic factor for improved OS (P = .007).

Conclusions: The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management.
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http://dx.doi.org/10.1016/j.cgh.2020.11.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407441PMC
December 2020

Significance of Uncinate Duct Dilatation in IPMNs: A New High-risk Criterion?

Ann Surg 2020 Nov 12. Epub 2020 Nov 12.

Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.

Objective: To evaluate the significance of UDD in IPMNs.

Background: The uncinate process of the pancreas has an independent ductal drainage system. International consensus guidelines of IPMNs still consider it as a branch-duct, even though it is the main drainage system for the uncinate process.

Methods: A retrospective review of all surgically treated IPMNs at our institution after 2008 was performed. Preoperative radiological studies were reviewed by an abdominal radiologist who was blinded to the pathological results. In addition to the Fukuoka criteria, presence of UDD was recorded. Using multivariate analysis, the pathological significance of UDD in predicting advanced neoplasia [high grade dysplasia or invasive carcinoma (HGD/IC)] was determined.

Results: Two hundred sixty patients were identified (mean age at diagnosis was 68 years and 49% were females): 122 (47%) had HGD/IC. UDD was noted in 59 (23%), of which 36 (61%) had HGD/IC (P < 0.003). On multivariate analysis, UDD was an independent predictor of HGD/IC (odds ratio = 2.99, P < 0.04). Subgroup analysis on patients with IPMNs confined to the dorsal portion of the gland (n = 161), also demonstrated UDD to be a significant predictor of HGD/IC in those remote lesions (odds ratio: 4.41, P = 0.039).

Conclusions: This is the largest study to evaluate the significance of UDD in IPMNs and shows it to be a high-risk feature. This association persisted for remote IPMNs limited to the dorsal pancreas, suggesting UDD may be associated with an aggressive phenotype even in remote IPMN lesions.
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http://dx.doi.org/10.1097/SLA.0000000000004307DOI Listing
November 2020

Divergent trends in lifetime drinking and smoking between Black and White Americans diagnosed with chronic pancreatitis.

Pancreatology 2020 Dec 12;20(8):1667-1672. Epub 2020 Oct 12.

Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Background/objectives: Black Americans are at increased risk of chronic pancreatitis (CP) compared to their White counterparts. We aimed to describe the race-specific smoking history and lifetime drinking in patients diagnosed with CP.

Methods: We analyzed data on 334 Black and White CP participants of the North American Pancreatitis Study 2 Continuation and Validation Study and Ancillary Study. Lifetime drinking history and lifetime smoking history were collected through in-person interviews. Intensity, frequency, duration and current status of drinking and smoking were compared between Black and White CP participants, stratified by physician-defined alcohol etiology. In addition, drinking levels at each successive decades in life (20s, 30s, 40s) were compared by race and graphically portrayed as heat diagrams.

Results: Among patients with alcoholic CP, current smoking levels were not different by race (67-70%), but a smaller proportion of Black patients reported having smoked 1 or more packs per day in the past (32%) as compared to White patients (58%, p < 0.0001). Black patients were more likely to report current consumption of alcohol (31%), as opposed to White patients (17%, p = 0.016). Black patients also reported more intense drinking at age 35 and 45 years as compared to White patients, while age at CP onset were similar between the two groups.

Conclusion: We found more intense drinking but less intense smoking history in Black CP patients as compared to White CP patients. Effective alcohol abstinence and smoking cessation program with sustained impact are needed in CP patients.
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http://dx.doi.org/10.1016/j.pan.2020.10.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737506PMC
December 2020

Phenotypic Differences in Juvenile Polyposis Syndrome With or Without a Disease-causing / Variant.

Cancer Prev Res (Phila) 2021 02 23;14(2):215-222. Epub 2020 Oct 23.

