Imaging patterns from endoscopic ultrasound (EUS)-guided needle-based confocal laser endomicroscopy (nCLE) have been associated with specific pancreatic cystic lesions (PCLs). We compared the ...accuracy of EUS with nCLE in differentiating mucinous from nonmucinous PCLs with that of measurement of carcinoembryonic antigen (CEA) and cytology analysis.
We performed a prospective study of 144 consecutive patients with a suspected PCL (≥20 mm) who underwent EUS with fine-needle aspiration of pancreatic cysts from June 2015 through December 2018 at a single center; 65 patients underwent surgical resection. Surgical samples were analyzed by histology (reference standard). During EUS, the needle with the miniprobe was placed in the cyst, which was analyzed by nCLE. Fluid was aspirated and analyzed for level of CEA and by cytology. We compared the accuracy of nCLE in differentiating mucinous from nonmucinous lesions with that of measurement of CEA and cytology analysis.
The mean size of dominant cysts was 36.4 ± 15.7 mm and the mean duration of nCLE imaging was 7.3 ± 2.8 min. Among the 65 subjects with surgically resected cysts analyzed histologically, 86.1% had at least 1 worrisome feature based on the 2012 Fukuoka criteria. Measurement of CEA and cytology analysis identified mucinous PCLs with 74% sensitivity, 61% specificity, and 71% accuracy. EUS with nCLE identified mucinous PCLs with 98% sensitivity, 94% specificity, and 97% accuracy. nCLE was more accurate in classifying mucinous vs nonmucinous cysts than the standard method (P < .001). The overall incidence of postprocedure acute pancreatitis was 3.5% (5 of 144); all episodes were mild, based on the revised Atlanta criteria.
In a prospective study, we found that analysis of cysts by nCLE identified mucinous cysts with greater accuracy than measurement of CEA and cytology analysis. EUS with nCLE can be used to differentiate mucinous from nonmucinous PCLs. ClincialTrials.gov no: NCT02516488.
Type 1 autoimmune pancreatitis can be diagnosed by and is synonymous with its pathognomonic histopathologic appearance called lymphoplasmacytic sclerosing pancreatitis. Type 1 autoimmune ...pancreatitis, also called IgG4-related pancreatitis, is the pancreatic manifestation of IgG4-related disease. However, the role of IgG4 in the pathogenesis of IgG4-related disease is unclear. We describe patients with LPSP without serum or tissue IgG4 abnormalities. From the Mayo Clinic database of autoimmune pancreatitis patients, we identified three patients with histologically confirmed type 1 autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis) who had normal serum IgG4 and no increase in IgG4-positive plasma cells in tissue. We reviewed original clinical records and pathologic specimens, and describe the clinical and histologic features of these three patients. All patients (age/gender: 63/F, 70/M and 68/M) had normal serum IgG and IgG4 levels, and multiple sections of pancreatic histology did not show increased IgG4-positive plasma cells. Two patients were diagnosed retrospectively following pancreatic surgery, one relapsed in another organ and one has remained relapse free. Another patient was diagnosed by pancreatic core biopsy and has suffered multiple relapses that have been controlled by rituximab. These cases highlight the fact that although the currently agreed upon name for type 1 autoimmune pancreatitis is IgG4-related pancreatitis, serum and tissue IgG4 abnormalities are best considered characteristic, but not essential for the diagnosis of this enigmatic condition.
Pancreatic ductal adenocarcinoma (PDAC) is often accompanied by weight loss. We sought to characterize factors associated with weight loss and observed nutritional interventions, as well as define ...the effect of weight loss on survival.
Consecutive subjects diagnosed with PDAC (N = 123) were retrospectively evaluated. Univariate analysis was used to compare subjects with and without substantial (>5%) weight loss. Multivariate logistic regression was performed to identify factors associated with weight loss, and survival analyses were performed using Kaplan-Meier curves and Cox survival models.
Substantial weight loss at diagnosis was present in 71.5% of subjects and was independently associated with higher baseline body mass index, longer symptom duration, and increased tumor size. Recommendations for nutrition consultation and pancreatic enzyme replacement therapy occurred in 27.6% and 36.9% of subjects, respectively. Weight loss (>5%) was not associated with worse survival on multivariate analysis (hazard ratio, 1.32; 95% confidence interval, 0.76-2.30), unless a higher threshold (>10%) was used (hazard ratio, 1.77; 95% confidence interval, 1.09-2.87).