Hospital of the University of Pennsylvania and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Juvenile polyposis syndrome (JPS) is a clinically diagnosed hamartomatous polyposis syndrome that increases the risk of gastrointestinal cancer. Approximately 40%-50% of JPS is caused by a germline disease-causing variant (DCV) in the or genes. The aim of this study was to characterize the phenotype of DCV-negative JPS and compare it with DCV-positive JPS. Herein, we analyzed a cohort of 145 individuals with JPS from nine institutions, including both pediatric and adult centers. Data analyzed included age at diagnosis, family history, cancer history, need for colectomy/gastrectomy, and polyp number and location. Compared with DCV-positive JPS, DCV-negative JPS was associated with younger age at diagnosis ( < 0.001), lower likelihood of having a family history of JPS ( < 0.001), and a lower risk of colectomy ( = 0.032). None of the DCV-negative individuals had gastric or duodenal polyps, and polyp burden decreased after the first decade compared with DCV-positive JPS. Subgroup analysis between and carriers showed that carriers were more likely to have a family history of JPS and required gastrectomy. Taken together, these data provide the largest phenotypic characterization of individuals with DCV-negative JPS to date, showing that this group has distinct differences compared with JPS due to a or variant. Better understanding of phenotype and cancer risk associated with JPS both with and without a DCV may ultimately allow for individualized management of polyposis and cancer risk. Juvenile Polyposis Syndrome (JPS) is a gastrointestinal cancer predisposition syndrome requiring lifelong surveillance, however there is limited data comparing individuals with and without a germline disease-causing variant in or Herein we show that individuals with JPS without an underlying disease-causing variant have distinct phenotypic differences including lack of upper gastrointestinal polyps and lower rates of a family history of JPS, suggesting that a different approach to management may be appropriate in this population.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0348DOI Listing
February 2021

Detection of Chemotherapy-resistant Pancreatic Cancer Using a Glycan Biomarker, sTRA.

Clin Cancer Res 2021 01 22;27(1):226-236. Epub 2020 Oct 22.

Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, Michigan.

Purpose: A subset of pancreatic ductal adenocarcinomas (PDACs) is highly resistant to systemic chemotherapy, but no markers are available in clinical settings to identify this subset. We hypothesized that a glycan biomarker for PDACs called sialylated tumor-related antigen (sTRA) could be used for this purpose.

Experimental Design: We tested for differences between PDACs classified by glycan expression in multiple systems: sets of cell lines, organoids, and isogenic cell lines; primary tumors; and blood plasma from human subjects.

Results: The sTRA-expressing models tended to have stem-like gene expression and the capacity for mesenchymal differentiation, in contrast to the nonexpressing models. The sTRA cell lines also had significantly increased resistance to seven different chemotherapeutics commonly used against pancreatic cancer. Patients with primary tumors that were positive for a gene expression classifier for sTRA received no statistically significant benefit from adjuvant chemotherapy, in contrast to those negative for the signature. In another cohort, based on direct measurements of sTRA in tissue microarrays, the patients who were high in sTRA again had no statistically significant benefit from adjuvant chemotherapy. Furthermore, a blood plasma test for the sTRA glycan identified the PDACs that showed rapid relapse following neoadjuvant chemotherapy.

Conclusions: This research demonstrates that a glycan biomarker could have value to detect chemotherapy-resistant PDAC in clinical settings. This capability could aid in the development of stratified treatment plans and facilitate biomarker-guided trials targeting resistant PDAC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785673PMC
January 2021

Low serum trypsinogen levels in chronic pancreatitis: Correlation with parenchymal loss, exocrine pancreatic insufficiency, and diabetes but not CT-based cambridge severity scores for fibrosis.

Pancreatology 2020 Oct 5;20(7):1368-1378. Epub 2020 Sep 5.

Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Cell Biology and Molecular Physiology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Background: Chronic pancreatitis (CP) is a complex inflammatory disorder of the pancreas affecting acinar cells, duct cells, islet cells and inflammatory cells including fibrosis-producing stellate cells. Serum trypsinogen is a biomarkers of acinar cell function.

Aim: To define the degree of correlation between low trypsinogen levels as a marker of acinar cell function and variable features of CP.

Methods: Serum samples from previously ascertained and well phenotyped case and control subjects from the North American Pancreatitis Study II (NAPS2) were used to measure serum trypsinogen levels in a commercial laboratory. Control samples were used to define normal ranges and compared with levels in CP patients with defined features.

Results: A final cohort of 279 CP patients and 262 controls from the NAPS2 studies were evaluated. In controls trypsinogen had a mean of 34.96 ng/ml and SD = 11.99. Cut-off values for low trypsinogen ranged from <20 to 10 ng/ml and very low trypsinogen at <10 ng/ml. Compared to controls, CP was associated with very low trypsinogen levels (p < 0.0001). Within CP, very low trypsinogen levels correlated with parenchymal loss (pancreatic surgery [p < 0.05]; atrophy with calcifications, [p < 0.001]), EPI (p < 0.01, trend p < 0.001) and diabetes (trend p < 0.01) but not CT-based criteria for fibrosis (pancreatic duct dilation, irregularity, strictures).

Conclusions: Very low serum trypsinogen levels correlate with measures of acinar cell loss including surgical resection, atrophic-calcific CP, diabetes and functional symptoms EPI but not duct morphology criteria. Serum trypsinogen levels correlate with decreased acinar cell function and therefore have biomarker utility clinical management.
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http://dx.doi.org/10.1016/j.pan.2020.08.025DOI Listing
October 2020

Bone health assessment in clinical practice is infrequenty performed in patients with chronic pancreatitis.

Pancreatology 2020 Sep 25;20(6):1109-1114. Epub 2020 Jul 25.

Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address:

Background: Chronic pancreatitis (CP) patients have a high prevalence of osteoporotic fractures. In addition to prevalence of osteoporotic fractures, we evaluated how often bone health is assessed by dual-energy x-ray absorptiometry (DXA) in clinical practice, and the performance of Fracture Risk Assessment Tool (FRAX®) in predicting fracture risk in CP patients.

Methods: Medical records of CP patients age ≥40 years prospectively enrolled in the North American Pancreatitis Study 2 (NAPS2) from the University of Pittsburgh Medical Center from 2000 to 2014 were retrospectively reviewed to gather additional relevant data before, at, and after enrollment until December 2016. We determined if patients underwent DXA, compared their observed prevalence of fractures with published data from two large US studies based on administrative data, and their predicted fracture risk with US population based on FRAX®.

Results: Only 21% (49/239) patients were evaluated by DXA during their care. The observed cumulative prevalence of fragility fractures in NAPS2 CP patients (9.2%, 95% confidence interval 5.9-13.6) was significantly greater than in controls (1.46% and 2.16%, p ≤ 0.001 for each comparison) and CP patients (4.66%, and 5.13%, p < 0.005 for each comparison) in the two US administrative data studies. The FRAX® 10-year probability of major osteoporotic fracture of ≥20% (5.1% vs. 8.3%, p > 0.05) and for hip fracture of ≥3% (19.6% vs. 18.9%, p > 0.05) in NAPS2 CP patients did not differ from the US population.

Conclusions: Despite their high risk of fragility fractures, bone health is infrequently assessed in CP patients. FRAX® may not adequately predict fracture risk in CP patients.
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http://dx.doi.org/10.1016/j.pan.2020.07.396DOI Listing
September 2020

International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

Pancreatology 2020 Jul 31;20(5):910-918. Epub 2020 May 31.

Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. Electronic address:

Background: Patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer. We present the international consensus guidelines for surveillance of pancreatic cancer in CP.

Methods: The international group evaluated 10 statements generated from evidence on 5 questions relating to pancreatic cancer in CP. The GRADE approach was used to evaluate the level of evidence available per statement. The working group voted on each statement for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient.