Despite the high prevalence of weight loss at PDAC diagnosis, there are low observed rates of nutritional interventions. Weight loss based on current criteria for cancer cachexia is not associated with poor survival in PDAC.
The diagnosis and management of exocrine pancreatic dysfunction (EPD) can be challenging. EPD classically results from conditions that cause loss of pancreatic acinar cell function and decreased ...digestive enzyme production. However, several conditions may contribute to signs or symptoms of EPD with otherwise normal pancreatic exocrine function. A thoughtful approach to considering these conditions, along with their specific therapies, can guide a tailored management approach.
An EPD severity classification schema has been proposed, which emphasizes a shift towards a more restrictive prescription of pancreas enzyme replacement therapy (PERT) for patients with milder EPD. In contrast, PERT use has been associated with a measurable survival benefit among individuals with EPD and pancreatic cancer, so the prescription of PERT may be more liberal in this population. Recent publications in the cystic fibrosis population offer pearls guiding the titration and optimization of PERT.
Among individuals with severe EPD, PERT is an effective therapy. Among individuals with milder EPD, although PERT is effective, there may be opportunities to provide additional and potentially more effective therapies.
The empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores assess the insulinemic and inflammatory potentials of habitual dietary patterns, ...irrespective of the macronutrient content, and are based on plasma insulin response or inflammatory biomarkers, respectively. The glycemic index (GI) and glycemic load (GL) assess postprandial glycemic potential based on dietary carbohydrate content. We tested the hypothesis that dietary patterns promoting hyperinsulinemia, chronic inflammation, or hyperglycemia may influence type 2 diabetes risk.
We calculated dietary scores from baseline (1993-1998) food frequency questionnaires among 73,495 postmenopausal women in the Women's Health Initiative, followed through March 2019. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% CIs for type 2 diabetes risk. We also estimated multivariable-adjusted absolute risk of type 2 diabetes.
During a median 13.3 years of follow-up, 11,009 incident cases of type 2 diabetes were diagnosed. Participants consuming the most hyperinsulinemic or proinflammatory dietary patterns experienced greater risk of type 2 diabetes; HRs (95% CI) comparing highest to lowest dietary index quintiles were EDIH 1.49 (1.32-1.68;
< 0.0001) and EDIP 1.45 (1.29-1.63;
< 0.0001). The absolute excess incidence for the same comparison was 220 (EDIH) and 271 (EDIP) cases per 100,000 person-years. GI and GL were not associated with type 2 diabetes risk: GI 0.99 (0.88-1.12;
= 0.46) and GL 1.01 (0.89-1.16;
= 0.30).
Our findings in this diverse cohort of postmenopausal women suggest that lowering the insulinemic and inflammatory potentials of the diet may be more effective in preventing type 2 diabetes than focusing on glycemic foods.
BackgroundA significant challenge to overcome in pancreatic ductal adenocarcinoma (PDAC) is the profound systemic immunosuppression that renders this disease non-responsive to immunotherapy. Our ...supporting data provide evidence that CD200, a regulator of myeloid cell activity, is expressed in the PDAC microenvironment. Additionally, myeloid-derived suppressor cells (MDSC) isolated from patients with PDAC express elevated levels of the CD200 receptor (CD200R). Thus, we hypothesize that CD200 expression in the PDAC microenvironment limits responses to immunotherapy by promoting expansion and activity of MDSC.MethodsImmunofluorescent staining was used to determine expression of CD200 in murine and human PDAC tissue. Flow cytometry was utilized to test for CD200R expression by immune populations in patient blood samples. In vivo antibody blocking of CD200 was conducted in subcutaneous MT-5 tumor-bearing mice and in a genetically engineered PDAC model (KPC-Brca2 mice). Peripheral blood mononuclear cells (PBMC) from patients with PDAC were analyzed by single-cell RNA sequencing. MDSC expansion assays were completed using healthy donor PBMC stimulated with IL-6/GM-CSF in the presence of recombinant CD200 protein.ResultsWe found expression of CD200 by human pancreatic cell lines (BxPC3, MiaPaca2, and PANC-1) as well as on primary epithelial pancreatic tumor cells and smooth muscle actin+ stromal cells. CD200R expression was found to be elevated on CD11b+CD33+HLA-DRlo/− MDSC immune populations from patients with PDAC (p=0.0106). Higher expression levels of CD200R were observed in CD15+ MDSC compared with CD14+ MDSC (p<0.001). In vivo studies demonstrated that CD200 antibody blockade limited tumor progression in MT-5 subcutaneous tumor-bearing and in KPC-Brca2 mice (p<0.05). The percentage of intratumoral MDSC was significantly reduced in anti-CD200 treated mice compared with controls. Additionally, in vivo blockade of CD200 can also significantly enhance the efficacy of PD-1 checkpoint antibodies compared with single antibody therapies (p<0.05). Single-cell RNA sequencing of PBMC from patients revealed that CD200R+ MDSC expressed genes involved in cytokine signaling and MDSC expansion. Further, in vitro cytokine-driven expansion and the suppressive activity of human MDSC was enhanced when cocultured with recombinant CD200 protein.ConclusionsThese results indicate that CD200 expression in the PDAC microenvironment may regulate MDSC expansion and that targeting CD200 may enhance activity of checkpoint immunotherapy.