Results: In the following domains there was strong consensus: (1) the risk of pancreatic cancer in affected individuals with hereditary pancreatitis due to inherited PRSS1 mutations is high enough to justify surveillance; (2) the risk of pancreatic cancer in patients with CP associated with SPINK1 p. N34S is not high enough to justify surveillance; (3) surveillance should be undertaken in pancreatic specialist centers; (4) surveillance should only be introduced after the age of 40 years and stopped when the patient would no longer be suitable for surgical intervention. All patients with CP should be advised to lead a healthy lifestyle aimed at avoiding risk factors for progression of CP and pancreatic cancer. There was only moderate or weak agreement on the best methods of screening and surveillance in other types of environmental, familial and genetic forms of CP.

Conclusions: Patients with inherited PRSS1 mutations should undergo surveillance for pancreatic cancer, but the best methods for cancer detection need further investigation.
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http://dx.doi.org/10.1016/j.pan.2020.05.011DOI Listing
July 2020

Systemic Proteome Alterations Linked to Early Stage Pancreatic Cancer in Diabetic Patients.

Cancers (Basel) 2020 Jun 11;12(6). Epub 2020 Jun 11.

Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

Background: Diabetes is a risk factor associated with pancreatic ductal adenocarcinoma (PDAC), and new adult-onset diabetes can be an early sign of pancreatic malignancy. Development of blood-based biomarkers to identify diabetic patients who warrant imaging tests for cancer detection may represent a realistic approach to facilitate earlier diagnosis of PDAC in a risk population.

Methods: A spectral library-based proteomic platform was applied to interrogate biomarker candidates in plasma samples from clinically well-defined diabetic cohorts with and without PDAC. Random forest algorithm was used for prediction model building and receiver operating characteristic (ROC) curve analysis was applied to evaluate the prediction probability of potential biomarker panels.

Results: Several biomarker panels were cross-validated in the context of detection of PDAC within a diabetic background. In combination with carbohydrate antigen 19-9 (CA19-9), the panel, which consisted of apolipoprotein A-IV (APOA4), monocyte differentiation antigen CD14 (CD14), tetranectin (CLEC3B), gelsolin (GSN), histidine-rich glycoprotein (HRG), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), plasma kallikrein (KLKB1), leucine-rich alpha-2-glycoprotein (LRG1), pigment epithelium-derived factor (SERPINF1), plasma protease C1 inhibitor (SERPING1), and metalloproteinase inhibitor 1 (TIMP1), demonstrated an area under curve (AUC) of 0.85 and a two-fold increase in detection accuracy compared to CA19-9 alone. The study further evaluated the correlations of protein candidates and their influences on the performance of biomarker panels.

Conclusions: Proteomics-based multiplex biomarker panels improved the detection accuracy for diagnosis of early stage PDAC in diabetic patients.
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http://dx.doi.org/10.3390/cancers12061534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352938PMC
June 2020

Biomarkers and Strategy to Detect Preinvasive and Early Pancreatic Cancer: State of the Field and the Impact of the EDRN.

Cancer Epidemiol Biomarkers Prev 2020 12 12;29(12):2513-2523. Epub 2020 Jun 12.

Van Andel Institute, Grand Rapids, Michigan.

Patients afflicted with pancreatic ductal adenocarcinoma (PDAC) face a dismal prognosis, but headway could be made if physicians could identify the disease earlier. A compelling strategy to broaden the use of surveillance for PDAC is to incorporate molecular biomarkers in combination with clinical analysis and imaging tools. This article summarizes the components involved in accomplishing biomarker validation and an analysis of the requirements of molecular biomarkers for disease surveillance. We highlight the significance of consortia for this research and highlight resources and infrastructure of the Early Detection Research Network (EDRN). The EDRN brings together the multifaceted expertise and resources needed for biomarker validation, such as study design, clinical care, biospecimen collection and handling, molecular technologies, and biostatistical analysis, and studies coming out of the EDRN have yielded biomarkers that are moving forward in validation. We close the article with an overview of the current investigational biomarkers, an analysis of their performance relative to the established benchmarks, and an outlook on the current needs in the field. The outlook for improving the early detection of PDAC looks promising, and the pace of further research should be quickened through the resources and expertise of the EDRN and other consortia.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710622PMC
December 2020

KRAS amplification in metastatic colon cancer is associated with a history of inflammatory bowel disease and may confer resistance to anti-EGFR therapy.

Mod Pathol 2020 09 6;33(9):1832-1843. Epub 2020 May 6.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Mutations in RAS occur in 30-50% of metastatic colorectal carcinomas (mCRCs) and correlate with resistance to anti-EGFR therapy. Consequently, mCRC biomarker guidelines state RAS mutational testing should be performed when considering EGFR inhibitor treatment. However, a small subset of mCRCs are reported to harbor RAS amplification. In order to elucidate the clinicopathologic features and anti-EGFR treatment response associated with RAS amplification, we retrospectively reviewed a large cohort of mCRC patients that underwent targeted next-generation sequencing and copy number analysis for KRAS, NRAS, HRAS, BRAF, and PIK3CA. Molecular testing was performed on 1286 consecutive mCRC from 1271 patients as part of routine clinical care, and results were correlated with clinicopathologic findings, mismatch repair (MMR) status and follow-up. RAS amplification was detected in 22 (2%) mCRCs and included: KRAS, NRAS, and HRAS for 15, 5, and 2 cases, respectively (6-21 gene copies). Patients with a KRAS-amplified mCRC were more likely to report a history of inflammatory bowel disease (p < 0.001). In contrast, mutations in KRAS were associated with older patient age, right-sided colonic origin, low-grade differentiation, mucinous histology, and MMR proficiency (p ≤ 0.017). Four patients with a KRAS-amplified mCRC and no concomitant RAS/BRAF/PIK3CA mutations received EGFR inhibitor-based therapy, and none demonstrated a clinicoradiographic response. The therapeutic impact of RAS amplification was further evaluated using a separate, multi-institutional cohort of 23 patients. Eight of 23 patients with KRAS-amplified mCRC received anti-EGFR therapy and all 8 patients exhibited disease progression on treatment. Although the number of KRAS-amplified mCRCs is limited, our data suggest the clinicopathologic features associated with mCRC harboring a KRAS amplification are distinct from those associated with a KRAS mutation. However, both alterations seem to confer EGFR inhibitor resistance and, therefore, RAS testing to include copy number analyses may be of consideration in the treatment of mCRC.
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http://dx.doi.org/10.1038/s41379-020-0560-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483889PMC
September 2020

Pattern of Invasion in Human Pancreatic Cancer Organoids Is Associated with Loss of SMAD4 and Clinical Outcome.

Cancer Res 2020 07 6;80(13):2804-2817. Epub 2020 May 6.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by extensive local invasion and systemic spread. In this study, we employed a three-dimensional organoid model of human pancreatic cancer to characterize the molecular alterations critical for invasion. Time-lapse microscopy was used to observe invasion in organoids from 25 surgically resected human PDAC samples in collagen I. Subsequent lentiviral modification and small-molecule inhibitors were used to investigate the molecular programs underlying invasion in PDAC organoids. When cultured in collagen I, PDAC organoids exhibited two distinct, morphologically defined invasive phenotypes, mesenchymal and collective. Each individual PDAC gave rise to organoids with a predominant phenotype, and PDAC that generated organoids with predominantly mesenchymal invasion showed a worse prognosis. Collective invasion predominated in organoids from cancers with somatic mutations in the driver gene (or its signaling partner ). Reexpression of SMAD4 abrogated the collective invasion phenotype in -mutant PDAC organoids, indicating that SMAD4 loss is required for collective invasion in PDAC organoids. Surprisingly, invasion in passaged -mutant PDAC organoids required exogenous TGFβ, suggesting that invasion in -mutant organoids is mediated through noncanonical TGFβ signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGFβ-stimulated invasion in -mutant PDAC organoids, as inhibition of these GTPases suppressed collective invasion in our model. These data suggest that PDAC utilizes different invasion programs depending on status, with collective invasion uniquely present in PDAC with SMAD4 loss. SIGNIFICANCE: Organoid models of PDAC highlight the importance of SMAD4 loss in invasion, demonstrating that invasion programs in -mutant and wild-type tumors are different in both morphology and molecular mechanism.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335355PMC
July 2020

Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis.