Chronic pancreatitis (CP) causes an abdominal pain syndrome associated with poor quality of life. We conducted a clinical trial to further investigate the efficacy and safety of camostat, an oral ...serine protease inhibitor that has been used to alleviate pain in CP.
This was a double-blind randomized controlled trial that enrolled adults with CP with a baseline average daily worst pain score ≥4 on a numeric rating system. Participants were randomized (1:1:1:1) to receive camostat at 100, 200, or 300 mg 3 times daily or placebo. The primary end point was a 4-week change from baseline in the mean daily worst pain intensity score (0–10 on a numeric rating system) using a mixed model repeated measure analysis. Secondary end points included changes in alternate pain end points, quality of life, and safety.
A total of 264 participants with CP were randomized. Changes in pain from baseline were similar between the camostat groups and placebo, with differences of least squares means of –0.11 (95% CI, –0.90 to 0.68), –0.04 (95% CI, –0.85 to 0.78), and –0.11 (95% CI, –0.94 to 0.73) for the 100 mg, 200 mg, and 300 mg groups, respectively. Multiple subgroup analyses were similar for the primary end point, and no differences were observed in any of the secondary end points. Treatment-emergent adverse events attributed to the study drug were identified in 42 participants (16.0%).
We were not able to reject the null hypothesis of no difference in improvements in pain or quality of life outcomes in participants with painful CP who received camostat compared with placebo. Studies are needed to further define mechanisms of pain in CP to guide future clinical trials, including minimizing placebo responses and selecting targeted therapies. ClinicalTrials.gov, Number: NCT02693093.
Large symptomatic improvements were not detected in participants with chronic pancreatitis after 1 month of intervention with oral camostat compared with placebo.
EUS-guided needle-based confocal laser endomicroscopy (EUS-nCLE) can differentiate high-grade dysplasia/adenocarcinoma (HGD-Ca) in intraductal papillary mucinous neoplasms (IPMNs) but requires manual ...interpretation. We sought to derive predictive computer-aided diagnosis (CAD) and artificial intelligence (AI) algorithms to facilitate accurate diagnosis and risk stratification of IPMNs.
A post hoc analysis of a single-center prospective study evaluating EUS-nCLE (2015-2019; INDEX study) was conducted using 15,027 video frames from 35 consecutive patients with histopathologically proven IPMNs (18 with HGD-Ca). We designed 2 CAD-convolutional neural network (CNN) algorithms: (1) a guided segmentation-based model (SBM), where the CNN-AI system was trained to detect and measure papillary epithelial thickness and darkness (indicative of cellular and nuclear stratification), and (2) a reasonably agnostic holistic-based model (HBM) where the CNN-AI system automatically extracted nCLE features for risk stratification. For the detection of HGD-Ca in IPMNs, the diagnostic performance of the CNN-CAD algorithms was compared with that of the American Gastroenterological Association (AGA) and revised Fukuoka guidelines.
Compared with the guidelines, both n-CLE-guided CNN-CAD algorithms yielded higher sensitivity (HBM, 83.3%; SBM, 83.3%; AGA, 55.6%; Fukuoka, 55.6%) and accuracy (SBM, 82.9%; HBM, 85.7%; AGA, 68.6%; Fukuoka, 74.3%) for diagnosing HGD-Ca, with comparable specificity (SBM, 82.4%; HBM, 88.2%; AGA, 82.4%; Fukuoka, 94.1%). Both CNN-CAD algorithms, the guided (SBM) and agnostic (HBM) models, were comparable in risk stratifying IPMNs.
EUS-nCLE-based CNN-CAD algorithms can accurately risk stratify IPMNs. Future multicenter validation studies and AI model improvements could enhance the accuracy and fully automatize the process for real-time interpretation.
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