Nat Commun 2020 04 20;11(1):1899. Epub 2020 Apr 20.

Biomedical Optical Imaging Laboratory, Departments of Medicine and Bioengineering, University of Pittsburgh, Pittsburgh, PA, 15213, USA.

Genomic DNA is folded into a higher-order structure that regulates transcription and maintains genomic stability. Although progress has been made on understanding biochemical characteristics of epigenetic modifications in cancer, the in-situ higher-order folding of chromatin structure during malignant transformation remains largely unknown. Here, using optimized stochastic optical reconstruction microscopy (STORM) for pathological tissue (PathSTORM), we uncover a gradual decompaction and fragmentation of higher-order chromatin folding throughout all stages of carcinogenesis in multiple tumor types, and prior to tumor formation. Our integrated imaging, genomic, and transcriptomic analyses reveal functional consequences in enhanced transcription activities and impaired genomic stability. We also demonstrate the potential of imaging higher-order chromatin disruption to detect high-risk precursors that cannot be distinguished by conventional pathology. Taken together, our findings reveal gradual decompaction and fragmentation of higher-order chromatin structure as an enabling characteristic in early carcinogenesis to facilitate malignant transformation, which may improve cancer diagnosis, risk stratification, and prevention.
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http://dx.doi.org/10.1038/s41467-020-15718-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171144PMC
April 2020

Bizarre benign cells in peri-rectal endoscopic ultrasound-guided fine-needle aspiration due to seminal vesicle sampling.

Diagn Cytopathol 2020 Jun 19;48(6):586-588. Epub 2020 Mar 19.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States.

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http://dx.doi.org/10.1002/dc.24415DOI Listing
June 2020

Unusual Infection of the Small Intestine: Mycobacterium avium Complex.

Clin Gastroenterol Hepatol 2021 03 7;19(3):e26. Epub 2020 Feb 7.

Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1016/j.cgh.2020.01.043DOI Listing
March 2021

Detection of DNA mismatch repair deficient crypts in random colonoscopic biopsies identifies Lynch syndrome patients.

Fam Cancer 2020 04;19(2):169-175

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

The hallmark of Lynch syndrome (LS)-associated neoplasia is DNA mismatch repair protein (MMR) deficiency. Recent studies have demonstrated that histologically normal colonic crypts in patients with LS can exhibit deficient MMR expression. The aim of this study was to determine the feasibility of detecting MMR deficient crypts in random colonoscopic biopsies of normal mucosa in patients with and without LS. Forty-nine patients, including 33 with LS, 12 without LS, and 4 with germline MMR gene variants of uncertain significance (VUS), were prospectively and blindly evaluated by immunohistochemistry for MMR deficient crypts within random normal-appearing mucosal biopsies obtained during surveillance colonoscopy. MMR deficient crypts were identified in 70% (23/33) of patients with LS and in no patients without LS (0/12) (p < 0.001). MMR deficient crypts were identified with nearly equal frequency in both LS patients with and without a cancer history and were associated with germline variants in all four MMR genes and EPCAM. MMR deficient crypts were also identified in LS patients with a history of non-colorectal cancer types, including patients with endometrial cancer, skin sebaceous neoplasms, and renal cancer. Two of the four patients with germline MMR gene VUS had MMR deficient crypts. In conclusion, MMR deficient crypts are a specific biomarker of LS and can be identified in random normal mucosal biopsies in LS patients. Evaluation for MMR deficient crypts in colonoscopic biopsies of normal mucosa can help identify LS patients.
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http://dx.doi.org/10.1007/s10689-020-00161-wDOI Listing
April 2020
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